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Next generation sequencing reveals novel compound heterozygous deletions in NDUFAF2 in a child with mitochondrial complex I deficiency, nuclear type 10 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-13 Aren E. Marshall, Lauren Brady, Ed Yeh, Alan J. Mears, Melanie Lacaria, Pranesh Chakraborty, Mark A. Tarnopolsky, Kristin D. Kernohan
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Intracranial calcifications simulating Aicardi‐Goutières syndrome in PARS2‐related mitochondrial disease Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-12 Amanda Gerard, Elizabeth Mizerik, Carrie A. Mohila, Sarah AlAwami, Jill V. Hunter, Debra L. Kearney, Seema R. Lalani, Fernando Scaglia
PARS2 encodes an aminoacyl‐tRNA synthetase that catalyzes the ligation of proline to mitochondrial prolyl‐tRNA molecules. Diseases associated with PARS2 primarily affect the central nervous system, causing early infantile developmental epileptic encephalopathies (EIDEE; DEE75; MIM #618437) with infantile‐onset neurodegeneration. Dilated cardiomyopathy has also been reported in the affected individuals
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Table of Contents, Volume 194A, Number 4, April 2024 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09
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Three Genes Associated with Neurodevelopmental Disorders Identified Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09
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First Gene Therapies Approved for Sickle Cell Disease Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09
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Estimation of carrier frequencies utilizing the gnomAD database for ACMG recommended carrier screening and Finnish disease heritage conditions in non‐Finnish European, Finnish, and Ashkenazi Jewish populations Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09 Miska Kandolin, Minna Pöyhönen, Eveliina Jakkula
American College of Medical Genetics and Genomics (ACMG) recommends offering Tier 3 carrier screening to pregnant patients and those planning a pregnancy for conditions with a carrier frequency of ≥1/200 (96 genes for autosomal recessive [AR] conditions). Certain AR conditions referred to as Finnish disease heritage (FINDIS) have a higher prevalence in Finland than elsewhere. Data from gnomAD v2.1
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Megalencephaly secondary to a novel germline missense variant p.Asp322Tyr in AKT3 associated with growth hormone deficiency and central hypothyroidism: A case report Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09 E. Renard, C. Bonnet, M. Di Patrizio, E. Schmitt, A. C. Madkaud, C. Chabot, M. Kuchenbuch, L. Lambert
Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of
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LUMBAR syndrome–OEIS complex overlap: A case series and review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-07 L. Barrios, S. Chamlin, Kim M. Keppler‐Noreuil, K. L. Rialon, Paul Austin, A. Alhajjat, D. Bowen, Denise W. Metry, D. H. Siegel
We present three new and six published infants with overlapping features of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, spinal cord malformations, bony deformities, anorectal/arterial anomalies and renal anomalies) and OEIS complex (omphalocele, exstrophy, imperforate anus, and spinal defects), also known as cloacal exstrophy. OEIS is included under the recently proposed umbrella
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Taking the risk. A systematic review of ethical reasons and moral arguments in the clinical use of polygenic risk scores Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-07 Lara Andreoli, Hilde Peeters, Kristel Van Steen, Kris Dierickx
Debates about the prospective clinical use of polygenic risk scores (PRS) have grown considerably in the last years. The potential benefits of PRS to improve patient care at individual and population levels have been extensively underlined. Nonetheless, the use of PRS in clinical contexts presents a number of unresolved ethical challenges and consequent normative gaps that hinder their optimal implementation
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TECPR2‐related hereditary sensory and autonomic neuropathy in two siblings from Palestine Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-04 Reham Khalaf‐Nazzal, Imad Dweikat, Nishanka Ubeyratna, James Fasham, Maysa Alawneh, Joseph Leslie, Mosab Maree, Adam Gunning, Deyala Z. Zayed, Nikol Voutsina, Lucy McGavin, Reem Sawafta, Martina Owens, Wisam Baker, Peter Turnpenny, Fida’ Al‐Hijawi, Emma L. Baple, Andrew H. Crosby, Lettie E. Rawlins
Due to the majority of currently available genome data deriving from individuals of European ancestry, the clinical interpretation of genomic variants in individuals from diverse ethnic backgrounds remains a major diagnostic challenge. Here, we investigated the genetic cause of a complex neurodevelopmental phenotype in two Palestinian siblings. Whole exome sequencing identified a homozygous missense
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Unraveling a history of overlap: A phenotypic comparison of RBCK1‐related disease and glycogen storage disease type IV Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-04 Haley M. Crane, Stephanie Asher, Laura Conway, Theodore G. Drivas, Staci Kallish
RBCK1‐related disease is a rare, multisystemic disorder for which our current understanding of the natural history is limited. A number of individuals initially carried clinical diagnoses of glycogen storage disease IV (GSD IV), but were later found to harbor RBCK1 pathogenic variants, demonstrating challenges of correctly diagnosing RBCK1‐related disease. This study carried out a phenotypic comparison
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Rare predicted deleterious FEZF2 variants are associated with a neurodevelopmental phenotype Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-01 Alison Garber, Lisa S. Weingarten, Nicolas J. Abreu, Houda Zghal Elloumi, Tobias Haack, Clara Hildebrant, Núria Martínez‐Gil, Jennifer Mathews, Amelie Johanna Müller, Irene Valenzuela Palafoll, Connolly Steigerwald, Wendy K. Chung
FEZF2 encodes a transcription factor critical to neurodevelopment that regulates other neurodevelopment genes. Rare variants in FEZF2 have previously been suggested to play a role in autism, and cases of 3p14 microdeletions that include FEZF2 share a neurodevelopmental phenotype including mild dysmorphic features and intellectual disability. We identified seven heterozygous predicted deleterious variants
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Communication of individuals with CDKL5 deficiency disorder as observed by caregivers: A descriptive qualitative study Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-01 Jessica Keeley, Sofia Benson‐Goldberg, Jacinta Saldaris, Judy Lariviere, Helen Leonard, Eric D. Marsh, Scott T. Demarest, Tim A. Benke, Peter Jacoby, Jenny Downs
CDKL5 deficiency disorder (CDD) is a genetically caused developmental epileptic encephalopathy that causes severe communication impairments. Communication of individuals with CDD is not well understood in the literature and currently available measures are not well validated in this population. Accurate and sensitive measurement of the communication of individuals with CDD is important for understanding
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SMC1A epilepsy syndrome: clinical data from a large international cohort Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-29 Elisabetta Gibellato, Paola Cianci, Milena Mariani, Barbara Parma, Sylvia Huisman, Robert Śmigiel, Anne‐Marie Bisgaard, Valentina Massa, Cristina Gervasini, Alex Moretti, Alessandro Cattoni, Andrea Biondi, Angelo Selicorni
SMC1A epilepsy syndrome or developmental and epileptic encephalopathy‐85 with or without midline brain defects (DEE85, OMIM #301044) is an X‐linked neurologic disorder associated with mutations of the SMC1A gene, which is also responsible for about 5% of patients affected by Cornelia de Lange syndrome spectrum (CdLS). Only described in female patients, SMC1A epilepsy syndrome is characterized by the
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3q29 duplications: A cohort of 46 patients and a literature review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-29 Marie Massier, Martine Doco‐Fenzy, Matthieu Egloff, Xavier Le Guillou, Gwenaël Le Guyader, Sylvia Redon, Caroline Benech, Karine Le Millier, Kevin Uguen, Juliette Ropars, Elise Sacaze, Séverine Audebert‐Bellanger, Andreea Apetrei, Arnaud Molin, Nicolas Gruchy, Aline Vincent‐Devulder, Marta Spodenkiewicz, Clémence Jacquin, Gauthier Loron, Marie Thibaud, Geoffroy Delplancq, Sophie Brisset, Marion Lesieur‐Sebellin
Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap
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De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-29 Thoa Ha, Angela Morgan, Meghan N. Bartos, Katelyn Beatty, Benjamin Cogné, Dominique Braun, Céline B. Gerber, Harald Gaspar, Anna M. Kopps, Claudine Rieubland, Anna C. E. Hurst, David J. Amor, Mathilde Nizon, Laurent Pasquier, Rolph Pfundt, André Reis, Victoria Mok Siu, Marine Tessarech, Michelle L. Thompson, Marie Vincent, Bert B. A. de Vries, Matthew B. Walsh, Stephanie Burns Wechsler, Christiane
The disconnected (disco)‐interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase‐associated protein 1 (DMAP1) binding domain, Acyl‐CoA synthetase domain and AMP‐binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues
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Hematologic malignancies in Li–Fraumeni syndrome: A case report Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-27 Bethany Bundrant, Yoheved Gerstein, Banu Arun, Courtney D. DiNardo
Li–Fraumeni syndrome (LFS) is a rare syndrome characterized by an increased lifetime risk of cancer development in multiple organ systems, typically caused by de novo or inherited germline pathogenic variants in the tumor suppressor TP53 gene. LFS is more classically associated with solid tumors; however, it is also associated with hematologic malignancies such as therapy‐related acute myeloid leukemia
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RET 634 germline/gonadal mosaicism generating a second pathogenic amino acid change in multiple endocrine neoplasia type 2A Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-26 Flávia O. F. Valente, Cléber P. Camacho, Susan C. Lindsey, Ji H. Yang, Ilda S. Kunii, Roberto B. Santos, Marina M. L. Kizys, Janete M. Cerutti, Magnus R. Dias‐da‐Silva, Rui M. B. Maciel
Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel
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Identification of a novel splice‐site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-26 Megumi Nishino, Mai Tanaka, Kazuo Imagawa, Katsuyuki Yaita, Takashi Enokizono, Tatsuyuki Ohto, Hisato Suzuki, Mamiko Yamada, Toshiki Takenouchi, Kenjiro Kosaki, Hidetoshi Takada
WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug‐resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice‐site mutation with uniparental isodisomy. A 1‐year and 7‐month‐old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities
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Biallelic OTUD6B variants associated with a Kabuki syndrome‐like disorder in three siblings: A clinical report and literature review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-23 Balram Gangaram, Virgina Lee, Anne Slavotinek
Biallelic variants in the OTUD6B gene have been reported in the literature in association with an intellectual developmental disorder featuring dysmorphic facies, seizures, and distal limb abnormalities. Physical differences described for affected individuals suggest that the disorder may be clinically recognizable, but previous publications have reported an initial clinical suspicion for Kabuki syndrome
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Metastatic adrenal gland neuroblastoma in an infant with trisomy 18: A case report Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-22 Shadi Tamur
I present a patient with trisomy 18 associated with neuroblastoma. To the best of my knowledge, this is the second report of such an individual in the relevant literature. A 19‐month‐old girl known to have trisomy 18 presented with respiratory distress secondary to pleural effusion. Work‐up showed metastatic neuroblastoma to multiple sites, and the patient's clinical situation was critical. The physician–parent's
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Growth charts for weight and height of Indian children with Down syndrome Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-22 Anil Kumar Bhalla, Harvinder Kaur, Rupinder Kaur, Inusha Panigrahi
Age and gender specific growth charts for Indian children with Down syndrome (DS) based on longitudinal data have not been published. To establish percentile growth charts for DS children inhabiting northwestern parts of India, body weight and length/height of 1125 (Male: 752, Female: 373) children with DS aged <1 month to 10 years, enrolled from the “Genetics Clinic” were measured at half yearly age
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Experience with cascade screening: A comprehensive family pedigree analysis of two index patients with Fabry disease Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-19 Pelin Teke Kisa, Burcu Ozturk Hismi, Mehmet Kocabey, Zumrut Arslan Gulten, Bulent Huddam, Selim Ekinci, Evrim Bozkaya, Harun Akar, Ozge K. Karalar Pekuz, Ayca Aydogan, Nur Arslan
The wide range of clinical symptoms observed in patients with Fabry disease (FD) often leads to delays in diagnosis and initiation of treatment. Delayed initiation of therapy may result in end‐organ damage, such as chronic renal failure, hypertrophic cardiomyopathy, and stroke. Although some tools are available to identify undiagnosed patients, new comprehensive screening methods are needed. In this
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Common epilepsy variants from the general population are not associated with epilepsy among individuals with tuberous sclerosis complex Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-17 Melissa A. Richard, Philip J. Lupo, Erik A. Ehli, Mustafa Sahin, Darcy A. Krueger, Joyce Y. Wu, Elizabeth M. Bebin, Kit Sing Au, Hope Northrup, Laura S. Farach
Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy
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Monodactyly in a patient with CHARGE syndrome: An additional case report Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-14 Henrique Regonaschi Serigatto, Roseli Maria Zechi-Ceide, Isabella Parizotto, Nancy Mizue Kokitsu-Nakata
CHARGE syndrome is a rare autosomal dominant syndrome characterized by multiple congenital anomalies including coloboma, heart defects, ear anomalies, and developmental delay, caused by pathogenic variants in the CHD7 gene. The discovery of the molecular basis of this syndrome increased the number of cases reported and expanded the phenotype and clinical variability. Limb anomalies are occasional clinical
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PRKACA-related, atrial defects-polydactyly-multiple congenital malformation syndrome in an Indian patient Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-15 Sivagamy Sithambaram, Prince Jacob, Kausthubham Neethukrishna, Gandham SriLakshmi Bhavani, Ashwin Dalal, Hitesh Shah, Katta Mohan Girisha
PRKACA-related, atrial defects-polydactyly-multiple congenital malformation syndrome is a recently described skeletal ciliopathy, which is caused by disease-causing variants in PRKACA. The primary phenotypic description includes atrial septal defects, and limb anomalies including polydactyly and short limbs. To date, only four molecularly proven patients have been reported in the literature with a
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Australian researcher's perspectives on the Australian industry-led moratorium on genetic tests in life insurance Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-14 Tatiane Yanes, Marisa Blencoe, Antonia Howard, Jane Tiller, Courtney Wallingford, Margaret Otlowski, Louise Keogh, Paul Lacaze, Aideen McInerney-Leo
Fear of insurance discrimination can inhibit genetic research participation. In 2019, an industry-led partial moratorium on using genetic results in Australian life insurance underwriting was introduced. This mixed-methods study used online surveys (n = 59 participants) and semi-structured interviews (n = 22 participants) to capture researchers’ perceptions about the moratorium. 66% (n = 39/59) were
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Identification of novel MYH14 variants in families with autosomal dominant sensorineural hearing loss Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-14 Duygu Duman, Memoona Ramzan, Asli Subasioglu, Ahmet Mutlu, LéShon Peart, Serhat Seyhan, Shengru Guo, Kadri Ila, Burhan Balta, Mahmut Tayyar Kalcioglu, Guney Bademci, Mustafa Tekin
Autosomal dominant sensorineural hearing loss (ADSNHL) is a genetically heterogeneous disorder caused by pathogenic variants in various genes, including MYH14. However, the interpretation of pathogenicity for MYH14 variants remains a challenge due to incomplete penetrance and the lack of functional studies and large families. In this study, we performed exome sequencing in six unrelated families with
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A case report on deficiency of adenosine deaminase 2 with relapse–remission course and analysis of genotype–phenotype correlation Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-14 Qianyun Cai, Fan Feng, Yanmei Tian, Rong Luo, Dezhi Mu, Fan Yang, Zuozhen Yang, Zhongjie Zhou
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in adenosine deaminase 2 (ADA2). The varying phenotypes of the disease often lead to delayed diagnosis or misdiagnosis. We report an 11-year-old boy with DADA2 and provide a preliminary analysis of genotype–phenotype correlation. The age of onset of the disease was 8 years old. The disease successively
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EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-13 Irman Forghani, Steven H. Lang, Matthew J. Rodier, Stephanie A. Bivona, , Alejo A. Morales, Stephan Zuchner, Guney Bademci, Mustafa Tekin
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed
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RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-09 Noboru Uchida, Tomohiro Ishii, Gen Nishimura, Takeshi Sato, Gen Kuratsuji, Keisuke Nagasaki, Yuki Hosokawa, Eriko Adachi, Kei Takasawa, Kenichi Kashimada, Yuko Tsujioka, Tomonobu Hasegawa
Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset
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First-trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP-based amplicon sequencing: An earlier, rapid and safer way Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-08 Xinyu Fu, Zhenhua Zhao, Lingrong Kong, Shaojun Li, Feifei Li, Xiujuan Han, Luming Sun, Di Wu, Yanan Wang, Xiangdong Kong
The study is to explore the feasibility and value of SNP-based noninvasive prenatal diagnosis (NIPD) for facioscapulohumeral muscular dystrophy type 1 (FSHD1) in early pregnancy weeks. We prospectively collected seven FSHD1 families, with an average gestational age of 8+6. Among these seven couples, there were three affected FSHD1 mothers and four affected fathers. A multiplex-PCR panel comprising
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Personal journeys to and in human genetics and dysmorphology Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-08 Charles E. Schwartz, Arthur S. Aylsworth, Judith Allanson, Agatino Battaglia, John C. Carey, Cynthia J. Curry, Kay E. Davies, Evan E. Eichler, John M. Graham, Bryan Hall, Judith G. Hall, Lewis B. Holmes, H. Eugene Hoyme, Alasdair Hunter, Jeffrey Innis, John Johnson, Kim M. Keppler-Noreuil, Jules G. Leroy, Cynthia Moore, David L. Nelson, Giovanni Neri, John M. Opitz, David Picketts, F. Lucy Raymond
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties
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Erratum to “De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities” Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-07
Ward, S. K., Wadley, A., Tsai, C. (A.), Benke, P. J., Emrick, L., Fisher, K., Houck, K. M., Dai, H., Undiagnosed Diseases Network, Guillen Sacoto, M. J., Craigen, W., Glaser, K., Murdock, D. R., Rohena, L., Diderich, K. E. M., Bruggenwirth, H. T., Lee, B., Bacino, C., Burrage, L. C., & Rosenfeld, J. A. (2024). De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia,
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Cerebellar heterotopia in an 11-year-old child with KDM6B-related neurodevelopmental disorder: A case report and review of the literature Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-07 Davide Politano, Fulvio D'Abrusco, Ludovica Pasca, Francesca Ferraro, Simone Gana, Jessica Garau, Martina Paola Zanaboni, Elisa Rognone, Anna Pichiecchio, Renato Borgatti, Enza Maria Valente, Valentina De Giorgis, Romina Romaniello
Heterozygous pathogenic variants in KDM6B have recently been associated to a rare neurodevelopmental disorder referred to as “Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities” and characterized by non-pathognomonic facial and body dysmorphisms, a wide range of neurodevelopmental and behavioral disorders and nonspecific neuroradiological findings. KDM6B encodes a
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The impact of a virtual mind–body program on symptoms of depression and anxiety among international English-speaking adults with neurofibromatosis Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-06 Katherine McDermott, Jafar Bakhshaie, Julie Brewer, Ana-Maria Vranceanu
The neurofibromatoses (NFs) are a set of incurable genetic disorders that predispose individuals to nervous system tumors. Although many patients experience anxiety and depression, there is little research on psychosocial interventions in this population. The present study examined the effects of a mind–body intervention on depression and anxiety in adults with NF. This is a secondary analysis of the
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Epilepsy with faint capillary malformation or reticulated telangiectasia associated with mosaic AKT3 pathogenic variants Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-06 Martina De Bortoli, Marta Ivars, Nicole Revencu, Marie-Cécile Nassogne, Cinzia Lavarino, Sonia Paco, Martin Lammens, Anne Renders, Dana Dumitriu, Raphaël Helaers, Laurence M. Boon, Eulalia Baselga, Miikka Vikkula
Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase–protein kinase B–mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we
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A longitudinal characterization of the adaptive and behavioral profile in Sotos syndrome Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-06 Martina Siracusano, Caterina Dante, Rachele Sarnataro, Lucrezia Arturi, Assia Riccioni, Elisa Carloni, Mariagrazia Cicala, Leonardo Emberti Gialloreti, Cinzia Galasso, Giuseppina Conteduca, Domenico Coviello, Luigi Mazzone
Delineation of a developmental and behavioral trajectory is a key-topic in the context of a genetic syndrome. Short- and long-term implications concerning school outcome, independent living, and working opportunities are strictly linked to the cognitive and behavioral profile of an individual. For the first time, we present a longitudinal characterization of the adaptive and behavioral profile of a
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Expanding the phenotype of UPF3B-related disorder: Case reports and literature review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-06 Ferruccio Romano, Maria K. Haanpää, Pawel Pomianowski, Amanda Rose Peraino, John R. Pollard, Maria Francesca Di Feo, Monica Traverso, Mariasavina Severino, Maria Derchi, Edoardo Henzen, Federico Zara, Francesca Faravelli, Valeria Capra, Marcello Scala
UPF3B encodes the Regulator of nonsense transcripts 3B protein, a core-member of the nonsense-mediated mRNA decay pathway, protecting the cells from the potentially deleterious actions of transcripts with premature termination codons. Hemizygous variants in the UPF3B gene cause a spectrum of neuropsychiatric issues including intellectual disability, autism spectrum disorder, attention deficit hyperactivity
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Development of specific growth charts for children with Fanconi anemia Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-05 Crystal Barbus, Arpana Rayannavar, Bradley S. Miller, Mica J. Jenkins, O. Yaw Addo, Ahmad Rayes, Natasha Ahrweiler, Alisha Olson, Zachary Pohlkamp, John E. Wagner, Margaret L. MacMillan
Patients with Fanconi anemia (FA) are often perceived to have poor growth when general population growth curves are utilized. We hypothesize that FA patients have unique growth and aimed to create FA-specific growth charts. Height and weight data from ages 0 to 20 years were extracted from medical records of patients treated at the Fanconi Anemia Comprehensive Care Clinic at the University of Minnesota
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Prevalence and descriptive epidemiology of choanal atresia and stenosis in Texas, 1999–2018 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-05 Renata H. Benjamin, Lisa K. Marengo, Angela E. Scheuerle, A. J. Agopian, Laura E. Mitchell
Choanal atresia and stenosis are common causes of congenital nasal obstruction, but their epidemiology is poorly understood. Compared to bilateral choanal atresia/stenosis, unilateral choanal atresia/stenosis is generally diagnosed later and might be under-ascertained in birth defect registries. Data from the population-based Texas Birth Defects Registry and Texas vital records, 1999–2018, were used
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Unraveling the molecular diagnosis of metaphyseal enchondromatosis with D-2-hydroxyglutaric aciduria: A 22-year quest Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-02 Khanti Rattanapornsompong, Wanna Chetruengchai, Chalurmpon Srichomthong, Thanakorn Theerapanon, Thantrira Porntaveetus, Vorasuk Shotelersuk
CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.
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Feeding tube use and complications in Prader-Willi syndrome: Data from the Global Prader-Willi Syndrome Registry Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-02-01 Sani M. Roy, Deborah Rafferty, Amy Trejo, Luke Hamilton, Jessica E. Bohonowych, Theresa V. Strong, Lusine Ambartsumyan, Samson Cantu, Ann Scheimann, Jessica Duis
Guidance on indications for, and types of, feeding tubes recommended in Prader-Willi syndrome (PWS) is needed. A Global PWS Registry survey was developed to investigate nasogastric (NG) and gastrostomy (G) tube use and associated complications. Of 346 participants, 242 (69.9%) had NG-tubes, 17 (4.9%) had G-tubes, and 87 (25.1%) had both NG- and G-tubes. Primary indication for placement was “feeding
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PUF60 loss-of-function with normal cognition should be considered in the differential diagnosis of Klippel–Feil syndrome Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-31 Michal Yacobi Bach, Sivan Reytan Miron, Alina Kurolap, Hagit Baris Feldman
Klippel–Feil syndrome (KFS) has a genetically heterogeneous phenotype with six known genes, exhibiting both autosomal dominant and autosomal recessive inheritance patterns. PUF60 is a nucleic acid-binding protein, which is involved in a number of nuclear processes, including pre-mRNA splicing, apoptosis, and transcription regulation. Pathogenic variants in this gene have been described in Verheij syndrome
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Medulloblastoma and other neoplasms in patients with heterozygous germline SUFU variants: A scoping review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-28 Stephanie G. Lee, Gareth Evans, Maddie Stephen, Rachel Goren, Melissa Bondy, Steven Goodman
In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB). Other neoplasms associated with pathologic germline SUFU+/− variants have also been described among patients with basal cell nevus syndrome (BCNS; BCNS is also known as Gorlin syndrome, nevoid basal cell carcinoma [BCC] syndrome
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Epilepsy in Legius syndrome: Coincidence or causation? Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-24 Adalbeis Medina Lemus, Cyrus Boelman, Kenneth A. Myers
Legius syndrome is a rare genetic disorder, caused by heterozygous SPRED1 pathogenic variants, which shares phenotypic features with neurofibromatosis type 1 (NF1). Both conditions typically involve café-au-lait macules, axillary freckling, and macrocephaly; however, patients with NF1 are also at risk for tumors, such as optic nerve gliomas and neurofibromas. Seizure risk is known to be elevated in
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Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-23 Michele P. Migliavacca, Joselito Sobreira, Diana Bermeo, Mireille Gomes, Dayse Alencar, Luciane Sussuchi, Camila Alves Souza, Juliana Santos Silva, José Eduardo Kroll, Matheus Burger, Rodrigo Guarischi-Sousa, Darine Villela, Guilherme L. Yamamoto, Fernanda Milanezi, Nelson Horigoshi, Regina Grigolli Cesar, Werther Brunow de Carvalho, Rachel Sayuri Honjo, Debora Romeo Bertola, Chong Ae Kim, Lucian de
In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis
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Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-24 Duha Hejla, Stephanie Huynh, Simran Samra, Phillip A. Richmond, Joshua Dalmann, Kate L. Del Bel, Loryn Byres, Anna Lehman, Stuart E. Turvey, Cornelius F. Boerkoel
Pathogenic PHF21A variation causes PHF21A-related neurodevelopmental disorders (NDDs). Although amorphic alleles, including haploinsufficiency, have been established as a disease mechanism, increasing evidence suggests that missense variants as well as frameshift variants extending the BHC80 carboxyl terminus also cause disease. Expanding on these, we report a proposita with intellectual disability
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Early diagnostic clues of mucolipidosis type II: Significance of radiological findings Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-24 Ezgi Burgac, İrem Kaplan, Burcu Köseci, Esra Kara, Deniz Kor, Fatma Derya Bulut, Anıl Atmış, Ferhatcan Pişkin, Sevcan Tuğ Bozdoğan, Gizem Urel Demir, Faruk İncecik, Neslihan Önenli Mungan
Mucolipidosis type-II (ML-II) is an ultra-rare disorder caused by deficiency of N-acetylglucosaminyl-1-phosphotransferase enzyme due to biallelic pathogenic variants in GNPTAB gene. There are a few known about the natural history of ML-II. In this study, we presented the natural course of 24 patients diagnosed with ML-II. Mean age at diagnosis was 9.3 ± 5.7 months. All patients had coarse face, developmental
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ARID2, a milder cause of Coffin-Siris Syndrome? Broadening the phenotype with 17 additional individuals Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-19 Samantha A. Schrier Vergano
Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex, including ARID1B, ARID1A, ARID2, SMARCA4, SMARCE1, SMARCB1, SOX11, SMARCC2, DPF2, and more recently, BICRA. Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties
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Corrigendum to “Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome” Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-18
Lin AE, Alali A, Starr LJ, et al. Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome. Am J Med Genet Part A. 2020;182A:328–337. During a review of a series of adult patients with Myhre syndrome (MIM #139210), the authors discovered a discrepancy in the SMAD4 pathogenic variant that was reported in one of six patients with neoplasia, who was one of three females
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X-linked congenital adrenal hypoplasia: Report of long clinical follow-up and description of a new complex variant in the NR0B1 gene Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-19 Adriana Mangue Esquiaveto-Aun, Maricilda Palandi de Mello, Mara Sanches Guaragna, Vera Lúcia Gil da Silva Lopes, Ana Paula Francese-Santos, Cristiane dos Santos Cruz Piveta, Taís Nitsh Mazolla, Sofia Helena Valente de Lemos-Marini, Gil Guerra-Junior
Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype–phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring
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Understanding chronic pain in Neurofibromatosis Type 1 using the Neurofibromatosis Pain Module (NFPM) Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-17 Frank D. Buono, Kaitlyn Larkin, William T. Zempsky, Lauretta E. Grau, Staci Martin
Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that can cause an individual significant chronic pain (CP). CP affects quality of life and daily functioning, yet there are limited effective treatments for CP within NF1. The current study describes the impact of CP using the Neurofibromatosis Pain Module (NFPM). The NFPM is a self-reported clinical assessment that evaluates
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Complex balanced intrachromosomal rearrangement involving PITX2 identified as a cause of Axenfeld-Rieger Syndrome Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-17 Joseph Farris, Cheryl Khanna, James B. Smadbeck, Sarah H. Johnson, Erick Bothun, Tyler Kaplan, Francis Hoffman, Katarzyna Polonis, Gavin Oliver, Linda M. Reis, Elena V. Semina, Laura Rust, Nicole L. Hoppman, George Vasmatzis, Cherisse A. Marcou, Lisa A. Schimmenti, Eric W. Klee
Axenfeld-Rieger Syndrome (ARS) type 1 is a rare autosomal dominant condition characterized by anterior chamber anomalies, umbilical defects, dental hypoplasia, and craniofacial anomalies, with Meckel's diverticulum in some individuals. Here, we describe a clinically ascertained female of childbearing age with ARS for whom clinical targeted sequencing and deletion/duplication analysis followed by clinical
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Metabolic and other morbid complications in congenital generalized lipodystrophy type 4 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-17 Gulcin Akinci, Saif Alyaarubi, Nivedita Patni, Nadia Alhashmi, Azza Al-Shidhani, Flavia Prodam, Nancy Gagne, Funmbi Babalola, Aisha Al Senani, Kavitha Muniraj, Solaf M. Elsayed, Marianna Beghini, Basak Ozgen Saydam, Moosa Allawati, Madhumati S. Vaishnav, Ender Can, Ilgin Y. Simsir, Ekaterina Sorkina, Fatma Dursun, Clemens Kamrath, Umit Cavdar, Partha P. Chakraborty, Ozlem Akgun Dogan, Aliya Al Hosin
Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes
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Data from electronic healthcare records expand our understanding of X-linked genetic diseases Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-16 Rory J. Tinker, Lisa Bastarache, Kimberly Ezell, Serena M. Neumann, Yutaka Furuta, Karee A. Morgan, John A. Phillips
Disease specific cohort studies have reported details on X linked (XL) disorders affecting females. We investigated the spectrum and penetrance of XL disorders seen in electronic health records (EHR). We generated a cohort of individuals diagnosed with XL disorders at Vanderbilt University Medical Center over 20 years. Our cohort included 477 males and 203 females diagnosed with 108 different XL genetic
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The first Turkish family with a novel biallelic missense variant of the ALKBH8 gene: A study on the clinical and variant spectrum of ALKBH8-related intellectual developmental disorders Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-08 Mustafa Yılmaz, Tülay Kamaşak, Kerem Teralı, Alper Han Çebi, Ayberk Türkyılmaz
ABH8, the protein encoded by the ALKBH8 gene, modifies tRNAs by methylating their anticodon wobble uridine residues. The variations in the ALKBH8 gene are associated with the “intellectual developmental disorder, autosomal recessive type 71” (MIM: 618504) phenotype in the OMIM database. This phenotype is characterized by global developmental delay, facial dysmorphic features, and psychiatric problems
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Evaluation of functionality-mobility in patients with skeletal dysplasias. Application of the STEMS tool (“everyday symptoms and mobility screening tool for skeletal dysplasias”) Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-12 Rosario Ramos-Mejia, G. Isoldi, P. J. Ireland, M. Rodriguez Celin, V. Fano
Individuals with differing forms of skeletal dysplasias (SD) frequently report impaired mobility and symptoms. With the objetive to evaluate mobility and associated symptoms in people with SD at an Argentinian pediatric hospital, using an Argentinian version of the Screening Tool for Everyday Mobility and Symptoms (STEMS), a simple questionnaire that allows clinicians to quickly identify the presence
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Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-01-12 Marissa Cepress, Ethan Grund, Tomas Leng, Marc Patterson, Mariya Saify, Nessa Aghazadeh Mohandesi, Jason Homme
Metabolic pathways are known to generate byproducts—some of which have no clear metabolic function and some of which are toxic. Nicotinamide adenine dinucleotide phosphate hydrate (NAD(P)HX) is a toxic metabolite that is produced by stressors such as a fever, infection, or physical stress. Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) and nicotinamide adenine dinucleotide phosphate