Correction: Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease Genet. Med. (IF 9.937) Pub Date : 2018-11-16 Matthew Neil Wakeling, Thomas William Laver, Caroline Fiona Wright, Elisa De Franco, Karen Lucy Stals, Ann-Marie Patch, Andrew Tym Hattersley, Sarah Elizabeth Flanagan, Sian Ellard
Correction: Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian diseaseCorrection: Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease, Published online: 16 November 2018; doi:10.1038/s41436-018-0357-1Correction: Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease
Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin Genet. Med. (IF 9.937) Pub Date : 2018-11-14 Ellen H. J. van den Bogaard, Michel van Geel, Ivonne M. J. J. van Vlijmen-Willems, Patrick A. M. Jansen, Malou Peppelman, Piet E. J. van Erp, Selma Atalay, Hanka Venselaar, Marleen E. H. Simon, Marieke Joosten, Joost Schalkwijk, Patrick L. J. M. Zeeuwen
PurposeWe aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin.MethodsExome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes.ResultsWe identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant.ConclusionThe herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis.
Nonimmune hydrops fetalis: identifying the underlying genetic etiology Genet. Med. (IF 9.937) Pub Date : 2018-11-09 Teresa N. Sparks, Kao Thao, Billie R. Lianoglou, Nina M. Boe, Kari G. Bruce, Ilina Datkhaeva, Nancy T. Field, Victoria M. Fratto, Jennifer Jolley, Louise C. Laurent, Anne H. Mardy, Aisling M. Murphy, Emily Ngan, Naseem Rangwala, Catherine A. M. Rottkamp, Lisa Wilson, Erica Wu, Cherry C. Uy, Priscila Valdez Lopez, Mary E. Norton
PurposeNumerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes.MethodsRetrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal–Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology.ResultsSixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach–Merritt syndrome.ConclusionIn this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.
Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort Genet. Med. (IF 9.937) Pub Date : 2018-11-08 Qingping Zhang, Xiaoxu Yang, Jiaping Wang, Jiarui Li, Qixi Wu, Yongxin Wen, Ying Zhao, Xiaoying Zhang, He Yao, Xiru Wu, Shujie Yu, Liping Wei, Xinhua Bao
Purpose To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders. Methods We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting MECP2, CDKL5, and FOXG1 was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic MECP2 variants was further quantified. Results Pathogenic variants of MECP2/CDKL5/FOXG1 were found in 324/471 (68.7%) patients. Somatic MECP2 mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic MECP2 mosaicism had mosaicism at MECP2-Arg106. Germline MECP2 mosaicism was detected in 5/21 (23.8%) fathers. Conclusion This is the first systematic screening of somatic and paternal germline MECP2 mosaicism at a cohort level. Our findings indicate that somatic MECP2 mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline MECP2 mosaicism indicates an underestimated mechanism underlying the paternal origin bias of MECP2 variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.
eKLIPse: a sensitive tool for the detection and quantification of mitochondrial DNA deletions from next-generation sequencing data Genet. Med. (IF 9.937) Pub Date : 2018-11-05 David Goudenège, Celine Bris, Virginie Hoffmann, Valerie Desquiret-Dumas, Claude Jardel, Benoit Rucheton, Sylvie Bannwarth, Veronique Paquis-Flucklinger, Anne Sophie Lebre, Estelle Colin, Patrizia Amati-Bonneau, Dominique Bonneau, Pascal Reynier, Guy Lenaers, Vincent Procaccio
Purpose Accurate detection of mitochondrial DNA (mtDNA) alterations is essential for the diagnosis of mitochondrial diseases. The development of high-throughput sequencing technologies has enhanced the detection sensitivity of mtDNA pathogenic variants, but the detection of mtDNA rearrangements, especially multiple deletions, is still poorly processed. Here, we present eKLIPse, a sensitive and specific tool allowing the detection and quantification of large mtDNA rearrangements from single and paired-end sequencing data. Methods The methodology was first validated using a set of simulated data to assess the detection sensitivity and specificity, and second with a series of sequencing data from mitochondrial disease patients carrying either single or multiple deletions, related to pathogenic variants in nuclear genes involved in mtDNA maintenance. Results eKLIPse provides the precise breakpoint positions and the cumulated percentage of mtDNA rearrangements at a given gene location with a detection sensitivity lower than 0.5% mutant. eKLIPse software is available either as a script to be integrated in a bioinformatics pipeline, or as user-friendly graphical interface to visualize the results through a Circos representation (https://github.com/dooguypapua/eKLIPse). Conclusion Thus, eKLIPse represents a useful resource to study the causes and consequences of mtDNA rearrangements, for further genotype/phenotype correlations in mitochondrial disorders.
Foundation of the Newborn Screening Translational Research Network and its tools for research Genet. Med. (IF 9.937) Pub Date : 2018-11-05 Michele Lloyd-Puryear, Amy Brower, Susan A. Berry, Jeffrey P. Brosco, Bruce Bowdish, Michael S. Watson
In the past 20 years, several policy activities were undertaken that shaped today’s newborn screening (NBS) programs and their associated NBS research activities: the Newborn Screening Task Force Report; the Child Health Act of 2000, Screening for Heritable Disorders; the American College of Medical Genetics and Genomics’ (ACMG’s) Newborn Screening Uniform Panel; and the ACMG expert panel to examine the development of a national collaborative study system for rare genetic diseases. These activities helped conceptualize the Newborn Screening Translational Research Network (NBSTRN) infrastructure and lay the foundation for its current activities. After 10 years, NBSTRN has grown into an organization that provides tools and resources for researchers to conduct research relevant to NBS programs for rare diseases for which data has been siloed locally. Infrastructure includes tools for the analytical and clinical validation of screening tests; the collection, analysis, sharing, and reporting of longitudinal laboratory and clinical data on newborn-screened individuals; and a web-based tool that allows researchers to acquire dried blood spots available for use in research from state NBS programs. NBSTRN also provides tools for researchers such as informed consent templates, disease registries, state NBS profiles, and consultation on planning pilot studies. In time, the growing data will become a resource itself.
Disparities in genetic services utilization in a random sample of young breast cancer survivors Genet. Med. (IF 9.937) Pub Date : 2018-11-02 Christos Nikolaidis, Debra Duquette, Kari E. Mendelsohn-Victor, Beth Anderson, Glenn Copeland, Kara J. Milliron, Sofia D. Merajver, Nancy K. Janz, Laurel L. Northouse, Sonia A. Duffy, Maria C. Katapodi
Purpose Increasing use of genetic services (counseling/testing) among young breast cancer survivors (YBCS) can help decrease breast cancer incidence and mortality. The study examined use of genetic services between Black and White/Other YBCS, attitudes and knowledge of breast cancer risk factors, and reasons for disparities in using genetic services. Methods We used baseline data from a randomized control trial including a population-based, stratified random sample of 3000 potentially eligible YBCS, with oversampling of Black YBCS. Results Among 883 YBCS (353 Black, 530 White/Other) were significant disparities between the two racial groups. More White/Other YBCS had received genetic counseling and had genetic testing than Blacks. Although White/Other YBCS resided farther away from board-certified genetic counseling centers, they had fewer barriers to access these services. Black race, high out-of-pocket costs, older age, and more years since diagnosis were negatively associated with use of genetic services. Black YBCS had lower knowledge of breast cancer risk factors. Higher education and genetic counseling were associated with higher genetic knowledge. Conclusion Racial inequalities of cost-related access to care and education create disparities in genetic services utilization. System-based interventions that reduce socioeconomic disparities and empower YBCS with genetic knowledge, as well as physician referrals, can increase access to genetic services.
Increasing evidence of combinatory variant effects calls for revised classification of low-penetrance alleles Genet. Med. (IF 9.937) Pub Date : 2018-11-02 Nicholas K. Wang, John P. W. Chiang
Increasing evidence of combinatory variant effects calls for revised classification of low-penetrance alleles Increasing evidence of combinatory variant effects calls for revised classification of low-penetrance alleles, Published online: 02 November 2018; doi:10.1038/s41436-018-0347-3 Increasing evidence of combinatory variant effects calls for revised classification of low-penetrance alleles
Knowledge, motivations, expectations, and traits of an African, African-American, and Afro-Caribbean sequencing cohort and comparisons to the original ClinSeq® cohort Genet. Med. (IF 9.937) Pub Date : 2018-11-01 Katie L. Lewis, Alexis R. Heidlebaugh, Sandra Epps, Paul K. J. Han, Kristen P. Fishler, William M. P. Klein, Ilana M. Miller, David Ng, Charlotte Hepler, Barbara B. Biesecker, Leslie G. Biesecker
Purpose Racial minority populations are underrepresented in genomics research. This study enrolled African-descended individuals in a sequencing study and reported their characteristics. Methods We purposively recruited 467 individuals self-identified as African, African American, or Afro-Caribbean to the ClinSeq® study and surveyed them about knowledge, motivations, expectations, and traits. Summary statistics were calculated and compared with data from the study’s original cohort, which was primarily White and self-referred. Results Recruitment took five years and 83% of enrollees completed the survey. Participants had modest knowledge about benefits and limitations of sequencing (x̅s = 5.1, ranges: 0–10), and less than the original cohort (x̅ = 7.5 and 7.7, respectively). Common motivations to enroll were learning information relevant to personal health (49%) or family members’ health (33%), and most had realistic expectations of sequencing. Like the original cohort, they had high levels of optimism, openness, and resilience. Conclusion Early adopters may have relatively consistent personality traits irrespective of majority/minority status and recruitment methods, but high levels of genomics knowledge are not universal. Research should determine whether recruitment and consent procedures provide adequate education to promote informed choices and realistic expectations, which are vital to ethical research and increasing genomics research participation in underrepresented communities.
Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease Genet. Med. (IF 9.937) Pub Date : 2018-10-31 Stijn Van de Sompele, Claire Smith, Marianthi Karali, Marta Corton, Kristof Van Schil, Frank Peelman, Timothy Cherry, Toon Rosseel, Hannah Verdin, Julien Derolez, Thalia Van Laethem, Kamron N. Khan, Martin McKibbin, Carmel Toomes, Manir Ali, Annalaura Torella, Francesco Testa, Belen Jimenez, Francesca Simonelli, Julie De Zaeytijd, Jenneke Van den Ende, Bart P. Leroy, Frauke Coppieters, Carmen Ayuso, Chris F. Inglehearn, Sandro Banfi, Elfride De Baere
Purpose RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested Genet. Med. (IF 9.937) Pub Date : 2018-10-31 Lina Basel Salmon, Naama Orenstein, Keren Markus-Bustani, Noa Ruhrman-Shahar, Yael Kilim, Nurit Magal, Monika Weisz Hubshman, Lily Bazak
Purpose Reanalysis of exome sequencing data when results are negative may yield additional diagnoses. We sought to estimate the contribution of clinical geneticists to the interpretation of sequencing data of their patients. Methods The cohort included 84 probands attending a tertiary genetics institute (2015–2018) with a nondiagnostic result on clinical exome sequencing performed in one of five external laboratories. The raw data were uploaded to the Emedgene bioinformatics and interpretation platform for reanalysis by a team of two clinical geneticists, the geneticist directly involved in the patient’s care, and a bioinformatician. Results In ten probands (11.9%), a new definitive diagnosis was reached based on genes that were known to be associated with the phenotype at the time the original report was issued. The main reasons for a negative exome result were incorrect interpretation of the clinical context and absence of OMIM entry. Pathogenic variants in genes with previously unknown gene–disease associations were discovered to be causative in three probands. In total, new diagnoses were established in 13/84 individuals (15.5%). Conclusion Direct access to complete clinical data and shortening of time to including gene–phenotype associations in databases can assist the analytics team and reduce the need for additional unnecessary tests.
Stakeholders’ views on the value of outcomes from clinical genetic and genomic interventions Genet. Med. (IF 9.937) Pub Date : 2018-10-31 Maren T. Scheuner, Marcia M. Russell, Catherine Chanfreau-Coffinier, Jane Peredo, Elizabeth M. Yano, Alison B. Hamilton, Barbara Lerner, Dawn Provenzale, Sara J. Knight, Corrine I. Voils
Purpose Robust evidence about the value of clinical genomic interventions (CGIs), such as genetic/genomic testing or clinical genetic evaluation, is limited. We obtained stakeholders’ perspectives on outcomes from CGIs to help inform their value. Methods We used an adapted Delphi expert panel process. Two anonymous survey rounds assessed the value of 44 CGI outcomes and whether a third party should pay for them, with discussion in between rounds. Results Sixty-six panelists responded to the first-round survey and 60 to the second. Policy-makers/payers gave the lowest ratings for value and researchers gave the highest. Patients/consumers had the most uncertainty about value and payment by a third party. Uncertainty about value was observed when evidence of proven health benefit was lacking, potential harms outweighed benefits for reproductive outcomes, and outcomes had only personal utility for individuals or family members. Agreement about outcomes for which a third party should not pay included prevention through surgery with unproven health benefits, establishing ancestry, parental consanguinity, and paternity. Conclusion Research is needed to understand factors contributing to uncertainty and stakeholder differences about the value of CGI outcomes. Reaching consensus will accelerate the creation of metrics to generate the evidence needed to inform value and guide policies that promote availability, uptake, and coverage of CGIs.
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance Genet. Med. (IF 9.937) Pub Date : 2018-10-30 Ginger J. Tsai, John Michael O. Rañola, Christina Smith, Lauren Thomas Garrett, Timothy Bergquist, Silvia Casadei, Deborah J. Bowen, Brian H. Shirts
Purpose Family studies are an important but underreported source of information for reclassification of variants of uncertain significance (VUS). We evaluated outcomes of a patient-driven framework that offered familial VUS reclassification analysis to any adult with any clinically ascertained VUS from any laboratory in the United States. Methods With guidance from FindMyVariant.org, participants recruited their own relatives for study participation. We genotyped relatives, calculated quantitative cosegregation likelihood ratios, and evaluated variant classifications using Tavtigian’s unified framework for Bayesian analysis with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. We report participation and VUS reclassification rates from the 50 families enrolled for at least one year and reclassification results for 112 variants from the larger 92-family cohort. Results For the 50-family cohort, 6.7 relatives per family were invited to participate and 67% of relatives returned samples for genotyping. Sixty-one percent of VUS were reclassified, 84% of which were classified as benign or likely benign. Genotyping relatives identified a de novo variant, phase variants, and relatives with phenotypes highly specific for or incompatible with specific classifications. Conclusions Motivated families can contribute to successful VUS reclassification at substantially higher rates than those previously published. Clinical laboratories could consider offering family studies to all patients with VUS.
Giving adolescents a voice: the types of genetic information adolescents choose to learn and why Genet. Med. (IF 9.937) Pub Date : 2018-10-29 Josie Pervola, Melanie F. Myers, Michelle L. McGowan, Cynthia A. Prows
Purpose The American College of Medical Genetics and Genomics supports parents’ opting in or out of secondary analysis of 59 genes when their child has clinical exome/genome sequencing. We explored the reasons adolescents choose to learn certain types of results and the reasons they want to involve or not involve parents in decision-making. Methods Adolescents recruited without clinical indication were offered independent, followed by joint choices with a parent to learn genomic results. After making independent choices, adolescent/parent dyads were interviewed to explore the reasons for their choices. Interviews were audio-recorded and transcribed. The constant comparative method was used to analyze 64 purposefully selected transcripts that included 31 from adolescents who excluded some or all potential results. Results Three major themes informed adolescents’ choices: (1) actionability of information, (2) knowledge seeking, and (3) psychological impact. Of adolescents who independently excluded some conditions (n=31), 58% changed their initial choices during the joint interview due to parental influence or improved understanding. Nearly all adolescents (98%) wanted to be involved in the decision-making process, and 53% wanted to make choices independently. Conclusions Our findings contribute empirical evidence to support the refinement of professional guidelines for adolescents’ engagement and preferences in genetic testing decisions.
Population data improves variant interpretation in autosomal dominant polycystic kidney disease Genet. Med. (IF 9.937) Pub Date : 2018-10-29 Amali C. Mallawaarachchi, Timothy J. Furlong, John Shine, Peter C. Harris, Mark J. Cowley
Purpose Autosomal dominant polycystic kidney disease (ADPKD) is a common adult-onset monogenic disorder, with prevalence of 1/1000. Population databases including ExAC have improved pathogenic variant prioritization in many diseases. Due to pseudogene homology of PKD1, the predominant ADPKD disease gene, and the variable disease severity and age of onset, we aimed to investigate the utility of ExAC for variant assessment in ADPKD. Methods We assessed coverage and variant quality in the ExAC cohort and combined allele frequency and age data from the ExAC database (n = 60,706) with curated variants from 2000 ADPKD pedigrees (ADPKD Mutation Database). Results Seventy-six percent of PKD1 and PKD2 were sequenced adequately for variant discovery and variant quality was high in ExAC. In ExAC, we identified 25 truncating and 393 previously reported disease-causing variants in PKD1 and PKD2, 6.9-fold higher than expected. Fifty-four different variants, previously classified as disease-causing, were observed in ≥5 participants in ExAC. Conclusion Our study demonstrates that many previously implicated disease-causing variants are too common, challenging their pathogenicity, or penetrance. The presence of protein-truncating variants in older participants in ExAC demonstrates the complexity of variant classification and highlights need for further study of prevalence and penetrance of this common monogenic disease.
The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature Genet. Med. (IF 9.937) Pub Date : 2018-10-25 Juliette Piard, Lara Hawkes, Mathieu Milh, Laurent Villard, Renato Borgatti, Romina Romaniello, Melanie Fradin, Yline Capri, Delphine Héron, Marie-Christine Nougues, Caroline Nava, Oana Tarta Arsene, Debbie Shears, Yoshimi Sogawa, Diana Johnson, Helen Firth, Pradeep Vasudevan, Gabriela Jones, Marie-Ange Nguyen-Morel, Tiffany Busa, Agathe Roubertie, Myrthe van den Born, Elise Brischoux-Boucher, Michel Koenig, Cyril Mignot, Usha Kini, Christophe Philippe
Purpose Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. Methods We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing). Results Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. Conclusion Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.
A logic model for precision medicine implementation informed by stakeholder views and implementation science Genet. Med. (IF 9.937) Pub Date : 2018-10-23 Catherine Chanfreau-Coffinier, Jane Peredo, Marcia M. Russell, Elizabeth M. Yano, Alison B. Hamilton, Barbara Lerner, Dawn Provenzale, Sara J. Knight, Corrine I. Voils, Maren T. Scheuner
Purpose Precision medicine promises to improve patient outcomes, but much is unknown about its adoption within health-care systems. A comprehensive implementation plan is needed to realize its benefits. Methods We convened 80 stakeholders for agenda setting to inform precision medicine policy, delivery, and research. Conference proceedings were audio-recorded, transcribed, and thematically analyzed. We mapped themes representing opportunities, challenges, and implementation strategies to a logic model, and two implementation science frameworks provided context. Results The logic model components included inputs: precision medicine infrastructure (clinical, research, and information technology), big data (from data sources to analytics), and resources (e.g., workforce and funding); activities: precision medicine research, practice, and education; outputs: precision medicine diagnosis; outcomes: personal utility, clinical utility, and health-care utilization; and impacts: precision medicine value, equity and access, and economic indicators. Precision medicine implementation challenges include evidence gaps demonstrating precision medicine utility, an unprepared workforce, the need to improve precision medicine access and reduce variation, and uncertain impacts on health-care utilization. Opportunities include integrated health-care systems, partnerships, and data analytics to support clinical decisions. Examples of implementation strategies to promote precision medicine are: changing record systems, data warehousing techniques, centralized technical assistance, and engaging consumers. Conclusion We developed a theory-based, context-specific logic model that can be used by health-care organizations to facilitate precision medicine implementation.
A framework to build capacity for a reflex-testing program for Lynch syndrome Genet. Med. (IF 9.937) Pub Date : 2018-10-22 Vanessa N. Palter, Natalie A. Baker, Linda Rabeneck, Jill Tinmouth, Anna R. Gagliardi, Erin D. Kennedy, June C. Carroll, Steven Gallinger, Nancy N. Baxter
Purpose Lynch syndrome (LS) is the most common inherited cause of colorectal cancer. Although testing all colorectal tumors for LS is recommended, the uptake of reflex-testing programs within health systems has been limited. This multipronged study describes the design of a provincial program for reflex testing in Ontario, Canada. Methods We recruited key stakeholders to participate in qualitative interviews to explore the barriers and facilitators to the implementation of a reflex-testing program. Data were analyzed in an iterative manner, key themes identified, and a framework for a proposed program developed. Results Twenty-six key informants participated in our interviews, and several themes were identified. These included providing education for stakeholders (patients, primary care providers, surgeons); challenges with sustaining various resources (laboratory costs, increased workload for pathologists); ensuring consistency of reporting test results; and developing a plan to measure program success. Using these themes, a framework for the reflex-testing program was developed. At a subsequent stakeholder meeting, the framework was refined, and recommendations were identified. Conclusions This study identifies factors to ensure the effective implementation of a population-level program for reflex LS testing. The final product is a prototype that can be utilized in other jurisdictions, taking into account local environmental considerations.
The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome Genet. Med. (IF 9.937) Pub Date : 2018-10-22 Eline (P.J.) van der Sluijs, Sandra Jansen, Samantha A. Vergano, Miho Adachi-Fukuda, Yasemin Alanay, Adila AlKindy, Anwar Baban, Allan Bayat, Stefanie Beck-Wödl, Katherine Berry, Emilia K. Bijlsma, Levinus A. Bok, Alwin F. J. Brouwer, Ineke van der Burgt, Philippe M. Campeau, Natalie Canham, Krystyna Chrzanowska, Yoyo W. Y. Chu, Brain H. Y. Chung, Karin Dahan, Marjan De Rademaeker, Anne Destree, Tracy Dudding-Byth, Rachel Earl, Nursel Elcioglu, Ellen R. Elias, Christina Fagerberg, Alice Gardham, Blanca Gener, Erica H. Gerkes, Ute Grasshoff, Arie van Haeringen, Karin R. Heitink, Johanna C. Herkert, Nicolette S. den Hollander, Denise Horn, David Hunt, Sarina G. Kant, Mitsuhiro Kato, Hülya Kayserili, Rogier Kersseboom, Esra Kilic, Malgorzata Krajewska-Walasek, Kylin Lammers, Lone W. Laulund, Damien Lederer, Melissa Lees, Vanesa López-González, Saskia Maas, Grazia M. S. Mancini, Carlo Marcelis, Francisco Martinez, Isabelle Maystadt, Marianne McGuire, Shane McKee, Sarju Mehta, Kay..
Purpose Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods Clinicians entered clinical data in an extensive web-based survey. Results 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
Biallelic GALM pathogenic variants cause a novel type of galactosemia Genet. Med. (IF 9.937) Pub Date : 2018-10-19 Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure
Purpose Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. Methods Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. Results The highest blood galactose levels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. Conclusion Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.
Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG) Genet. Med. (IF 9.937) Pub Date : 2018-10-19 J. Daniel Sharer, Irene De Biase, Dietrich Matern, Sarah Young, Michael J. Bennett, Adviye A. Tolun
Amino acid abnormalities are observed in a broad spectrum of inherited metabolic diseases, such as disorders of amino acid metabolism and transport, organic acidemias, and ureagenesis defects. Comprehensive analysis of physiologic amino acids in blood, urine, and cerebrospinal fluid is typically performed in the following clinical settings: evaluation of symptomatic patients in whom a diagnosis is not known; evaluation of previously diagnosed patients to monitor treatment efficacy; evaluation of asymptomatic or presymptomatic (at-risk) relatives of known patients; follow-up testing for an abnormal newborn screen; and assessment of dietary protein adequacy or renal function in general patient populations. Currently, the most common analytical method to quantify amino acids is based on ion exchange chromatography using post-column derivatization with ninhydrin and spectrophotometric detection. Newer methodologies are based on liquid chromatographic separation with detection by mass spectrometry or spectrophotometry. Amino acid analysis by nonseparation methods, such as the flow injection–tandem mass spectrometric (MS/MS) method used for newborn screening, is considered inadequate for the diagnosis of at-risk patients. The purpose of this document is to provide a technical standard for amino acid analysis as applied to the diagnosis and management of inborn errors of metabolism.
Psychological adaptation to molecular autopsy findings following sudden cardiac death in the young Genet. Med. (IF 9.937) Pub Date : 2018-10-16 Kezia Bates, Joanna Sweeting, Laura Yeates, Kristie McDonald, Christopher Semsarian, Jodie Ingles
Purpose Sudden cardiac death (SCD) in the young is a devastating event occurring in otherwise healthy individuals. Postmortem genetic testing (molecular autopsy) may help identify a cause, though there is potential for uncertainty. We report psychological adaptation to molecular autopsy findings amongst family members after a young SCD. Methods First-degree relatives who had experienced a SCD of a young relative and attended a specialized cardiac genetic clinic were invited to complete a cross-sectional, self-report survey comprising a number of validated scales. Clinical, genetic, and family history information was collected from the medical record. Results Thirty-three individuals from 27 families (response rate 48%) completed a survey (mean age 49 ± 12 years, 49% were mothers of the decedent). Eleven (36%) reported poor adaptation to genetic information, and compared with those with good adaptation, they were more likely to have worse posttraumatic stress symptoms (p = 0.0004) and depression (p = 0.01). Perceived support was lower in those reporting poor adaptation, including social support (p < 0.0001) and perceived support from significant others (p = 0.03), family members (p = 0.001), and friends (p = 0.0002). Conclusion Adaptation to molecular autopsy findings may be difficult for some relatives following a young SCD. Careful pretest genetic counseling and integration of psychological support is needed.
Trends over 42 years in the Adult Medical Genetics Clinic at the University of Washington Genet. Med. (IF 9.937) Pub Date : 2018-10-16 Elizabeth A. Gay, Peter H. Byers, Robin L. Bennett, Thomas D. Bird, Fuki M. Hisama
Purpose We analyzed the patients served by the University of Washington Adult Genetic Medicine Clinic (UWAGMC) over a 42-year period to determine how clinical services have changed and to evaluate the contributing factors. Methods We conducted a retrospective survey of patients seen by UWAGMC that included patients seen from 1975 to 2016. Variables considered included referral indication, disease status, and clinic visit date. Indications for referral were then binned into clinical categories for descriptive analysis. Results Of 30,780 patient visits during the 39 years for which data were available, 57.3% occurred in the last decade. Referrals for breast/ovarian cancer or colon/endometrial cancer account for 74.8% of cancer referrals since 1998. Huntington disease patients made up 46% of neurological referral indications. Telephone screening implemented in 2013 has reduced the number of referrals for hypermobile Ehlers–Danlos syndrome. Conclusion Referral indications increased with clinical testing availability and because of the academic programs of UWAGMC providers. With increased public awareness of heritable conditions, prescreening self-referrals were used to allocate limited resources. These trends demonstrate the need for more geneticists in adult medicine to expand centers of excellence for rare diseases and to serve the increasing numbers of adult patients with genetic conditions.
Response to Suthers and Mina Genet. Med. (IF 9.937) Pub Date : 2018-10-16 Edwin P. Kirk, Kristine Barlow-Stewart, Sarah Josephi-Taylor, Tony Roscioli
Response to Suthers and Mina Response to Suthers and Mina, Published online: 16 October 2018; doi:10.1038/s41436-018-0318-8 Response to Suthers and Mina
Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations: challenges and solutions Genet. Med. (IF 9.937) Pub Date : 2018-10-16 Sulev Reisberg, Kristi Krebs, Maarja Lepamets, Mart Kals, Reedik Mägi, Kristjan Metsalu, Volker M. Lauschke, Jaak Vilo, Lili Milani
Purpose Biomedical databases combining electronic medical records and phenotypic and genomic data constitute a powerful resource for the personalization of treatment. To leverage the wealth of information provided, algorithms are required that systematically translate the contained information into treatment recommendations based on existing genotype–phenotype associations. Methods We developed and tested algorithms for translation of preexisting genotype data of over 44,000 participants of the Estonian biobank into pharmacogenetic recommendations. We compared the results obtained by genome sequencing, exome sequencing, and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia. Results Our most striking result was that the performance of genotyping arrays is similar to that of genome sequencing, whereas exome sequencing is not suitable for pharmacogenetic predictions. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants. Conclusion We find that microarrays are a cost-effective solution for creating preemptive pharmacogenetic reports, and with slight modifications, existing databases can be applied for automated pharmacogenetic decision support for clinicians.
Comparing ethnicity-based and expanded carrier screening methods at a single fertility center reveals significant differences in carrier rates and carrier couple rates Genet. Med. (IF 9.937) Pub Date : 2018-10-16 Alexandra Peyser, Tomer Singer, Christine Mullin, Sara L. Bristow, Amber Gamma, Kenan Onel, Avner Hershlag
Purpose To evaluate the efficiency of expanded carrier screening (ECS) compared with ethnicity-based screening in identifying carriers. Methods A total of 4232 infertility patients underwent ECS from a single genetic testing laboratory at our center between June 2013 and July 2015. Self-reported ethnicity was recorded. Carrier rates based on ECS were calculated. In addition, carrier status was determined for two other screening panels: ethnicity-based guidelines or the ECS panel recommended by the American College of Obstetricians and Gynecologists (ACOG) using ECS results. Carrier rate and carrier couple rates were compared in the overall study population and in each self-reported ethnicity. Results The ECS panel used to screen the patient population identified 1243 carriers (29.4%). For the same population, ethnicity-based screening and the ACOG panel would have identified 359 (8.5%) and 659 carriers (15.6%), respectively, representing statistically significant differences. Differences in identifying carriers across self-reported ethnicities varied. In 15 couples (1.2%), both partners carried pathogenic variants for the same genes, 47% of whom would have been missed had screening been ethnicity-based. Conclusion We propose that all reproductive-aged women should be offered ECS. Carrier couple rates would likely increase further with expansion of the panel, playing a pivotal role in preventing genetic disease in fertility clinics.
Correction: TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants Genet. Med. (IF 9.937) Pub Date : 2018-10-15 Jennifer N. Dines, Katie Golden-Grant, Amy LaCroix, Alison M. Muir, Dianne Laboy Cintrón, Kirsty McWalter, Megan T. Cho, Angela Sun, J. Lawrence Merritt, Jenny Thies, Dmitriy Niyazov, Barbara Burton, Katherine Kim, Leah Fleming, Rachel Westman, Peter Karachunski, Joline Dalton, Alice Basinger, Can Ficicioglu, Ingo Helbig, Manuela Pendziwiat, Hiltrud Muhle, Katherine L. Helbig, Almuth Caliebe, René Santer, Kolja Becker, Sharon Suchy, Ganka Douglas, Francisca Millan, Amber Begtrup, Kristin G. Monaghan, Heather C. Mefford
Correction: TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants Correction: TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants, Published online: 15 October 2018; doi:10.1038/s41436-018-0336-6 Correction: TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants
Clinical utility of expanded carrier screening: results-guided actionability and outcomes Genet. Med. (IF 9.937) Pub Date : 2018-10-11 Katherine A. Johansen Taber, Kyle A. Beauchamp, Gabriel A. Lazarin, Dale Muzzey, Aishwarya Arjunan, James D. Goldberg
Purpose Expanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date. Methods Couples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management. Results Three hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis. Conclusion ECS results impacted couples’ reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.
Venous thromboembolism laboratory testing (factor V Leiden and factor II c.*97G>A), 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG) Genet. Med. (IF 9.937) Pub Date : 2018-10-09 Shulin Zhang, Annette K. Taylor, Xuan Huang, Biao Luo, Elaine B. Spector, Ping Fang, C. Sue Richards
Factor V Leiden and factor II c.*97G>A (formerly referred to as prothrombin 20210G>A) are the two most common genetic variants associated with venous thromboembolism (VTE). Testing for these variants is one of the most common referrals in clinical genetics laboratories. While the methodologies for testing these two variants are relatively straightforward, the clinical implementation can be complicated with regard to test indications, risk assessment of occurrence and recurrence of VTE, and related genetic counseling. This document provides an overview of VTE, information about the variants and their influence on risk, considerations before initiating genetic testing, and the clinical and analytical sensitivity and specificity of the tests. Key information that should be included in the laboratory report is also provided. Disease-specific statements are intended to augment the general American College of Medical Genetics and Genomics (ACMG) technical standards for clinical genetics laboratories. Individual laboratories are responsible for meeting the Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) quality assurance standards with respect to appropriate sample documentation, assay validation, general proficiency testing, and quality control measures. This 2018 edition of the ACMG technical standard updates and supersedes the 2005 edition on this topic. It is designed to be a checklist for genetic testing professionals who are already familiar with the disease and the methods of analysis.
Pitfalls of clinical exome and gene panel testing: alternative transcripts Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Dale L. Bodian, Prachi Kothiyal, Natalie S. Hauser
Purpose Clinical exome and gene panel testing can provide molecular diagnoses for patients with rare Mendelian disorders, but for many patients these tests are nonexplanatory. We investigated whether interrogation of alternative transcripts in known disease genes could provide answers for additional patients. Methods We integrated alternative transcripts for known neonatal epilepsy genes with RNA-Seq data to identify brain-expressed coding regions that are not evaluated by popular neonatal epilepsy clinical gene panel and exome tests. Results We found brain-expressed alternative coding regions in 89 (30%) of 292 neonatal epilepsy genes. The 147 regions encompass 15,713 bases that are noncoding in the primary transcripts analyzed by the clinical tests. Alternative coding regions from at least 5 genes carry reported pathogenic variants. Three candidate variants in these regions were identified in public exome data from 337 epilepsy patients. Incorporating alternative transcripts into the analysis of neonatal epilepsy genes in 44 patient genomes identified the pathogenic variant for the epilepsy case and 2 variants of uncertain significance (VUS) among the 43 control cases. Conclusion Assessment of alternative transcripts in exon-based clinical genetic tests, including gene panel, exome, and genome sequencing, may provide diagnoses for patients for whom standard testing is unrevealing, without introducing many VUS.
Long-term follow-up in PMM2-CDG: are we ready to start treatment trials? Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Peter Witters, Tomas Honzik, Eric Bauchart, Ruqaiah Altassan, Tiffany Pascreau, Arnaud Bruneel, Sandrine Vuillaumier, Nathalie Seta, Delphine Borgel, Gert Matthijs, Jaak Jaeken, Wouter Meersseman, David Cassiman, Lonlay Pascale de, Eva Morava
Purpose PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution. Methods We performed data analysis on PMM2-CDG patients’ clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years. Results On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases. Conclusion PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.
Identification of clinically actionable variants from genome sequencing of families with congenital heart disease Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Dimuthu Alankarage, Eddie Ip, Justin O. Szot, Jacob Munro, Gillian M. Blue, Katrina Harrison, Hartmut Cuny, Annabelle Enriquez, Michael Troup, David T. Humphreys, Meredith Wilson, Richard P. Harvey, Gary F. Sholler, Robert M. Graham, Joshua W. K. Ho, Edwin P. Kirk, Nicholas Pachter, Gavin Chapman, David S. Winlaw, Eleni Giannoulatou, Sally L. Dunwoodie
Purpose Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. Methods Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband–parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Results Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. Conclusions Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.
Variant data sharing by clinical laboratories through public databases: consent, privacy and further contact for research policies Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Mahsa Shabani, Stephanie O. M. Dyke, Luca Marelli, Pascal Borry
Access to detailed variant data is key to inform and verify the interpretation of genomic data. Clinical laboratories can play a significant role in sharing patients’ data through public variant databases. To facilitate data sharing, various public databases, such as ClinVar and DECIPHER have been established, which accept data submission from laboratories, clinicians, researchers, and patients. Despite clear benefits to sharing, questions may arise about the adequate form of consent to be obtained from patients when sharing data from their clinical tests through public databases. In this paper, we provide an overview and critical analysis of the relevant consent policies of the major public databases, and of the consent forms of clinical laboratories that share variant data via ClinVar.
De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Gregory Costain, Bert Callewaert, Heinz Gabriel, Tiong Y. Tan, Susan Walker, John Christodoulou, Tamas Lazar, Björn Menten, Julia Orkin, Simon Sadedin, Meaghan Snell, Arnaud Vanlander, Sarah Vergult, Susan M. White, Stephen W. Scherer, Robin Z. Hayeems, Susan Blaser, Shoshana J. Wodak, David Chitayat, Christian R. Marshall, M. Stephen Meyn
Purpose RAC3 is an underexamined member of the Rho GTPase gene family that is expressed in the developing brain and linked to key cellular functions. De novo missense variants in the homolog RAC1 were recently associated with developmental disorders. In the RAC subfamily, transforming missense changes at certain shared residues have been observed in human cancers and previously characterized in experimental studies. The purpose of this study was to determine whether constitutional dysregulation of RAC3 is associated with human disease. Methods We discovered a RAC3 variant in the index case using genome sequencing, and searched for additional variants using international data-sharing initiatives. Functional effects of the variants were assessed using a multifaceted approach generalizable to most clinical laboratory settings. Results We rapidly identified five individuals with de novo monoallelic missense variants in RAC3, including one recurrent change. Every participant had severe intellectual disability and brain malformations. In silico protein modeling, and prior in vivo and in situ experiments, supported a transforming effect for each of the three different RAC3 variants. All variants were observed in databases of somatic variation in cancer. Conclusions Missense variants in RAC3 cause a novel brain disorder, likely through a mechanism of constitutive protein activation.
Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Kristof Van Schil, Sarah Naessens, Stijn Van de Sompele, Marjolein Carron, Alexander Aslanidis, Caroline Van Cauwenbergh, Anja K. Mayer, Mattias Van Heetvelde, Miriam Bauwens, Hannah Verdin, Frauke Coppieters, Michael E. Greenberg, Marty G. Yang, Marcus Karlstetter, Thomas Langmann, Katleen De Preter, Susanne Kohl, Timothy J. Cherry, Bart P. Leroy, James R Lupski, Claudia Carvalho, Max van Min, Petra Klous, Sarah De Jaegere, Sally Hooghe, Elfride De Baere
Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations, Published online: 08 October 2018; doi:10.1038/s41436-018-0305-0 Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations
Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Elizabeth Quinlan-Jones, Jenny Lord, Denise Williams, Sue Hamilton, Tamas Marton, Ruth Y. Eberhardt, Gabriele Rinck, Elena Prigmore, Rebecca Keelagher, Dominic J. McMullan, Eamonn R. Maher, Matthew E. Hurles, Mark D. Kilby
Purpose To determine the diagnostic yield of combined exome sequencing (ES) and autopsy in fetuses/neonates with prenatally identified structural anomalies resulting in termination of pregnancy, intrauterine, neonatal, or early infant death. Methods ES was undertaken in 27 proband/parent trios following full autopsy. Candidate pathogenic variants were classified by a multidisciplinary clinical review panel using American College of Medical Genetics and Genomics (ACMG) guidelines. Results A genetic diagnosis was established in ten cases (37%). Pathogenic/likely pathogenic variants were identified in nine different genes including four de novo autosomal dominant, three homozygous autosomal recessive, two compound heterozygous autosomal recessive, and one X-linked. KMT2D variants (associated with Kabuki syndrome postnatally) occurred in two cases. Pathogenic variants were identified in 5/13 (38%) cases with multisystem anomalies, in 2/4 (50%) cases with fetal akinesia deformation sequence, and in 1/4 (25%) cases each with cardiac and brain anomalies and hydrops fetalis. No pathogenic variants were detected in fetuses with genitourinary (1), skeletal (1), or abdominal (1) abnormalities. Conclusion This cohort demonstrates the clinical utility of molecular autopsy with ES to identify an underlying genetic cause in structurally abnormal fetuses/neonates. These molecular findings provided parents with an explanation of the developmental abnormality, delineated the recurrence risks, and assisted the management of subsequent pregnancies.
Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease Genet. Med. (IF 9.937) Pub Date : 2018-10-08 Andrew M. Gross, Subramanian S. Ajay, Vani Rajan, Carolyn Brown, Krista Bluske, Nicole J. Burns, Aditi Chawla, Alison J. Coffey, Alka Malhotra, Alicia Scocchia, Erin Thorpe, Natasa Dzidic, Karine Hovanes, Trilochan Sahoo, Egor Dolzhenko, Bryan Lajoie, Amirah Khouzam, Shimul Chowdhury, John Belmont, Eric Roller, Sergii Ivakhno, Stephen Tanner, Julia McEachern, Tina Hambuch, Michael Eberle, R. Tanner Hagelstrom, David R. Bentley, Denise L. Perry, Ryan J. Taft
Purpose Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test. Methods We performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases. Results We found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs. Conclusion Robust identification of CNVs by GS is possible within a clinical testing environment.
Putting genome-wide sequencing in neonates into perspective Genet. Med. (IF 9.937) Pub Date : 2018-10-05 Eline (P. J.) van der Sluijs, Emmelien Aten, Daniela Q. C. M. Barge-Schaapveld, Emilia K. Bijlsma, Regina Bökenkamp-Gramann, Laura Donker Kaat, Remco van Doorn, Dietje Fransen van de Putte, Arie van Haeringen, Arend D. J. ten Harkel, Yvonne Hilhorst-Hofstee, Mariette J. V. Hoffer, Nicolette S. den Hollander, Yvette van Ierland, Marije Koopmans, Marjolein Kriek, Setareh Moghadasi, Esther A. R. Nibbeling, Cacha M. P. C. D. Peeters-Scholte, Thomas P. Potjer, Maartje van Rij, Claudia A. L. Ruivenkamp, Julie W. Rutten, Sylke J. Steggerda, Manon Suerink, Ratna N. G. B. Tan, Karin van der Tuin, Remco Visser, Anne-Sophie van der Werf –’t Lam, Monique Williams, Ruben Witlox, Gijs W. E. Santen
Purpose Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. Methods We retrospectively evaluated all genetic NICU consultations in a 2-year period. Results In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. Conclusions Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.
Standard operating procedure for somatic variant refinement of sequencing data with paired tumor and normal samples Genet. Med. (IF 9.937) Pub Date : 2018-10-05 Erica K. Barnell, Peter Ronning, Katie M. Campbell, Kilannin Krysiak, Benjamin J. Ainscough, Lana M. Sheta, Shahil P. Pema, Alina D. Schmidt, Megan Richters, Kelsy C. Cotto, Arpad M. Danos, Cody Ramirez, Zachary L. Skidmore, Nicholas C. Spies, Jasreet Hundal, Malik S. Sediqzad, Jason Kunisaki, Felicia Gomez, Lee Trani, Matthew Matlock, Alex H. Wagner, S. Joshua Swamidass, Malachi Griffith, Obi L. Griffith
Purpose Following automated variant calling, manual review of aligned read sequences is required to identify a high-quality list of somatic variants. Despite widespread use in analyzing sequence data, methods to standardize manual review have not been described, resulting in high inter- and intralab variability. Methods This manual review standard operating procedure (SOP) consists of methods to annotate variants with four different calls and 19 tags. The calls indicate a reviewer’s confidence in each variant and the tags indicate commonly observed sequencing patterns and artifacts that inform the manual review call. Four individuals were asked to classify variants prior to, and after, reading the SOP and accuracy was assessed by comparing reviewer calls with orthogonal validation sequencing. Results After reading the SOP, average accuracy in somatic variant identification increased by 16.7% (p value = 0.0298) and average interreviewer agreement increased by 12.7% (p value < 0.001). Manual review conducted after reading the SOP did not significantly increase reviewer time. Conclusion This SOP supports and enhances manual somatic variant detection by improving reviewer accuracy while reducing the interreviewer variability for variant calling and annotation.
Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis Genet. Med. (IF 9.937) Pub Date : 2018-10-05 Isabelle Schrauwen, Hanne Valgaeren, Laura Tomas-Roca, Manou Sommen, Umut Altunoglu, Mieke Wesdorp, Matthias Beyens, Erik Fransen, Abdul Nasir, Geert Vandeweyer, Anne Schepers, Malika Rahmoun, Ellen van Beusekom, Matt J. Huentelman, Erwin Offeciers, Ingeborg Dhooghe, Alex Huber, Paul Van de Heyning, Diego Zanetti, Els M. R. De Leenheer, Christian Gilissen, Alexander Hoischen, Cor W. Cremers, Berit Verbist, Arjan P. M. de Brouwer, George W. Padberg, Ronald Pennings, Hülya Kayserili, Hannie Kremer, Guy Van Camp, Hans van Bokhoven
Purpose To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. Methods We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. Results Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006–0.0060). Conclusion MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.
Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study Genet. Med. (IF 9.937) Pub Date : 2018-10-05 M. Ragan Hart, Barbara B. Biesecker, Carrie L. Blout, Kurt D. Christensen, Laura M. Amendola, Katie L. Bergstrom, Sawona Biswas, Kevin M. Bowling, Kyle B. Brothers, Laura K. Conlin, Greg M. Cooper, Matthew C. Dulik, Kelly M. East, Jessica N. Everett, Candice R. Finnila, Arezou A. Ghazani, Marian J. Gilmore, Katrina A. B Goddard, Gail P. Jarvik, Jennifer J. Johnston, Tia L. Kauffman, Whitley V. Kelley, Joel B. Krier, Katie L. Lewis, Amy L. McGuire, Carmit McMullen, Jeffrey Ou, Sharon E. Plon, Heidi L. Rehm, C. Sue Richards, Edward J. Romasko, Ane Miren Sagardia, Nancy B. Spinner, Michelle L. Thompson, Erin Turbitt, Jason L. Vassy, Benjamin S. Wilfond, David L. Veenstra, Jonathan S. Berg, Robert C. Green, Leslie G. Biesecker, Lucia A. Hindorff
Purpose Clinical sequencing emerging in health care may result in secondary findings (SFs). Methods Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene–condition pair list; we assessed clinical and psychosocial actions. Results The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0–$678) and $421 (recommended, range: $141–$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene–condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. Conclusion Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.
Response to Hannah-Shmouni and Stratakis Genet. Med. (IF 9.937) Pub Date : 2018-10-04 Douglas R. Stewart, Bruce R. Korf, Katherine L. Nathanson, David A. Stevenson, Kaleb Yohay
Response to Hannah-Shmouni and Stratakis Response to Hannah-Shmouni and Stratakis, Published online: 04 October 2018; doi:10.1038/s41436-018-0313-0 Response to Hannah-Shmouni and Stratakis
Growth hormone excess in neurofibromatosis 1 Genet. Med. (IF 9.937) Pub Date : 2018-10-04 Fady Hannah-Shmouni, Constantine A. Stratakis
Growth hormone excess in neurofibromatosis 1 Growth hormone excess in neurofibromatosis 1, Published online: 04 October 2018; doi:10.1038/s41436-018-0312-1 Growth hormone excess in neurofibromatosis 1
Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease Genet. Med. (IF 9.937) Pub Date : 2018-10-03 Matthew Neil Wakeling, Thomas William Laver, Caroline Fiona Wright, Elisa De Franco, Karen Lucy Stals, Ann-Marie Patch, Andrew Tym Hattersley, Sarah Elizabeth Flanagan, Sian Ellard
Purpose One of the greatest challenges currently facing those studying Mendelian disease is identifying the pathogenic variant from the long list produced by a next-generation sequencing test. We investigate the predictive ability of homozygosity mapping for identifying the regions likely to contain the causative variant. Methods We use 179 homozygous pathogenic variants from three independent cohorts to investigate the predictive power of homozygosity mapping. Results We demonstrate that homozygous pathogenic variants in our cohorts are disproportionately likely to be found within one of the largest regions of homozygosity: 80% of pathogenic variants are found in a homozygous region that is in the ten largest regions in a sample. The maximal predictive power is achieved in patients with <8% homozygosity and variants >3 Mb from a telomere; this gives an area under the curve (AUC) of 0.735 and results in 92% of the causative variants being in one of the ten largest homozygous regions. Conclusion This predictive power can be used to prioritize the list of candidate variants in gene discovery studies. When classifying a homozygous variant the size and rank of the region of homozygosity in which the candidate variant is located can also be considered as supporting evidence for pathogenicity.
Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients Genet. Med. (IF 9.937) Pub Date : 2018-10-02 Cyril Mignot, Aoife C. McMahon, Claire Bar, Philippe M. Campeau, Claire Davidson, Julien Buratti, Caroline Nava, Marie-Line Jacquemont, Marilyn Tallot, Mathieu Milh, Patrick Edery, Pauline Marzin, Giulia Barcia, Christine Barnerias, Claude Besmond, Thierry Bienvenu, Ange-Line Bruel, Ledia Brunga, Berten Ceulemans, Christine Coubes, Ana G. Cristancho, Fiona Cunningham, Marie-Bertille Dehouck, Elizabeth J. Donner, Bénédicte Duban-Bedu, Christèle Dubourg, Elena Gardella, Julie Gauthier, David Geneviève, Stéphanie Gobin-Limballe, Ethan M. Goldberg, Eveline Hagebeuk, Fadi F. Hamdan, Miroslava Hančárová, Laurence Hubert, Christine Ioos, Shoji Ichikawa, Sandra Janssens, Hubert Journel, Anna Kaminska, Boris Keren, Marije Koopmans, Caroline Lacoste, Petra Laššuthová, Damien Lederer, Daphné Lehalle, Dragan Marjanovic, Julia Métreau, Jacques L. Michaud, Kathryn Miller, Berge A. Minassian, Joannella Morales, Marie-Laure Moutard, Arnold Munnich, Xilma R. Ortiz-Gonzalez, Jean-Marc Pinard, ..
Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients, Published online: 02 October 2018; doi:10.1038/s41436-018-0327-7 Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients
Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation Genet. Med. (IF 9.937) Pub Date : 2018-10-01 Magdalena Koczkowska, Tom Callens, Alicia Gomes, Angela Sharp, Yunjia Chen, Alesha D. Hicks, Arthur S. Aylsworth, Amedeo A. Azizi, Donald G. Basel, Gary Bellus, Lynne M. Bird, Maria A. Blazo, Leah W. Burke, Ashley Cannon, Felicity Collins, Colette DeFilippo, Ellen Denayer, Maria C. Digilio, Shelley K. Dills, Laura Dosa, Robert S. Greenwood, Cristin Griffis, Punita Gupta, Rachel K. Hachen, Concepción Hernández-Chico, Sandra Janssens, Kristi J. Jones, Justin T. Jordan, Peter Kannu, Bruce R. Korf, Andrea M. Lewis, Robert H. Listernick, Fortunato Lonardo, Maurice J. Mahoney, Mayra Martinez Ojeda, Marie T. McDonald, Carey McDougall, Nancy Mendelsohn, David T. Miller, Mari Mori, Rianne Oostenbrink, Sebastién Perreault, Mary Ella Pierpont, Carmelo Piscopo, Dinel A. Pond, Linda M. Randolph, Katherine A. Rauen, Surya Rednam, S. Lane Rutledge, Veronica Saletti, G. Bradley Schaefer, Elizabeth K. Schorry, Daryl A. Scott, Andrea Shugar, Elizabeth Siqveland, Lois J. Starr, Ashraf Syed, Pam..
Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation, Published online: 01 October 2018; doi:10.1038/s41436-018-0326-8 Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation
Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia Genet. Med. (IF 9.937) Pub Date : 2018-10-01 Maris Alver, Marili Palover, Aet Saar, Kristi Läll, Seyedeh Maryam Zekavat, Neeme Tõnisson, Liis Leitsalu, Anu Reigo, Tiit Nikopensius, Tiia Ainla, Mart Kals, Reedik Mägi, Stacey B. Gabriel, Jaan Eha, Eric S. Lander, Alar Irs, Anthony Philippakis, Toomas Marandi, Pradeep Natarajan, Andres Metspalu, Sekar Kathiresan, Tõnu Esko
Purpose Large-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy. Methods The Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants. Results Via genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations. Conclusion Genotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.
Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum Genet. Med. (IF 9.937) Pub Date : 2018-10-01 Victoria E. R. Parker, Kim M. Keppler-Noreuil, Laurence Faivre, Maxime Luu, Neal L. Oden, Leena De Silva, Julie C. Sapp, Katrina Andrews, Marc Bardou, Kong Y. Chen, Thomas N. Darling, Elodie Gautier, Barry R. Goldspiel, Smail Hadj-Rabia, Julie Harris, Georgios Kounidas, Parag Kumar, Marjorie J. Lindhurst, Romaric Loffroy, Ludovic Martin, Alice Phan, Kristina I. Rother, Brigitte C. Widemann, Pamela L. Wolters, Christine Coubes, Lucile Pinson, Marjolaine Willems, Catherine Vincent-Delorme, Pierre Vabres, Robert K. Semple, Leslie G. Biesecker
Purpose PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. Methods Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Results Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. Conclusion This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS.
Longitudinal growth curves for children with classical osteogenesis imperfecta (types III and IV) caused by structural pathogenic variants in type I collagen Genet. Med. (IF 9.937) Pub Date : 2018-10-01 Lauren A. Barber, Craig Abbott, Vihang Nakhate, An N. Dang Do, Angela R. Blissett, Joan C. Marini
Purpose Growth deficiency is a cardinal feature of osteogenesis imperfecta (OI) types III and IV, caused by pathogenic variants in type I collagen. OI-specific longitudinal growth charts are needed for patient care. Methods We compiled longitudinal length, weight, head circumference, and body mass index (BMI) data from 100 children with types III and IV OI and known type I collagen pathogenic variants. Effects of gender, OI type, and pathogenic variant were examined using multilevel modeling. OI-specific centile curves were constructed using generalized additive model for location, scale, and shape (GAMLSS). Results OI type and gender, but not the specific mutated collagen gene, significantly affect stature, but only OI type affects weight. Head circumference was not significantly different by gender, type, or mutated gene. In both genders, length curves for types III and IV OI overlap and the type IV 95th centile curve overlaps the lower US Centers for Disease Control and Prevention (CDC) curves for the general population. A pubertal growth spurt is generally absent or blunted in types III/IV OI. The body mass index 50th and 95th centile curves are distinctly shifted above respective US CDC curves in both genders. Conclusions OI type is a stronger contributing factor than gender for OI growth, while curves do not differ for COL1A1 versus COL1A2 pathogenic variants. Types III and IV OI-specific growth curves are presented.
Opening the “black box” of informed consent appointments for genome sequencing: a multisite observational study Genet. Med. (IF 9.937) Pub Date : 2018-10-01 Saskia C. Sanderson, Celine Lewis, Christine Patch, Melissa Hill, Maria Bitner-Glindzicz, Lyn S. Chitty
Purpose Little is known about how health-care professionals communicate with patients about consenting to genome sequencing. We therefore examined what topics health-care professionals covered and what questions patients asked during consent conversations. Methods Twenty-one genome sequencing consent appointments were audio recorded and analyzed. Participants were 35 individuals being invited to participate in the 100,000 Genomes Project (14 participants with rare diseases, 21 relatives), and 10 health-care professionals (“consenters”). Results Two-thirds of participants’ questions were substantive (e.g., genetics and inheritance); one-third administrative (e.g., filling in the consent form). Consenters usually (19/21) emphasized participant choice about secondary findings, but less often (13/21) emphasized the uncertainty about associated disease risks. Consenters primarily used passive statements and closed-ended, rather than open-ended, questions to invite participants’ questions and concerns. In two appointments, one parent expressed negative or uncertain views about secondary findings, but after discussion with the other parent opted to receive them. Conclusion Health-care professionals need to be prepared to answer patients’ questions about genetics to facilitate genome sequencing consent. Health-care professionals’ education also needs to address how to effectively listen and elicit each patient’s questions and views, and how to discuss uncertainty around the disease risks associated with secondary findings.
Sharing data for future research—engaging participants’ views about data governance beyond the original project: a DIRECT Study Genet. Med. (IF 9.937) Pub Date : 2018-09-28 Nisha Shah, Victoria Coathup, Harriet Teare, Ian Forgie, Giuseppe Nicola Giordano, Tue Haldor Hansen, Lenka Groeneveld, Michelle Hudson, Ewan Pearson, Hartmut Ruetten, Jane Kaye
Purpose Biomedical data governance strategies should ensure that data are collected, stored, and used ethically and lawfully. However, research participants’ preferences for how data should be governed is least studied. The Diabetes Research on Patient Stratification (DIRECT) project collected substantial amounts of health and genetic information from patients at risk of, and with type II diabetes. We conducted a survey to understand participants’ future data governance preferences. Results will inform the postproject data governance strategy. Methods A survey was distributed in Denmark, Sweden, The Netherlands, and the United Kingdom. Results In total 855 surveys were returned. Ninety-seven percent were supportive of sharing data postproject, and 90% were happy to share data with universities, and 56% with commercial companies. The top three priorities for data sharing were highly secure database, DIRECT researchers to monitor data used by other researchers, and researchers cannot identify participants. Respondents frequently suggested that a postproject Data Access Committee should involve a DIRECT researcher, diabetes clinician, patient representative, and a DIRECT participant. Conclusion Preferences of how data should be governed, and what data could be shared and with whom varied between countries. Researchers are considered as key custodians of participant data. Engaging participants aids in designing governance to support their choices.
Functional analysis of DES-p.L398P and RBM20-p.R636C Genet. Med. (IF 9.937) Pub Date : 2018-09-28 Andreas Brodehl, Hans Ebbinghaus, Anna Gaertner-Rommel, Caroline Stanasiuk, Bärbel Klauke, Hendrik Milting
Functional analysis of DES-p.L398P and RBM20-p.R636C Functional analysis of DES-p.L398P and RBM20-p.R636C, Published online: 28 September 2018; doi:10.1038/s41436-018-0291-2 Functional analysis of DES-p.L398P and RBM20-p.R636C
Lessons from the premature adoption of preimplantation embryo testing Genet. Med. (IF 9.937) Pub Date : 2018-09-28 Shizuko Takahashi, Josephine Johnston, Pasquale Patrizio
Lessons from the premature adoption of preimplantation embryo testing Lessons from the premature adoption of preimplantation embryo testing, Published online: 28 September 2018; doi:10.1038/s41436-018-0314-z Lessons from the premature adoption of preimplantation embryo testing
Response to Brodehl et al. Genet. Med. (IF 9.937) Pub Date : 2018-09-28 Andre E. Minoche, Claire Horvat, Renee Johnson, Velimir Gayevskiy, Sarah U. Morton, Alexander P. Drew, Kerhan Woo, Aaron L. Statham, Ben Lundie, Richard D. Bagnall, Jodie Ingles, Christopher Semsarian, J. G. Seidman, Christine E. Seidman, Marcel E. Dinger, Mark J. Cowley, Diane Fatkin
Response to Brodehl et al. Response to Brodehl et al., Published online: 28 September 2018; doi:10.1038/s41436-018-0292-1 Response to Brodehl et al.
Correction: The landscape of epilepsy-related GATOR1 variants Genet. Med. (IF 9.937) Pub Date : 2018-09-27 Sara Baldassari, Fabienne Picard, Nienke E. Verbeek, Marjan van Kempen, Eva H. Brilstra, Gaetan Lesca, Valerio Conti, Renzo Guerrini, Francesca Bisulli, Laura Licchetta, Tommaso Pippucci, Paolo Tinuper, Edouard Hirsch, Anne de Saint Martin, Jamel Chelly, Gabrielle Rudolf, Mathilde Chipaux, Sarah Ferrand-Sorbets, Georg Dorfmüller, Sanjay Sisodiya, Simona Balestrini, Natasha Schoeler, Laura Hernandez-Hernandez, S. Krithika, Renske Oegema, Eveline Hagebeuk, Boudewijn Gunning, Charles Deckers, Bianca Berghuis, Ilse Wegner, Erik H. Niks, Floor E. Jansen, Kees Braun, Daniëlle de Jong, Guido Rubboli, Inga Talvik, Valentin Sander, Peter Uldall, Marie-Line Jacquemont, Caroline Nava, Eric Leguern, Sophie Julia, Antonio Gambardella, Giuseppe d’Orsi, Giovanni Crichiutti, Laurence Faivre, Veronique Darmency, Barbora Benova, Pavel Krsek, Arnaud Biraben, Anne-Sophie Lebre, Mélanie Jennesson, Shifteh Sattar, Cécile Marchal, Douglas R NordliJr, Kristin Lindstrom, Pasquale Striano, Lysa Boissé..
Correction: The landscape of epilepsy-related GATOR1 variants Correction: The landscape of epilepsy-related GATOR1 variants, Published online: 27 September 2018; doi:10.1038/s41436-018-0325-9 Correction: The landscape of epilepsy-related GATOR1 variants
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