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  • Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East
    Hum. Genet. (IF 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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 5.207) 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

  • Systematic microsatellite repeat expansion cloning and validation
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-10
    Kushal J. Rohilla, Katy N. Ovington, Adrian A. Pater, Maria Barton, Anthony J. Henke, Keith T. Gagnon

    Approximately 3% of the human genome is composed of short tandem repeat (STR) DNA sequence known as microsatellites, which can be found in both coding and non-coding regions. When associated with genic regions, expansion of microsatellite repeats beyond a critical threshold causes dozens of neurological repeat expansion disorders. To better understand the molecular pathology of repeat expansion disorders

  • CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-09
    Juan-Manuel Bonet-Fernández, José-Daniel Aroca-Aguilar, Marta Corton, Ana-Isabel Ramírez, Susana Alexandre-Moreno, María-Teresa García-Antón, Juan-José Salazar, Jesús-José Ferre-Fernández, Raquel Atienzar-Aroca, Cristina Villaverde, Ionut Iancu, Alejandra Tamayo, Carmen-Dora Méndez-Hernández, Laura Morales-Fernández, Blanca Rojas, Carmen Ayuso, Miguel Coca-Prados, José-Maria Martinez-de-la-Casa, Julián

    Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in

  • Joint modeling of eQTLs and parent-of-origin effects using an orthogonal framework with RNA-seq data
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-08
    Shirong Deng, James Hardin, Christopher I. Amos, Feifei Xiao

    Extensive studies have been conducted on the analysis of genome function, especially on the expression quantitative trait loci (eQTL). These studies offered promising results for characterization of the functional sequencing variation and understanding of the basic processes of gene regulation. Parent of origin effect (POE) is an important epigenetic phenomenon describing that the expression of certain

  • The place of metropolitan France in the European genomic landscape.
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-07
    Simone Andrea Biagini,Eva Ramos-Luis,David Comas,Francesc Calafell

    Unlike other European countries, the human population genetics and demographic history of Metropolitan France is surprisingly understudied. In this work, we combined newly genotyped samples from various zones in France with publicly available data and applied both allele frequency and haplotype-based methods to describe the internal structure of this country, using genome-wide single nucleotide polymorphism

  • Human genetics of Buruli ulcer.
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-07
    Jeremy Manry

    Buruli ulcer, the third most common mycobacterial disease worldwide, is caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions. Susceptibility to Buruli ulcer is thought to depend on host genetics, but very few genetic studies have been performed. The identification of a microdeletion on chromosome 8 in a familial form of severe Buruli ulcer suggested a monogenic

  • A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-07
    Cristina M Justice,Araceli Cuellar,Krithi Bala,Jeremy A Sabourin,Michael L Cunningham,Karen Crawford,Julie M Phipps,Yan Zhou,Deirdre Cilliers,Jo C Byren,David Johnson,Steven A Wall,Jenny E V Morton,Peter Noons,Elizabeth Sweeney,Astrid Weber,Katie E M Rees,Louise C Wilson,Emil Simeonov,Radka Kaneva,Nadezhda Yaneva,Kiril Georgiev,Assen Bussarsky,Craig Senders,Marike Zwienenberg,James Boggan,Tony Roscioli

    Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio

  • Structural variations in a non-coding region at 1q32.1 are responsible for the NYS7 locus in two large families
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-04
    Wenmin Sun, Shiqiang Li, Xiaoyun Jia, Panfeng Wang, J. Fielding Hejtmancik, Xueshan Xiao, Qingjiong Zhang

    Abstract Congenital motor nystagmus (CMN) is characterized by early-onset bilateral ocular oscillations without other ocular deficits. To date, mutations in only one gene have been identified to be responsible for CMN, i.e., FRMD7 for X-linked CMN. Four loci for autosomal dominant CMN, including NYS7 (OMIM 614826), have been mapped but the causative genes have yet to be identified. NYS7 was mapped

  • A framework for high-resolution phenotyping of candidate male infertility mutants: from human to mouse
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-04
    Brendan J. Houston, Donald F. Conrad, Moira K. O’Bryan

    Abstract Male infertility is a heterogeneous condition of largely unknown etiology that affects at least 7% of men worldwide. Classical genetic approaches and emerging next-generation sequencing studies support genetic variants as a frequent cause of male infertility. Meanwhile, the barriers to transmission of this disease mean that most individual genetic cases will be rare, but because of the large

  • ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-04
    Daniel F. Wallace, James S. Dooley

    Abstract Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of

  • Comprehensive functional annotation of susceptibility variants associated with asthma.
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-02
    Yadu Gautam,Yashira Afanador,Sudhir Ghandikota,Tesfaye B Mersha

    Genome-wide association studies (GWAS) have identified hundreds of primarily non-coding disease-susceptibility variants that further need functional interpretation to prioritize and discriminate the disease-relevant variants. We present a comprehensive genome-wide non-coding variant prioritization scheme followed by validation using Pyrosequencing and TaqMan assays in asthma. We implemented a composite

  • Two novel pleiotropic loci associated with osteoporosis and abdominal obesity.
    Hum. Genet. (IF 5.207) Pub Date : 2020-04-01
    Lu Liu,Xiao-Lin Yang,Hong Zhang,Zi-Jia Zhang,Xin-Tong Wei,Gui-Juan Feng,Ju Liu,Hui-Ping Peng,Rong Hai,Hui Shen,Qing Tian,Hong-Wen Deng,Yu-Fang Pei,Lei Zhang

    Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants

  • De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth.
    Hum. Genet. (IF 5.207) Pub Date : 2020-01-24
    Yu An,Linna Zhang,Wenwen Liu,Yunyun Jiang,Xue Chen,Xiaoping Lan,Gan Li,Qiang Hang,Jian Wang,James F Gusella,Yasong Du,Yiping Shen

    CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype-phenotype correlations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p

  • Optimized trio genome sequencing (OTGS) as a first-tier genetic test in critically ill infants: practice in China.
    Hum. Genet. (IF 5.207) Pub Date : 2020-01-21
    Huijun Wang,Yulan Lu,Xinran Dong,Guoping Lu,Guoqiang Cheng,Yanyan Qian,Qi Ni,Ping Zhang,Lin Yang,Bingbing Wu,Wenhao Zhou

    Genome sequencing is used to make genetic diagnoses in critically ill infants with rapid turnaround time (TAT). Herein, to delineate the value of a genetic diagnosis, we provide the results from 130 pediatric patients in a large, comprehensive children's hospital in China. This study was performed using an optimized trio genome sequencing (OTGS) test. The sequencing depth for patients was 40-50 × and

  • Concurrent hearing and genetic screening in a general newborn population.
    Hum. Genet. (IF 5.207) Pub Date : 2020-01-30
    Ling Guo,Jiale Xiang,Lei Sun,Xinyi Yan,Jingjing Yang,Haiyan Wu,Kejian Guo,Jiguang Peng,Xiaomei Xie,Ye Yin,Jian Wang,Huanming Yang,Jun Shen,Lijian Zhao,Zhiyu Peng

    Newborn hearing screening is not designed to detect delayed-onset prelingual hearing loss or aminoglycoside-antibiotic-induced ototoxicity. Cases with severe to profound hearing loss have been reported to have been missed by newborn hearing screens. The aim of this study was to evaluate the efficacy of concurrent hearing and genetic screening in the general population and demonstrate its benefits in

  • Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain.
    Hum. Genet. (IF 5.207) Pub Date : 2020-02-04
    Dazhi Zhang,Chao Yuan,Mengxue Liu,Xiaopei Zhou,Shunnan Ge,Xuelian Wang,Geng Luo,Meiqi Hou,Zhenxing Liu,Qing K Wang,Xu Wang,Haohong Li,Yang Tan,Weimin Jia,Jiarui Wang,Yanling Wu,Ali Wang,Xiaofei Yang,Xianqin Zhang

    Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that

  • Mosaic loss of human Y chromosome: what, how and why.
    Hum. Genet. (IF 5.207) Pub Date : 2020-02-04
    Xihan Guo,Xueqin Dai,Tao Zhou,Han Wang,Juan Ni,Jinglun Xue,Xu Wang

    Y chromosome (ChrY), the male-specific sex chromosome, has been considered as a genetic wasteland. Aging-related mosaic loss of ChrY (LOY) has been known for more than half a century, but it was constantly considered as a neutral karyotype related to normal aging. These views have been challenged with genome-wide association studies identifying mosaic LOY in human somatic cells is the most commonly

  • Comprehensive clinically oriented workflow for nucleotide level resolution and interpretation in prenatal diagnosis of de novo apparently balanced chromosomal translocations in their genomic landscape.
    Hum. Genet. (IF 5.207) Pub Date : 2020-02-06
    Dezső David,João P Freixo,Joana Fino,Inês Carvalho,Mariana Marques,Manuela Cardoso,Raul E Piña-Aguilar,Cynthia C Morton

    We present a comprehensive clinically oriented workflow for large-insert genome sequencing (liGS)-based nucleotide level resolution and interpretation of de novo (dn) apparently balanced chromosomal abnormalities (BCA) in prenatal diagnosis (PND). Retrospective or concomitant with conventional PND and liGS, molecular and newly developed clinically inspired bioinformatic tools (TAD-GConTool and CNV-ConTool)

  • A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis.
    Hum. Genet. (IF 5.207) Pub Date : 2020-01-24
    Pauline Arnaud,Caroline Racine,Nadine Hanna,Julien Thevenon,Jean-Luc Alessandri,Dominique Bonneau,Jill Clayton-Smith,Christine Coubes,Bruno Delobel,Sophie Dupuis-Girod,Laurent Gouya,Sylvie Odent,Virginie Carmignac,Christel Thauvin-Robinet,Carine Le Goff,Guillaume Jondeau,Catherine Boileau,Laurence Faivre

    SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course

  • Recessive mutations in SCYL2 cause a novel syndromic form of arthrogryposis in humans.
    Hum. Genet. (IF 5.207) Pub Date : 2020-01-20
    Mohammed Zain Seidahmed,Adila Al-Kindi,Hessa S Alsaif,Abeer Miqdad,Nasser Alabbad,Abdallah Alfifi,Omer Bashir Abdelbasit,Khalid Alhussein,Abdulmohsen Alsamadi,Niema Ibrahim,Amna Al-Futaisi,Almundher Al-Maawali,Fowzan S Alkuraya

    Arthrogryposis multiplex congenita (AMC) is an important birth defect with a significant genetic contribution. Many syndromic forms of AMC have been described, but remain unsolved at the molecular level. In this report, we describe a novel syndromic form of AMC in two multiplex consanguineous families from Saudi Arabia and Oman. The phenotype is highly consistent, and comprises neurogenic arthrogryposis

  • Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies.
    Hum. Genet. (IF 5.207) Pub Date : 2020-02-13
    Ivana Lessel,Mei-Jan Chen,Sabine Lüttgen,Florian Arndt,Sigrid Fuchs,Stefanie Meien,Holger Thiele,Julie R Jones,Brandon R Shaw,David K Crossman,Peter Nürnberg,Bruce R Korf,Christian Kubisch,Davor Lessel

    Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related

  • Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities.
    Hum. Genet. (IF 5.207) Pub Date : 2020-02-19
    Sheng Kang

    Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptors (LDLRs) family and accumulating evidence points to the critical role of LRP6 in cardiovascular health and homeostasis. In addition to presenting the well-appreciated roles in canonical signaling regulating blood pressure, blood glucose, lipid metabolism, atherosclerosis, cardiac valve disease

  • Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease
    Hum. Genet. (IF 5.207) Pub Date : 2020-03-21
    Biagio Cangiano, Du Soon Swee, Richard Quinton, Marco Bonomi

    Abstract A genetic basis of congenital isolated hypogonadotropic hypogonadism (CHH) can be defined in almost 50% of cases, albeit not necessarily the complete genetic basis. Next-generation sequencing (NGS) techniques have led to the discovery of a great number of loci, each of which has illuminated our understanding of human gonadotropin-releasing hormone (GnRH) neurons, either in respect of their

  • Genetic susceptibility to EBV infection: insights from inborn errors of immunity
    Hum. Genet. (IF 5.207) Pub Date : 2020-03-09
    Stuart G. Tangye

    Abstract Epstein–Barr virus (EBV) is a ubiquitous human pathogen, infecting > 90% of the adult population. In the vast majority of healthy individuals, infection with EBV runs a relatively benign course. However, EBV is by no means a benign pathogen. Indeed, apart from being associated with at least seven different types of malignancies, EBV infection can cause severe and often fatal diseases—hemophagocytic

  • Human genetics and malaria resistance
    Hum. Genet. (IF 5.207) Pub Date : 2020-03-04
    Silvia N. Kariuki, Thomas N. Williams

    Abstract Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure on the human genome yet described. Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects. Many individual variants

  • Human inborn errors of immunity underlying superficial or invasive candidiasis.
    Hum. Genet. (IF 5.207) Pub Date : 2020-03-02
    Anne Puel

    Candida species, including C. albicans in particular, can cause superficial or invasive disease, often in patients with known acquired immunodeficiencies or iatrogenic conditions. The molecular and cellular basis of these infections in patients with such risk factors remained largely elusive, until the study of inborn errors of immunity clarified the basis of the corresponding inherited and "idiopathic"

  • Genetic determinants of host immunity against human rhinovirus infections.
    Hum. Genet. Pub Date : 2020-02-29
    Ian T Lamborn,Helen C Su

    Human rhinoviruses (RV) are a frequent cause of respiratory tract infections with substantial morbidity and mortality in some patients. Nevertheless, the genetic basis of susceptibility to RV in humans has been relatively understudied. Experimental infections of mice and in vitro infections of human cells have indicated that various pathogen recognition receptors (TLRs, RIG-I, and MDA5) regulate innate

  • 更新日期:2020-02-27
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