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  • Systematic identification of genetic systems associated with phenotypes in patients with rare genomic copy number variations
    Hum. Genet. (IF 5.743) Pub Date : 2020-08-10
    F. M. Jabato, Pedro Seoane, James R. Perkins, Elena Rojano, Adrián García Moreno, M. Chagoyen, Florencio Pazos, Juan A. G. Ranea

    Copy number variation (CNV) related disorders tend to show complex phenotypic profiles that do not match known diseases. This makes it difficult to ascertain their underlying molecular basis. A potential solution is to compare the affected genomic regions for multiple patients that share a pathological phenotype, looking for commonalities. Here, we present a novel approach to associate phenotypes with

  • The shared genetic architecture of schizophrenia, bipolar disorder and lifespan
    Hum. Genet. (IF 5.743) Pub Date : 2020-08-09
    Gerard Muntané, Xavier Farré, Elena Bosch, Lourdes Martorell, Arcadi Navarro, Elisabet Vilella

    Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied

  • Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-30
    Morgan Sanders, James M. J. Lawlor, Xiaopeng Li, John N. Schuen, Susan L. Millard, Xi Zhang, Leah Buck, Bethany Grysko, Katie L. Uhl, David Hinds, Cynthia L. Stenger, Michele Morris, Neil Lamb, Hara Levy, Caleb Bupp, Jeremy W. Prokop

    Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure

  • Genetic evidence suggests a sense of family, parity and conquest in the Xiongnu Iron Age nomads of Mongolia
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-30
    Christine Keyser, Vincent Zvénigorosky, Angéla Gonzalez, Jean-Luc Fausser, Florence Jagorel, Patrice Gérard, Turbat Tsagaan, Sylvie Duchesne, Eric Crubézy, Bertrand Ludes

    In an effort to characterize the people who composed the groups known as the Xiongnu, nuclear and whole mitochondrial DNA data were generated from the skeletal remains of 52 individuals excavated from the Tamir Ulaan Khoshuu (TUK) cemetery in Central Mongolia. This burial site, attributed to the Xiongnu period, was used from the first century BC to the first century AD. Kinship analyses were conducted

  • Overview of PAX gene family: analysis of human tissue-specific variant expression and involvement in human disease
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-29
    Brian Thompson, Emily A. Davidson, Wei Liu, Daniel W. Nebert, Elspeth A. Bruford, Hongyu Zhao, Emmanouil T. Dermitzakis, David C. Thompson, Vasilis Vasiliou

    Paired-box (PAX) genes encode a family of highly conserved transcription factors found in vertebrates and invertebrates. PAX proteins are defined by the presence of a paired domain that is evolutionarily conserved across phylogenies. Inclusion of a homeodomain and/or an octapeptide linker subdivides PAX proteins into four groups. Often termed “master regulators”, PAX proteins orchestrate tissue and

  • Deciphering the complexity of simple chromosomal insertions by genome sequencing
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-29
    Zirui Dong, Matthew Hoi Kin Chau, Yanyan Zhang, Peng Dai, Xiaofan Zhu, Tak Yeung Leung, Xiangdong Kong, Yvonne K. Kwok, Paweł Stankiewicz, Sau Wai Cheung, Kwong Wai Choy

    Chromosomal insertions are thought to be rare structural rearrangements. The current understanding of the underlying mechanisms of their origin is still limited. In this study, we sequenced 16 cases with apparent simple insertions previously identified by karyotyping and/or chromosomal microarray analysis. Using mate-pair genome sequencing (GS), we identified all 16 insertions and revised previously

  • Identifying adaptive alleles in the human genome: from selection mapping to functional validation
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-29
    Elizabeth A. Werren, Obed Garcia, Abigail W. Bigham

    The suite of phenotypic diversity across geographically distributed human populations is the outcome of genetic drift, gene flow, and natural selection throughout human evolution. Human genetic variation underlying local biological adaptations to selective pressures is incompletely characterized. With the emergence of population genetics modeling of large-scale genomic data derived from diverse populations

  • Disclosure of secondary findings in exome sequencing of 2480 Japanese cancer patients
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-24
    Yasue Horiuchi, Hiroyuki Matsubayashi, Yoshimi Kiyozumi, Seiichiro Nishimura, Satomi Higashigawa, Nobuhiro Kado, Takeshi Nagashima, Maki Mizuguchi, Sumiko Ohnami, Makoto Arai, Kenichi Urakami, Masatoshi Kusuhara, Ken Yamaguchi

    High-throughput sequencing has greatly contributed to precision medicine. However, challenges remain in reporting secondary findings (SFs) of germline pathogenic variants and managing the affected patients. The aim of this study was to examine the incidence of SFs in Japanese cancer patients using whole exome sequencing (WES) and to understand patient preferences regarding SF disclosure. WES was conducted

  • Compound heterozygous mutation of the ASXL3 gene causes autosomal recessive congenital heart disease
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-21
    Fang Fu, Ru Li, Ting-ying Lei, Dan Wang, Xin Yang, Jin Han, Min Pan, Li Zhen, Jian Li, Fa-tao Li, Xiang-yi Jing, Dong-zhi Li, Can Liao

    To explore mutations in the additional sex combs-like 3 (ASXL3) gene in two Chinese families with congenital heart disease (CHD). Whole-exome sequencing (WES) was used to reveal a novel compound heterozygous mutation in the ASXL3 gene that was associated with CHD. Sanger sequencing of a further 122 CHD patients was used to determine an additional compound heterozygous mutation in the ASXL3 gene. Cell

  • Population genetics: past, present, and future
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-18
    Atsuko Okazaki, Satoru Yamazaki, Ituro Inoue, Jurg Ott

    We present selected topics of population genetics and molecular phylogeny. As several excellent review articles have been published and generally focus on European and American scientists, here, we emphasize contributions by Japanese researchers. Our review may also be seen as a belated 50-year celebration of Motoo Kimura’s early seminal paper on the molecular clock, published in 1968.

  • A pooled genome-wide association study identifies pancreatic cancer susceptibility loci on chromosome 19p12 and 19p13.3 in the full-Jewish population
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-15
    Samantha A. Streicher, Alison P. Klein, Sara H. Olson, Robert C. Kurtz, Laufey T. Amundadottir, Andrew T. DeWan, Hongyu Zhao, Harvey A. Risch

    Jews are estimated to be at increased risk of pancreatic cancer compared to non-Jews, but their observed 50–80% excess risk is not explained by known non-genetic or genetic risk factors. We conducted a GWAS in a case–control sample of American Jews, largely Ashkenazi, including 406 pancreatic cancer patients and 2332 controls, identified in the dbGaP, PanScan I/II, PanC4 and GERA data sets. We then

  • A Southeast Asian origin for present-day non-African human Y chromosomes
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-14
    Pille Hallast, Anastasia Agdzhoyan, Oleg Balanovsky, Yali Xue, Chris Tyler-Smith

    The genomes of present-day humans outside Africa originated almost entirely from a single out-migration ~ 50,000–70,000 years ago, followed by mixture with Neanderthals contributing ~ 2% to all non-Africans. However, the details of this initial migration remain poorly understood because no ancient DNA analyses are available from this key time period, and interpretation of present-day autosomal data

  • Disease gene discovery in male infertility: past, present and future
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-07
    M. J. Xavier, A. Salas-Huetos, M. S. Oud, K. I. Aston, J. A. Veltman

    Identifying the genes causing male infertility is important to increase our biological understanding as well as the diagnostic yield and clinical relevance of genetic testing in this disorder. While significant progress has been made in some areas, mainly in our knowledge of the genes underlying rare qualitative sperm defects, the same cannot be said for the genetics of quantitative sperm defects.

  • Interplay between probe design and test performance: overlap between genomic regions of interest, capture regions and high quality reference calls influence performance of WES-based assays
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-05
    Erinija Pranckeviciene, Lemuel Racacho, Mahdi Ghani, Landry Nfonsam, Ryan Potter, Elizabeth Sinclair-Bourque, Gabrielle Mettler, Amanda Smith, Lucas Bronicki, Lijia Huang, Olga Jarinova

    Whole exome sequencing (WES)-based assays undergo rigorous validation before being implemented in diagnostic laboratories. This validation process generates experimental evidence that allows laboratories to predict the performance of the intended assay. The NA12878 Genome in a Bottle (GIAB) HapMap reference sample is commonly used for validation in diagnostic laboratories. We investigated what data

  • The molecular genetic basis of atrial fibrillation
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-02
    Xin Huang, Yuhui Li, Junguo Zhang, Xiaojie Wang, Ziyi Li, Guowei Li

    As the most common cardiac arrhythmia, atrial fibrillation (AF) is a major risk factor for stroke, heart failure, and premature death with considerable associated costs. However, no available treatment options have optimal benefit-harm profiles currently, reflecting an incomplete understanding of the biological mechanisms underlying this complex arrhythmia. Recently, molecular epidemiological studies

  • Combi -CRISPR: combination of NHEJ and HDR provides efficient and precise plasmid-based knock-ins in mice and rats
    Hum. Genet. (IF 5.743) Pub Date : 2020-07-02
    Kazuto Yoshimi, Yuichiro Oka, Yoshiki Miyasaka, Yuko Kotani, Misato Yasumura, Yoshihiro Uno, Kosuke Hattori, Arisa Tanigawa, Makoto Sato, Manami Oya, Kazuhiro Nakamura, Natsuki Matsushita, Kazuto Kobayashi, Tomoji Mashimo

    CRISPR-Cas9 are widely used for gene targeting in mice and rats. The non-homologous end-joining (NHEJ) repair pathway, which is dominant in zygotes, efficiently induces insertion or deletion (indel) mutations as gene knockouts at targeted sites, whereas gene knock-ins (KIs) via homology-directed repair (HDR) are difficult to generate. In this study, we used a double-stranded DNA (dsDNA) donor template

  • The Human Gene Mutation Database (HGMD ® ): optimizing its use in a clinical diagnostic or research setting
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-28
    Peter D. Stenson, Matthew Mort, Edward V. Ball, Molly Chapman, Katy Evans, Luisa Azevedo, Matthew Hayden, Sally Heywood, David S. Millar, Andrew D. Phillips, David N. Cooper

    The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that are thought to underlie, or are closely associated with human inherited disease. At the time of writing (June 2020), the database contains in excess of 289,000 different gene lesions identified in over 11,100 genes manually curated from 72,987 articles published in over

  • The cataract-linked RNA-binding protein Celf1 post-transcriptionally controls the spatiotemporal expression of the key homeodomain transcription factors Pax6 and Prox1 in lens development
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-27
    Sandeep Aryal, Justine Viet, Bailey A. T. Weatherbee, Archana D. Siddam, Francisco G. Hernandez, Carole Gautier-Courteille, Luc Paillard, Salil A. Lachke

    The homeodomain transcription factors (TFs) Pax6 (OMIM: 607108) and Prox1 (OMIM: 601546) critically regulate gene expression in lens development. While PAX6 mutations in humans can cause cataract, aniridia, microphthalmia, and anophthalmia, among other defects, Prox1 deletion in mice causes severe lens abnormalities, in addition to other organ defects. Furthermore, the optimal dosage/spatiotemporal

  • Identification of novel genetic variants associated with short stature in a Baka Pygmies population.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-24
    Matteo Zoccolillo,Claudia Moia,Sergio Comincini,Davide Cittaro,Dejan Lazarevic,Karen A Pisani,Jan M Wit,Mauro Bozzola

    Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide populations. Theoretically, a valuable approach to better

  • Novel loss-of-function mutations in COCH cause autosomal recessive nonsyndromic hearing loss.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-19
    Kevin T Booth,Amama Ghaffar,Muhammad Rashid,Luke T Hovey,Mureed Hussain,Kathy Frees,Erika M Renkes,Carla J Nishimura,Mohsin Shahzad,Richard J Smith,Zubair Ahmed,Hela Azaiez,Saima Riazuddin

    COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic

  • Complex chromosomal rearrangements of human chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-13
    Taichi Imaizumi,Keiko Yamamoto-Shimojima,Tomoe Yanagishita,Yumiko Ondo,Eriko Nishi,Nobuhiko Okamoto,Toshiyuki Yamamoto

    The chromosomal region critical in Down syndrome has long been analyzed through genotype–phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified

  • Study of telomere length in men who carry a fragile X premutation or full mutation allele.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-12
    Igor Albizua,Pankaj Chopra,Emily G Allen,Weiya He,Ashima S Amin,Stephanie L Sherman

    The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5′ UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual

  • A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-12
    Yongyun Li,Liu Yang,Jie Yang,Jiahao Shi,Peiwei Chai,Shengfang Ge,Yefei Wang,Xianqun Fan,Renbing Jia

    Vascular anomalies (VAs), comprising wide subtypes of tumors and malformations, are often caused by variants in multiple tyrosine kinase (TK) receptor signaling pathways including TIE2, PIK3CA and GNAQ/11. Yet, a portion of individuals with clinical features of VA do not have variants in these genes, suggesting that there are undiscovered pathogenic factors underlying these patients and possibly with

  • The necdin interactome: evaluating the effects of amino acid substitutions and cell stress using proximity-dependent biotinylation (BioID) and mass spectrometry.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-11
    Matthea R Sanderson,Katherine E Badior,Richard P Fahlman,Rachel Wevrick

    Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of function of a set of imprinted genes on chromosome 15q11–15q13. One of these genes, NDN, encodes necdin, a protein that is important for neuronal differentiation and survival. Loss of Ndn in mice causes defects in the formation and function of the nervous system. Necdin is a member of the melanoma-associated antigen

  • Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-08
    Mythily Ganapathi,Loukas Argyriou,Francisco Martínez-Azorín,Susanne Morlot,Gökhan Yigit,Teresa M Lee,Bernd Auber,Alexander von Gise,Donald S Petrey,Holger Thiele,Lukas Cyganek,María Sabater-Molina,Priyanka Ahimaz,Juan Cabezas-Herrera,Moisés Sorlí-García,Arne Zibat,Markus D Siegelin,Peter Burfeind,Christie M Buchovecky,Gerd Hasenfuss,Barry Honig,Yun Li,Alejandro D Iglesias,Bernd Wollnik

    Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20–30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton

  • DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-05
    Maëva Elzaiat,Delphine Flatters,Diana Carolina Sierra-Díaz,Berangère Legois,Paul Laissue,Reiner A Veitia

    In humans, pathogenic variants in the DHH gene underlie cases of 46,XY gonadal dysgenesis. DHH is part of the Hedgehog family of proteins, which require extensive processing, including self-cleavage of the precursor for efficient signalling. In our work, we have assessed the effect of several human DHH pathogenic variants involved in recessive complete or partial gonadal dysgenesis, on protein processing

  • Rare variant association testing in the non-coding genome.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-04
    Ozvan Bocher,Emmanuelle Génin

    The development of next-generation sequencing technologies has opened-up some new possibilities to explore the contribution of genetic variants to human diseases and in particular that of rare variants. Statistical methods have been developed to test for association with rare variants that require the definition of testing units and, in these testing units, the selection of qualifying variants to include

  • Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-02
    Flavia Palombo,Claudio Graziano,Nadia Al Wardy,Nayereh Nouri,Caterina Marconi,Pamela Magini,Giulia Severi,Chiara La Morgia,Gaetano Cantalupo,Duccio Maria Cordelli,Simone Gangarossa,Mohammed Nasser Al Kindi,Mazin Al Khabouri,Mansoor Salehi,Elisa Giorgio,Alfredo Brusco,Francesco Pisani,Giovanni Romeo,Valerio Carelli,Tommaso Pippucci,Marco Seri

    Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless

  • The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications.
    Hum. Genet. (IF 5.743) Pub Date : 2020-06-02
    Takema Kato,Hidehito Inagaki,Syunsuke Miyai,Fumihiko Suzuki,Yuki Naru,Yasuko Shinkai,Asuka Kato,Kazuo Kanyama,Seiji Mizuno,Yukako Muramatsu,Toshiyuki Yamamoto,Mitsuhisa Shinya,Yukiko Tazaki,Sayuri Hiwatashi,Toshiro Ikeda,Mamoru Ozaki,Hiroki Kurahashi

    An inverted duplication with a terminal deletion (inv-dup-del) is one of the complex constitutional structural rearrangements that can occur in a chromosome. Although breakages of dicentric chromosome have been suggested, the precise mechanism of this is yet to be fully understood. In our present study, we investigated the genomic structure of 10 inv-dup-del cases to elucidate this mechanism. Two recurrent

  • The human genetic determinism of life-threatening infectious diseases: genetic heterogeneity and physiological homogeneity?
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-27
    Jean-Laurent Casanova,Laurent Abel

    Multicellular eukaryotes emerged late in evolution from an ocean of viruses, bacteria, archaea, and unicellular eukaryotes. These macroorganisms are exposed to and infected by a tremendous diversity of microorganisms. Those that are large enough can even be infected by multicellular fungi and parasites. Each interaction is unique, if only because it operates between two unique living organisms, in

  • Low-pass genome sequencing: a validated method in clinical cytogenetics.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-25
    Matthew Hoi Kin Chau,Huilin Wang,Yunli Lai,Yanyan Zhang,Fuben Xu,Yanqing Tang,Yanfang Wang,Zihan Chen,Tak Yeung Leung,Jacqueline Pui Wah Chung,Yvonne K Kwok,Shuk Ching Chong,Kwong Wai Choy,Yuanfang Zhu,Likuan Xiong,Weihong Wei,Zirui Dong

    Clinically significant copy-number variants (CNVs) known to cause human diseases are routinely detected by chromosomal microarray analysis (CMA). Recently, genome sequencing (GS) has been introduced for CNV analysis; however, sequencing depth (determined by sequencing read-length and read-amount) is a variable parameter across different laboratories. Variating sequencing depths affect the CNV detection

  • Correction to: Genetic algorithms identify individuals with high risk of severe liver disease caused by schistosomes.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-22
    Hélia Dessein,Nicolas Duflot,Audrey Romano,Christopher Opio,Valeria Pereira,Carla Mola,Narcis Kabaterene,Ana Coutinho,Alain Dessein

    In the original article publication, the affiliation of the author Ana Coutinho is incorrect.

  • ATP1A3 mutation as a candidate cause of autosomal dominant cone-rod dystrophy.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-21
    Gao-Hui Zhou,Yue Ma,Meng-Lan Li,Xin-Yi Zhou,Hao Mou,Zi-Bing Jin

    Cone-rod dystrophy (CORD) is an inherited retinal degenerative disease characterized by progressive loss of cone and rod photoreceptors. Although several genes have been reported to cause autosomal dominant CORD (adCORD), the genetic causes of adCORD have not been fully elucidated. Here, we identified the ATP1A3 gene, encoding the α3 subunit of Na+, K+-ATPase, as a novel gene associated with adCORD

  • Human genetic dissection of papillomavirus-driven diseases: new insight into their pathogenesis.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-20
    Vivien Béziat

    Human papillomaviruses (HPVs) infect mucosal or cutaneous stratified epithelia. There are 5 genera and more than 200 types of HPV, each with a specific tropism and virulence. HPV infections are typically asymptomatic or result in benign tumors, which may be disseminated or persistent in rare cases, but a few oncogenic HPVs can cause cancers. This review deals with the human genetic and immunological

  • De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-18
    Roser Ufartes,Hanna Berger,Katharina Till,Gabriela Salinas,Marc Sturm,Janine Altmüller,Peter Nürnberg,Holger Thiele,Rudolf Funke,Neophytos Apeshiotis,Hendrik Langen,Bernd Wollnik,Annette Borchers,Silke Pauli

    We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome

  • Autoantibodies against cytokines: phenocopies of primary immunodeficiencies?
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-17
    Chen-Lung Ku,Chih-Yu Chi,Horst von Bernuth,Rainer Doffinger

    Anti-cytokine autoantibodies may cause immunodeficiency and have been recently recognized as 'autoimmune phenocopies of primary immunodeficiencies' and are found in particular, but not exclusively in adult patients. By blocking the cytokine's biological function, patients with anti-cytokine autoantibodies may present with a similar clinical phenotype as the related inborn genetic disorders. So far

  • Minding the gap in HIV host genetics: opportunities and challenges.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-14
    Shanelle N Gingras,David Tang,Jeffrey Tuff,Paul J McLaren

    Genome-wide association studies (GWAS) have been successful in identifying and confirming novel genetic variants that are associated with diverse HIV phenotypes. However, these studies have predominantly focused on European cohorts. HLA molecules have been consistently associated with HIV outcomes, some of which have been found to be population specific, underscoring the need for diversity in GWAS

  • Identifying disease-causing mutations in genomes of single patients by computational approaches.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-13
    Cigdem Sevim Bayrak,Yuval Itan

    Over the last decade next generation sequencing (NGS) has been extensively used to identify new pathogenic mutations and genes causing rare genetic diseases. The efficient analyses of NGS data is not trivial and requires a technically and biologically rigorous pipeline that addresses data quality control, accurate variant filtration to minimize false positives and false negatives, and prioritization

  • Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-12
    Frederic Tran Mau-Them,Sebastien Moutton,Caroline Racine,Antonio Vitobello,Ange-Line Bruel,Sophie Nambot,Steven A Kushner,Femke M S de Vrij,Daphné Lehalle,Nolwenn Jean-Marçais,François Lecoquierre,Julian Delanne,Julien Thevenon,Charlotte Poe,Thibaut Jouan,Martin Chevarin,David Geneviève,Marjolaine Willems,Christine Coubes,Nada Houcinat,Alice Masurel-Paulet,Anne-Laure Mosca-Boidron,Emilie Tisserant

    Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate

  • Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM).
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-12
    Elena J Tucker,Rocio Rius,Sylvie Jaillard,Katrina Bell,Phillipa J Lamont,André Travessa,Juliette Dupont,Lurdes Sampaio,Jérôme Dulon,Sandrine Vuillaumier-Barrot,Sandra Whalen,Arnaud Isapof,Tanya Stojkovic,Susana Quijano-Roy,Gorjana Robevska,Jocelyn van den Bergen,Chloe Hanna,Andrea Simpson,Katie Ayers,David R Thorburn,John Christodoulou,Philippe Touraine,Andrew H Sinclair

    Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals

  • SZDB2.0: an updated comprehensive resource for schizophrenia research.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-08
    Yong Wu,Xiaoyan Li,Jiewei Liu,Xiong-Jian Luo,Yong-Gang Yao

    During the past decade, genetic studies of schizophrenia have become one of the most exciting and fast-moving areas. Hundreds of genes implicated in schizophrenia have been identified by genetic, epigenetic, and gene expression studies. However, how to systematically and efficiently use these published data to pinpoint the causal genes becomes a major challenge in schizophrenia research. Here, we release

  • A comparative analysis of genetic hearing loss phenotypes in European/American and Japanese populations.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-07
    W Daniel Walls,Hideaki Moteki,Taylor R Thomas,Shin-Ya Nishio,Hidekane Yoshimura,Yoichiro Iwasa,Kathy L Frees,Carla J Nishimura,Hela Azaiez,Kevin T Booth,Robert J Marini,Diana L Kolbe,A Monique Weaver,Amanda M Schaefer,Kai Wang,Terry A Braun,Shin-Ichi Usami,Peter G Barr-Gillespie,Guy P Richardson,Richard J Smith,Thomas L Casavant

    We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic

  • An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-04
    Hanan E Shamseldin,Ibrahim Al Mogarri,Mansour M Alqwaiee,Adel S Alharbi,Khaled Baqais,Muslim AlSaadi,Talal AlAnzi,Amal Alhashem,Afaf Saghier,Waleed Ameen,Niema Ibrahim,Jason Yang,Firdous Abdulwahab,Mais Hashem,Raghu R Chivukula,Fowzan S Alkuraya

    Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients

  • Correction to: Comprehensive functional annotation of susceptibility variants associated with asthma.
    Hum. Genet. (IF 5.743) Pub Date : 2020-05-04
    Yadu Gautam,Yashira Afanador,Sudhir Ghandikota,Tesfaye B Mersha

    In the original article published, the "p" value in the Fig. 5 legend is incorrectly presented as *p < 0.50. The correct p value is *p < 0.050.

  • Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects.
    Hum. Genet. (IF 5.743) Pub Date : 2020-04-30
    Tian Tian,Yunping Lei,Yongyan Chen,Menuka Karki,Lei Jin,Richard H Finnell,Linlin Wang,Aiguo Ren

    Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in

  • Ethnogeographic and inter-individual variability of human ABC transporters.
    Hum. Genet. (IF 5.743) Pub Date : 2020-03-23
    Qingyang Xiao,Yitian Zhou,Volker M Lauschke

    ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and

  • The pharmacological chaperone N-n-butyl-deoxygalactonojirimycin enhances β-galactosidase processing and activity in fibroblasts of a patient with infantile GM1-gangliosidosis.
    Hum. Genet. (IF 5.743) Pub Date : 2020-03-26
    Fedah E Mohamed,Mohammad Al Sorkhy,Mohammad A Ghattas,Lihadh Al-Gazali,Osama Al-Dirbashi,Fatma Al-Jasmi,Bassam R Ali

    GM1-gangliosidosis, a lysosomal storage disorder, is associated with ~ 161 missense variants in the GLB1 gene. Affected patients present with β-galactosidase (β-Gal) deficiency in lysosomes. Loss of function in ER-retained misfolded enzymes with missense variants is often due to subcellular mislocalization. Deoxygalactonojirimycin (DGJ) and its derivatives are pharmaceutical chaperones that directly

  • CNP deficiency causes severe hypomyelinating leukodystrophy in humans.
    Hum. Genet. (IF 5.743) Pub Date : 2020-03-03
    Lama Al-Abdi,Fathiya Al Murshedi,Alaa Elmanzalawy,Asila Al Habsi,Rana Helaby,Anuradha Ganesh,Niema Ibrahim,Nisha Patel,Fowzan S Alkuraya

    Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e.g., leukodystrophy, neurological disorders. CNP encodes a major component of myelin and its CNS expression is exclusive to myelin-forming oligodendrocytes. Deficiency of CNP in mouse causes a lethal white matter neurodegenerative phenotype. However, a corresponding human phenotype has not been described

  • Decoding a highly mixed Kazakh genome.
    Hum. Genet. (IF 5.743) Pub Date : 2020-02-19
    Madina Seidualy,Asta Blazyte,Sungwon Jeon,Youngjune Bhak,Yeonsu Jeon,Jungeun Kim,Anders Eriksson,Dan Bolser,Changhan Yoon,Andrea Manica,Semin Lee,Jong Bhak

    We provide a Kazakh whole genome sequence (MJS) and analyses with the largest comparative Kazakh genomic data available to date. We found 102,240 novel SNVs and a high level of heterozygosity. ADMIXTURE analysis confirmed a significant proportion of variations in this individual coming from all continents except Africa and Oceania. A principal component analysis showed neighboring Kalmyk, Uzbek, and

  • Determining the incidence of rare diseases.
    Hum. Genet. (IF 5.743) Pub Date : 2020-02-13
    Matthew N Bainbridge

    Extremely rare diseases are increasingly recognized due to wide-spread, inexpensive genomic sequencing. Understanding the incidence of rare disease is important for appreciating its health impact and allocating recourses for research. However, estimating incidence of rare disease is challenging because the individual contributory alleles are, themselves, extremely rare. We propose a new method to determine

  • Delineation of phenotypes and genotypes related to cohesin structural protein RAD21.
    Hum. Genet. (IF 5.743) Pub Date : 2020-03-19
    Lianne C Krab,Iñigo Marcos-Alcalde,Melissa Assaf,Meena Balasubramanian,Janne Bayer Andersen,Anne-Marie Bisgaard,David R Fitzpatrick,Sanna Gudmundsson,Sylvia A Huisman,Tugba Kalayci,Saskia M Maas,Francisco Martinez,Shane McKee,Leonie A Menke,Paul A Mulder,Oliver D Murch,Michael Parker,Juan Pie,Feliciano J Ramos,Claudine Rieubland,Jill A Rosenfeld Mokry,Emanuela Scarano,Marwan Shinawi,Paulino Gómez-Puertas

    RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7

  • A population-based approach for gene prioritization in understanding complex traits.
    Hum. Genet. (IF 5.743) Pub Date : 2020-03-30
    Massimo Mezzavilla,Massimiliano Cocca,Francesca Guidolin,Paolo Gasparini

    Gene prioritization is the process of determining which variants and genes identified in genetic analyses are likely to cause a disease or a variation in a phenotype. For many genes, neither in vitro nor in vivo testing is available, thus assessing their pathogenic role could be challenging, leading to false-positive or false-negative results. In this paper, we propose an innovative score of gene prioritization

  • A large population-based investigation into the genetics of susceptibility to gastrointestinal infections and the link between gastrointestinal infections and mental illness.
    Hum. Genet. (IF 5.743) Pub Date : 2020-03-09
    Ron Nudel,Vivek Appadurai,Andrew J Schork,Alfonso Buil,Jonas Bybjerg-Grauholm,Anders D Børglum,Mark J Daly,Ole Mors,David M Hougaard,Preben Bo Mortensen,Thomas Werge,Merete Nordentoft,Wesley K Thompson,Michael E Benros

    Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders

  • A genomics approach to females with infertility and recurrent pregnancy loss.
    Hum. Genet. (IF 5.743) Pub Date : 2020-03-14
    Sateesh Maddirevula,Khalid Awartani,Serdar Coskun,Latifa F AlNaim,Niema Ibrahim,Firdous Abdulwahab,Mais Hashem,Saad Alhassan,Fowzan S Alkuraya

    Infertility affects 10% of reproductive-age women and is extremely heterogeneous in etiology. The genetic contribution to female infertility is incompletely understood, and involves chromosomal and single-gene defects. Our aim in this study is to decipher single-gene causes in infertile women in whom endocrinological, anatomical, and chromosomal causes have been excluded. Our cohort comprises women

  • Genetic innovations and our understanding of stillbirth.
    Hum. Genet. (IF 5.743) Pub Date : 2020-04-21
    Louise Wilkins-Haug

    Stillbirth after 20 weeks gestation happens in 1 in 200 pregnancies and occurs more commonly than neonatal loss and sudden infant death syndrome (SIDs) combined. The stillbirth rate is several times greater in low as opposed to high-resource countries. However, among high-resource countries, although a lower overall stillbirth rate exists, there has been little change for several decades. Molecular

  • Evidence for craniofacial enhancer variation underlying nonsyndromic cleft lip and palate.
    Hum. Genet. (IF 5.743) Pub Date : 2020-04-21
    Vershanna E Morris,S Shahrukh Hashmi,Lisha Zhu,Lorena Maili,Christian Urbina,Steven Blackwell,Matthew R Greives,Edward P Buchanan,John B Mulliken,Susan H Blanton,W Jim Zheng,Jacqueline T Hecht,Ariadne Letra

    Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified

  • AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect.
    Hum. Genet. (IF 5.743) Pub Date : 2020-04-18
    Katharina M C Klee,Andreas R Janecke,Hasret A Civan,Štefan Rosipal,Peter Heinz-Erian,Lukas A Huber,Thomas Müller,Georg F Vogel

    Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular

  • Evolutionary and population (epi)genetics of immunity to infection.
    Hum. Genet. (IF 5.743) Pub Date : 2020-04-13
    Luis B Barreiro,Lluis Quintana-Murci

    Immune response is one of the functions that have been more strongly targeted by natural selection during human evolution. The evolutionary genetic dissection of the immune system has greatly helped to distinguish genes and functions that are essential, redundant or advantageous for human survival. It is also becoming increasingly clear that admixture between early Eurasians with now-extinct hominins

  • Human genetic basis of fulminant viral hepatitis.
    Hum. Genet. (IF 5.743) Pub Date : 2020-04-13
    Emmanuelle Jouanguy

    In rare cases, hepatitis A virus (HAV) and hepatitis B virus (HBV) can cause fulminant viral hepatitis (FVH), characterized by massive hepatocyte necrosis and an inflammatory infiltrate. Other viral etiologies of FVH are rarer. FVH is life-threatening, but the patients are typically otherwise healthy, and normally resistant to other microbes. Only a small minority of infected individuals develop FVH

  • Genetic algorithms identify individuals with high risk of severe liver disease caused by schistosomes.
    Hum. Genet. (IF 5.743) Pub Date : 2020-04-10
    Hélia Dessein,Nicolas Duflot,Audrey Romano,Christopher Opio,Valeria Pereira,Carla Mola,Narcis Kabaterene,Ana Coutinho,Alain Dessein

    Schistosomes induce severe hepatic disease, which is fatal in 2-10% of cases, mortality being higher in cases of co-infection with HBV or HCV. Hepatic disease occurs as a consequence of the chronic inflammation caused by schistosome eggs trapped in liver sinusoids. In certain individuals, the repair process leads to a massive accumulation of fibrosis in the periportal spaces. We and others have shown

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