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Meta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn’s disease Hum. Genet. (IF 5.743) Pub Date : 2021-01-16 Antonio Di Narzo, Itziar Frades, Heidi M. Crane, Paul K. Crane, Jean-Sebastian Hulot, Andrew Kasarskis, Amy Hart, Carmen Argmann, Marla Dubinsky, Inga Peter, Ke Hao
To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci
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RET compound inheritance in Chinese patients with Hirschsprung disease: lack of penetrance from insufficient gene dysfunction Hum. Genet. (IF 5.743) Pub Date : 2021-01-12 Qian Jiang, Yang Wang, Yang Gao, Hui Wang, Zhen Zhang, Qi Li, Shuhua Xu, Wei Cai, Long Li
Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of enteric ganglia along variable lengths of the intestine. Genetic defects play a major role in HSCR pathogenesis with nearly 50% of patients having a structural or regulatory deficiency in the major susceptibility gene RET. However, complete molecular defects remain poorly characterized in most patients. Here, we performed
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Alternative splicing in normal and pathological human placentas is correlated to genetic variants Hum. Genet. (IF 5.743) Pub Date : 2021-01-12 Camino S. M. Ruano, Clara Apicella, Sébastien Jacques, Géraldine Gascoin, Cassandra Gaspar, Francisco Miralles, Céline Méhats, Daniel Vaiman
Two major obstetric diseases, preeclampsia (PE), a pregnancy-induced endothelial dysfunction leading to hypertension and proteinuria, and intra-uterine growth-restriction (IUGR), a failure of the fetus to acquire its normal growth, are generally triggered by placental dysfunction. Many studies have evaluated gene expression deregulations in these diseases, but none has tackled systematically the role
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Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth Hum. Genet. (IF 5.743) Pub Date : 2021-01-08 Médéric Jeanne, Marie-Laure Vuillaume, Dévina C. Ung, Valerie E. Vancollie, Christel Wagner, Stephan C. Collins, Sandrine Vonwill, Damien Haye, Nora Chelloug, Rolph Pfundt, Joost Kummeling, Marie-Pierre Moizard, Sylviane Marouillat, Tjitske Kleefstra, Binnaz Yalcin, Frédéric Laumonnier, Annick Toutain
The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene
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A network-based machine-learning framework to identify both functional modules and disease genes Hum. Genet. (IF 5.743) Pub Date : 2021-01-07 Kuo Yang, Kezhi Lu, Yang Wu, Jian Yu, Baoyan Liu, Yi Zhao, Jianxin Chen, Xuezhong Zhou
Disease gene identification is a critical step towards uncovering the molecular mechanisms of diseases and systematically investigating complex disease phenotypes. Despite considerable efforts to develop powerful computing methods, candidate gene identification remains a severe challenge owing to the connectivity of an incomplete interactome network, which hampers the discovery of true novel candidate
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Loss of PIGK function causes severe infantile encephalopathy and extensive neuronal apoptosis Hum. Genet. (IF 5.743) Pub Date : 2021-01-04 Xin Chen, Wu Yin, Siyi Chen, Wenyu Zhang, Hongyan Li, Hanzhe Kuang, Miaojin Zhou, Yanling Teng, Junlong Zhang, Guodong Shen, Desheng Liang, Zhuo Li, Bing Hu, Lingqian Wu
PIGK gene, encoding a key component of glycosylphosphatidylinositol (GPI) transamidase, was recently reported to be associated with inherited GPI deficiency disorders (IGDs). However, little is known about the specific downstream effects of PIGK on neurodevelopment due to the rarity of the disease and the lack of in vivo study. Here, we described 2 patients in a Chinese family presented with profound
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5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation Hum. Genet. (IF 5.743) Pub Date : 2021-01-03 Fabiola Quintero-Rivera, Celeste C. Eno, Christine Sutanto, Kelly L. Jones, Małgorzata J. M. Nowaczyk, Derek Wong, Dawn Earl, Ghayda Mirzaa, Anita Beck, Julian A. Martinez-Agosto
Purpose Nuclear receptor binding SET domain protein 1, NSD1, encodes a histone methyltransferase H3K36. NSD1 is responsible for the phenotype of the reciprocal 5q35.2q35.3 microdeletion-microduplication syndromes. We expand the phenotype and demonstrate the functional role of NSD1 in microduplication 5q35 syndrome. Methods Through an international collaboration, we report nine new patients, contributing
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Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia Hum. Genet. (IF 5.743) Pub Date : 2021-01-03 Ting Guo, Chao-Feng Tu, Dan-Hui Yang, Shui-Zi Ding, Cheng Lei, Rong-Chun Wang, Lv Liu, Xi Kang, Xiao-Qing Shen, Yi-Feng Yang, Zhi-Ping Tan, Yue-Qiu Tan, Hong Luo
Genetics-associated asthenoteratozoospermia is often seen in patients with multiple morphological abnormalities of the sperm flagella (MMAF). Although 24 causative genes have been identified, these explain only approximately half of patients with MMAF. Since sperm flagella and motile cilia (especially respiratory cilia) have similar axonemal structures, many patients with MMAF also exhibit respiratory
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A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes Hum. Genet. (IF 5.743) Pub Date : 2021-01-02 Muhammad Ali, Shahid Y. Khan, Tony A. Rodrigues, Tânia Francisco, Xiaodong Jiao, Hang Qi, Firoz Kabir, Bushra Irum, Bushra Rauf, Asma A. Khan, Azra Mehmood, Muhammad Asif Naeem, Muhammad Zaman Assir, Muhammad Hassaan Ali, Mohsin Shahzad, Khaled K. Abu-Amero, Shehla Javed Akram, Javed Akram, Sheikh Riazuddin, Saima Riazuddin, Michael L. Robinson, Myriam Baes, Jorge E. Azevedo, J. Fielding Hejtmancik
Peroxisomes, single-membrane intracellular organelles, play an important role in various metabolic pathways. The translocation of proteins from the cytosol to peroxisomes depends on peroxisome import receptor proteins and defects in peroxisome transport result in a wide spectrum of peroxisomal disorders. Here, we report a large consanguineous family with autosomal recessive congenital cataracts and
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PIGF deficiency causes a phenotype overlapping with DOORS syndrome Hum. Genet. (IF 5.743) Pub Date : 2021-01-02 Smrithi Salian, Hind Benkerroum, Thi Tuyet Mai Nguyen, Sheela Nampoothiri, Taroh Kinoshita, Têmis Maria Félix, Fiona Stewart, Sanjay M. Sisodiya, Yoshiko Murakami, Philippe M. Campeau
DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM_173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry
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Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance Hum. Genet. (IF 5.743) Pub Date : 2020-12-31 Sara Hägg, Juulia Jylhävä, Yunzhang Wang, Kamila Czene, Felix Grassmann
Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from
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Correction to: Disruption of human meiotic telomere complex genes TERB1 , TERB2 and MAJIN in men with non-obstructive azoospermia Hum. Genet. (IF 5.743) Pub Date : 2020-12-30 Albert Salas-Huetos, Frank Tüttelmann, Margot J. Wyrwoll, Sabine Kliesch, Alexandra M. Lopes, João Gonçalves, Steven E. Boyden, Marius Wöste, James M. Hotaling, Liina Nagirnaja, Donald F. Conrad, Douglas T. Carrell, Kenneth I. Aston
In the original article published, the family name of the 6th author is published incorrectly.
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Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes Hum. Genet. (IF 5.743) Pub Date : 2020-12-18 Aldesia Provenzano, Andrea La Barbera, Mirko Scagnet, Angelica Pagliazzi, Giovanna Traficante, Marilena Pantaleo, Lucia Tiberi, Debora Vergani, Nehir Edibe Kurtas, Silvia Guarducci, Sara Bargiacchi, Giulia Forzano, Rosangela Artuso, Viviana Palazzo, Ada Kura, Flavio Giordano, Daniele di Feo, Marzia Mortilla, Claudio De Filippi, Gianluca Mattei, Livia Garavelli, Betti Giusti, Lorenzo Genitori, Orsetta
Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between
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Hybrid sequencing resolves two germline ultra-complex chromosomal rearrangements consisting of 137 breakpoint junctions in a single carrier Hum. Genet. (IF 5.743) Pub Date : 2020-12-14 Jesper Eisfeldt, Maria Pettersson, Anna Petri, Daniel Nilsson, Lars Feuk, Anna Lindstrand
Chromoanagenesis is a genomic event responsible for the formation of complex structural chromosomal rearrangements (CCRs). Germline chromoanagenesis is rare and the majority of reported cases are associated with an affected phenotype. Here, we report a healthy female carrying two de novo CCRs involving chromosomes 4, 19, 21 and X and chromosomes 7 and 11, respectively, with a total of 137 breakpoint
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The relationship between the gut microbiome and host gene expression: a review Hum. Genet. (IF 5.743) Pub Date : 2020-11-22 Robert G. Nichols, Emily R. Davenport
Despite the growing knowledge surrounding host–microbiome interactions, we are just beginning to understand how the gut microbiome influences—and is influenced by—host gene expression. Here, we review recent literature that intersects these two fields, summarizing themes across studies. Work in model organisms, human biopsies, and cell culture demonstrate that the gut microbiome is an important regulator
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Disruption of human meiotic telomere complex genes TERB1 , TERB2 and MAJIN in men with non-obstructive azoospermia Hum. Genet. (IF 5.743) Pub Date : 2020-11-19 Albert Salas-Huetos, Frank Tüttelmann, Margot J. Wyrwoll, Sabine Kliesch, Alexandra M. Lopes, João Conçalves, Steven E. Boyden, Marius Wöste, James M. Hotaling, Liina Nagirnaja, Donald F. Conrad, Douglas T. Carrell, Kenneth I. Aston
Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing
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The microbiome, genetics, and gastrointestinal neoplasms: the evolving field of molecular pathological epidemiology to analyze the tumor–immune–microbiome interaction Hum. Genet. (IF 5.743) Pub Date : 2020-11-12 Kosuke Mima, Keisuke Kosumi, Yoshifumi Baba, Tsuyoshi Hamada, Hideo Baba, Shuji Ogino
Metagenomic studies using next-generation sequencing technologies have revealed rich human intestinal microbiome, which likely influence host immunity and health conditions including cancer. Evidence indicates a biological link between altered microbiome and cancers in the digestive system. Escherichia coli and Bacteroides fragilis have been found to be enriched in colorectal mucosal tissues from patients
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Correction to: Shared genetic architecture between metabolic traits and Alzheimer’s disease: a large-scale genome-wide cross-trait analysis Hum. Genet. (IF 5.743) Pub Date : 2020-11-10 Zhaozhong Zhu, Yifei Lin, Xihao Li, Jane A. Driver, Liming Liang
Page 4: In the “Results-Genetic correlation between AD and metabolic traits” section, the sentence “We also observed that HDL had a significant genetic correlation with AD (Rg = -0.137, P = 0.0436)” should be “We also observed that HDL had a significant genetic correlation with AD (Rg = 0.322, P = 0.017)”.
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Systematic analysis to identify transcriptome-wide dysregulation of Alzheimer’s disease in genes and isoforms Hum. Genet. (IF 5.743) Pub Date : 2020-11-02 Cong Fan, Ken Chen, Jiaxin Zhou, Ping-pui Wong, Dan He, Yiqi Huang, Xin Wang, Tianze Ling, Yuedong Yang, Huiying Zhao
Alzheimer’s disease (AD) is one of the most common neurodegeneration diseases caused by multiple factors. The mechanistic insight of AD remains limited. To disclose molecular mechanisms of AD, many studies have been proposed from transcriptome analyses. However, no analysis across multiple levels of transcription has been conducted to discover co-expression networks of AD. We performed gene-level and
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Towards systematic nomenclature for cell-free DNA Hum. Genet. (IF 5.743) Pub Date : 2020-10-29 Abel J. Bronkhorst, Vida Ungerer, Frank Diehl, Philippe Anker, Yuval Dor, Michael Fleischhacker, Peter B. Gahan, Lisa Hui, Stefan Holdenrieder, Alain R. Thierry
Cell-free DNA (cfDNA) has become widely recognized as a promising candidate biomarker for minimally invasive characterization of various genomic disorders and other clinical scenarios. However, among the obstacles that currently challenge the general progression of the research field, there remains an unmet need for unambiguous universal cfDNA nomenclature. To address this shortcoming, we classify
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Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player Hum. Genet. (IF 5.743) Pub Date : 2020-10-27 Tristan Celse, Caroline Cazin, Flore Mietton, Guillaume Martinez, Delphine Martinez, Nicolas Thierry-Mieg, Amandine Septier, Catherine Guillemain, Julie Beurois, Antoine Clergeau, Selima Fourati Ben Mustapha, Mahmoud Kharouf, Abdelali Zoghmar, Ahmed Chargui, Aline Papaxanthos, Béatrice Dorphin, Bernard Foliguet, Chema Triki, Christophe Sifer, Dominique Lauton, Gérard Tachdjian, Gilles Schuler, Hervé
Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50–70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20–100% of globozoospermia. Genetic analyses including multiplex ligation-dependent
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A CRISPR and high-content imaging assay compliant with ACMG/AMP guidelines for clinical variant interpretation in ciliopathies Hum. Genet. (IF 5.743) Pub Date : 2020-10-23 Liliya Nazlamova, N. Simon Thomas, Man-Kim Cheung, Jelmer Legebeke, Jenny Lord, Reuben J. Pengelly, William J. Tapper, Gabrielle Wheway
Ciliopathies are a broad range of inherited developmental and degenerative diseases associated with structural or functional defects in motile or primary non-motile cilia. There are around 200 known ciliopathy disease genes and whilst genetic testing can provide an accurate diagnosis, 24–60% of ciliopathy patients who undergo genetic testing do not receive a genetic diagnosis. This is partly because
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Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy Hum. Genet. (IF 5.743) Pub Date : 2020-10-13 Ashfaque Ahmed, Meng Wang, Gaber Bergant, Reza Maroofian, Rongjuan Zhao, Majid Alfadhel, Marwan Nashabat, Muhammad Talal AlRifai, Wafaa Eyaid, Abdulrahman Alswaid, Christian Beetz, Yan Qin, Tengfei Zhu, Qi Tian, Lu Xia, Huidan Wu, Lu Shen, Shanshan Dong, Xinyi Yang, Cenying Liu, Linya Ma, Qiumeng Zhang, Rizwan Khan, Abid Ali Shah, Jifeng Guo, Beisha Tang, Lea Leonardis, Karin Writzl, Borut Peterlin
We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant
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Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality. Hum. Genet. (IF 5.743) Pub Date : 2020-09-21 Emmanuel O Adewuyi,Divya Mehta,Yadav Sapkota,,,Asa Auta,Kosuke Yoshihara,Mette Nyegaard,Lyn R Griffiths,Grant W Montgomery,Daniel I Chasman,Dale R Nyholt
Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect
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The role of the gut microbiome in graft fibrosis after pediatric liver transplantation. Hum. Genet. (IF 5.743) Pub Date : 2020-09-13 Tian Qin,Jingyuan Fu,Henkjan J Verkade
Liver transplantation (LT) is a life-saving option for children with end-stage liver disease. However, about 50% of patients develop graft fibrosis in 1 year after LT, with normal liver function. Graft fibrosis may progress to cirrhosis, resulting in graft dysfunction and ultimately the need for re-transplantation. Previous studies have identified various risk factors for the post-LT fibrogenesis,
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Resolving misalignment interference for NGS-based clinical diagnostics. Hum. Genet. (IF 5.743) Pub Date : 2020-09-11 Che-Yu Lee,Hai-Yun Yen,Alan W Zhong,Hanlin Gao
Next-generation sequencing (NGS) is an incredibly useful tool for genetic disease diagnosis. However, the most commonly used bioinformatics methods for analyzing sequence reads insufficiently discriminate genomic regions with extensive sequence identity, such as gene families and pseudogenes, complicating diagnostics. This problem has been recognized for specific genes, including many involved in human
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Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population. Hum. Genet. (IF 5.743) Pub Date : 2020-09-09 Prashantha Hebbar,Jehad Ahmed Abubaker,Mohamed Abu-Farha,Osama Alsmadi,Naser Elkum,Fadi Alkayal,Sumi Elsa John,Arshad Channanath,Rasheeba Iqbal,Janne Pitkaniemi,Jaakko Tuomilehto,Robert Sladek,Fahd Al-Mulla,Thangavel Alphonse Thanaraj
While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further
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Severe DNM1 encephalopathy with dysmyelination due to recurrent splice site pathogenic variant. Hum. Genet. (IF 5.743) Pub Date : 2020-09-09 Ahmed N Sahly,Eric Krochmalnek,Judith St-Onge,Myriam Srour,Kenneth A Myers
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Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically significant secondary findings. Hum. Genet. (IF 5.743) Pub Date : 2020-09-06 Emma Reble,Mariana Gutierrez Salazar,Kathleen-Rose Zakoor,Sam Khalouei,Marc Clausen,Rita Kodida,Salma Shickh,Chloe Mighton,Iris Cohn,Kasmintan A Schrader,Raymond H Kim,Jordan Lerner-Ellis,Yvonne Bombard
Genomic sequencing advances have increased the potential to identify secondary findings (SFs). Current guidelines recommend the analysis of 59 medically actionable genes; however, patient preferences indicate interest in learning a broader group of SFs. We aimed to develop an analytical pipeline for the efficient analysis and return of all clinically significant SFs. We developed a pipeline consisting
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Special issue on "Feto-Maternal Genomic Medicine": a decade of incredible advances. Hum. Genet. (IF 5.743) Pub Date : 2020-09-01 Kathryn J Gray,Louise Wilkins-Haug
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Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon. Hum. Genet. (IF 5.743) Pub Date : 2020-08-29 Lisa Gianesello,Dorella Del Prete,Franca Anglani,Lorenzo A Calò
Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same disorder, but it is now widely accepted that the triad of symptoms low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis are pathognomonic of Dent disease. Although mutations on the CLCN5 and OCRL genes are
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Gut microbiota in inflammatory bowel diseases: moving from basic science to clinical applications. Hum. Genet. (IF 5.743) Pub Date : 2020-08-28 Valerie Collij,Marjolein A Y Klaassen,Rinse K Weersma,Arnau Vich Vila
In recent years, large efforts have been made to unravel the role of the gut microbiota in inflammatory bowel disease (IBD), which is a chronic inflammatory disorder of the gastro-intestinal tract. Considering the heterogeneity patients with IBD display in their disease course and response to treatment, there is a big need in translating these findings towards clinical practise. In this perspective
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
更新日期:2020-06-05