The role of the gut microbiome in graft fibrosis after pediatric liver transplantation
AbstractLiver 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, however, to date, neither of the factors seems to fully explain the cause of graft fibrosis. Recently, evidence has accumulated on the important role of the gut microbiome in outcomes after solid organ transplantati...
Source: Human Genetics - September 13, 2020 Category: Genetics & Stem Cells Source Type: research

Resolving misalignment interference for NGS-based clinical diagnostics
AbstractNext-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 disease, and diagnostic labs must perform additional costly steps to guarantee accurate diagnosis in these cases. Here we report a new data analysis method based on the comparison of read depth between highly homolog...
Source: Human Genetics - September 11, 2020 Category: Genetics & Stem Cells Source Type: research

Severe DNM1 encephalopathy with dysmyelination due to recurrent splice site pathogenic variant
(Source: Human Genetics)
Source: Human Genetics - September 9, 2020 Category: Genetics & Stem Cells Source Type: research

Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population
This study enlarges the population ancestry diversity of available GWAS and elucidates new variants in an ethnic group burdened with metabolic disorders. (Source: Human Genetics)
Source: Human Genetics - September 9, 2020 Category: Genetics & Stem Cells Source Type: research

Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically significant secondary findings
AbstractGenomic 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 of comprehensive gene lists for five categories of SFs and filtration parameters for prioritization of variants in each category. We applied the pipeline to 42 exomes to assess feasibility and efficiency. Comprehensiv...
Source: Human Genetics - September 6, 2020 Category: Genetics & Stem Cells Source Type: research

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon
AbstractDent 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 theCLCN5 andOCRL genes are known to cause Dent disease, no such mutations are found in about 25 –35% of cases, making diagnosis more challenging. This review outlines current knowledge regarding Dent disease from another perspective. Startin...
Source: Human Genetics - August 29, 2020 Category: Genetics & Stem Cells Source Type: research

Gut microbiota in inflammatory bowel diseases: moving from basic science to clinical applications
AbstractIn 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 article, we discuss strategies to facilitate the transition from basic science on gut microbiota in IBD to clinical applications. We suggest that setting gold standards, improving and increasing the biobanking efforts, a...
Source: Human Genetics - August 28, 2020 Category: Genetics & Stem Cells Source Type: research

Special issue on “Feto-Maternal Genomic Medicine”: a decade of incredible advances
(Source: Human Genetics)
Source: Human Genetics - August 25, 2020 Category: Genetics & Stem Cells Source Type: research

Systematic identification of genetic systems associated with phenotypes in patients with rare genomic copy number variations
AbstractCopy 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 functional systems, in terms of GO categories and KEGG and Reactome pathways, based on patient data. The approach uses genomic and phenomic data from the same patients, finding shared genomic regions between patients ...
Source: Human Genetics - August 10, 2020 Category: Genetics & Stem Cells Source Type: research

The shared genetic architecture of schizophrenia, bipolar disorder and lifespan
AbstractPsychiatric 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 by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap &mdash...
Source: Human Genetics - August 9, 2020 Category: Genetics & Stem Cells Source Type: research

Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis
AbstractCystic 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 within a lipid membrane, and 20  ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of unce...
Source: Human Genetics - July 30, 2020 Category: Genetics & Stem Cells Source Type: research

Genetic evidence suggests a sense of family, parity and conquest in the Xiongnu Iron Age nomads of Mongolia
AbstractIn 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 using autosomal and Y-chromosomal DNA markers along with complete sequences of the mitochondrial genome. These analyses suggested close kin relationships between many individuals. Nineteen such individuals composed a ...
Source: Human Genetics - July 30, 2020 Category: Genetics & Stem Cells Source Type: research

Identifying adaptive alleles in the human genome: from selection mapping to functional validation
AbstractThe 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, scientists are able to map signatures of natural selection in the genome in a process known as selection mapping. Inferred selection signals further can be used to identify candidate functional alleles that unde...
Source: Human Genetics - July 29, 2020 Category: Genetics & Stem Cells Source Type: research

Deciphering the complexity of simple chromosomal insertions by genome sequencing
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 designated karyotypes in 75.0% (12/16) of the cases. Additional cryptic rearrangements were identif ied in 68.8% of the cases (11/16). The incidence of additional cryptic rearrangements in chromosomal insertions was significantly higher compared to balanced translocations and inversions reported in other studies by GS. We characterized and classified the cryptic insertion&nbs...
Source: Human Genetics - July 29, 2020 Category: Genetics & Stem Cells Source Type: research

Overview of PAX gene family: analysis of human tissue-specific variant expression and involvement in human disease
AbstractPaired-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 organ development throughout cell differentiation and lineage determination, and are essential for tissue structure and function through maintenance of cell identity. Mutations in PAX genes are associated wit...
Source: Human Genetics - July 29, 2020 Category: Genetics & Stem Cells Source Type: research

Disclosure of secondary findings in exome sequencing of 2480 Japanese cancer patients
AbstractHigh-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 for 2480 cancer patients. Genomic data were screened and classified for variants of 59 genes listed by the American College of Medical Genetics and Genomics SF v2.0 and for an additional 13 hereditary cancer-relat...
Source: Human Genetics - July 24, 2020 Category: Genetics & Stem Cells Source Type: research

Compound heterozygous mutation of the ASXL3 gene causes autosomal recessive congenital heart disease
AbstractTo 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 theASXL3 gene that was associated with CHD. Sanger sequencing of a further 122 CHD patients was used to determine an additional compound heterozygous mutation in theASXL3 gene. Cell apoptosis was examined by MTS assay and flow cytometry. The cardiac structure was identified via hematoxylin –eosin (HE), Masson’s trichrome, and ultrasound scanning. RNA sequencing was performed to identify ...
Source: Human Genetics - July 21, 2020 Category: Genetics & Stem Cells Source Type: research

Population genetics: past, present, and future
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. (Source: Human Genetics)
Source: Human Genetics - July 18, 2020 Category: Genetics & Stem Cells Source Type: research

A pooled genome-wide association study identifies pancreatic cancer susceptibility loci on chromosome 19p12 and 19p13.3 in the full-Jewish population
AbstractJews 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 e xamined resulting SNPs withP 
Source: Human Genetics - July 15, 2020 Category: Genetics & Stem Cells Source Type: research

A Southeast Asian origin for present-day non-African human Y chromosomes
AbstractThe 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 autos omal data is complicated due to subsequent population movements/reshaping. One locus, however, does retain male-specific information from this early period: the Y chromosome, where a detail...
Source: Human Genetics - July 14, 2020 Category: Genetics & Stem Cells Source Type: research

Disease gene discovery in male infertility: past, present and future
AbstractIdentifying 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. Technological advances and approaches in genomics are critical for the process of disease gene identification. In this review we highlight the impact of various technological developments on male infertility gene discover...
Source: Human Genetics - July 7, 2020 Category: Genetics & Stem Cells Source Type: research

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
AbstractWhole 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 points should be taken into consideration when validating WES-based assays using the GIAB reference in a diagnostic setting. We delineate specific factors that require special consideration and identify OMIM genes associ...
Source: Human Genetics - July 5, 2020 Category: Genetics & Stem Cells Source Type: research

The molecular genetic basis of atrial fibrillation
AbstractAs 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, especially genome-wide association studies, have emphasized the substantial genetic component of AF etiology. A comprehensive mapping of the genetic underpinnings for AF can expand our knowledge of AF mechanism and fu...
Source: Human Genetics - July 2, 2020 Category: Genetics & Stem Cells Source Type: research

Combi -CRISPR: combination of NHEJ and HDR provides efficient and precise plasmid-based knock-ins in mice and rats
In this study, we used a double-stranded DNA (dsDNA) donor template with Cas9 and two single guide RNAs, one designed to cut the targeted genome sequences and the other to cut both the flanked genomic region and one homology arm of the dsDNA plasmid, which resulted in 20 –33% KI efficiency among G0 pups. G0 KI mice carried NHEJ-dependent indel mutations at one targeting site that was designed at the intron region, and HDR-dependent precise KIs of the various donor cassettes spanning from 1 to 5 kbp, such asEGFP, mCherry, Cre, and genes of interest, at the other exon site. These findings indicate that this combinatori...
Source: Human Genetics - July 2, 2020 Category: Genetics & Stem Cells Source Type: research

The Human Gene Mutation Database (HGMD ® ): optimizing its use in a clinical diagnostic or research setting
AbstractThe 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 3100 peer-reviewed journals. There are primarily two main groups of users who utilise HGMD on a regular basis; research scientists and clinical diagnosticians. This review aims to highlight how to make the most ou...
Source: Human Genetics - June 28, 2020 Category: Genetics & Stem Cells Source Type: research

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
AbstractThe homeodomain transcription factors (TFs) Pax6 (OMIM: 607108) and Prox1 (OMIM: 601546) critically regulate gene expression in lens development. WhilePAX6 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 expression of these key TFs is essential for development. In lens development, Pax6 expression is elevated in cells of the anterior epithelium compared to fiber cells, while Prox1 exhibits the opposite pattern. Whether pos...
Source: Human Genetics - June 27, 2020 Category: Genetics & Stem Cells Source Type: research

Identification of novel genetic variants associated with short stature in a Baka Pygmies population
In conclusion, our results suggested that theHYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population. (Source: Human Genetics)
Source: Human Genetics - June 24, 2020 Category: Genetics & Stem Cells Source Type: research

Novel loss-of-function mutations in COCH cause autosomal recessive nonsyndromic hearing loss
This study confirms the involvement of loss-of-function mutations inCOCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing. (Source: Human Genetics)
Source: Human Genetics - June 19, 2020 Category: Genetics & Stem Cells Source Type: research

Complex chromosomal rearrangements of human chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome
In this study, microarray-based comparative genomic hybridization analysis identified complex rearrangements of chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Although the patient did not show up-slanting palpebral fissures and single transverse palmar creases, other symptoms were consistent with Down syn drome. Rearrangements were analyzed by whole-genome sequencing using Nanopore long-read sequencing. The analysis revealed that chromosome 21 was fragmented into seven segments and reassembled by six connected points. Among 12 breakpoints, 5 are located within the ...
Source: Human Genetics - June 13, 2020 Category: Genetics & Stem Cells Source Type: research

A novel variant in GPAA1 , encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes
AbstractVascular anomalies (VAs), comprising wide subtypes of tumors and malformations, are often caused by variants in multiple tyrosine kinase (TK) receptor signaling pathways includingTIE2,PIK3CA andGNAQ/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 overlapping phenotypes. Here, we identified one rare non-synonymous variant (c.968A  >  G) in the seventh exon ofGPAA1 (Glycosylphosphatidylinositol Anchor Attachment Protein 1), shared by the four affect...
Source: Human Genetics - June 12, 2020 Category: Genetics & Stem Cells Source Type: research

Study of telomere length in men who carry a fragile X premutation or full mutation allele
AbstractThe fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5 ′ UTR of theFMR1 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 disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are “biologically older”, as suggested by the associated ag...
Source: Human Genetics - June 12, 2020 Category: Genetics & Stem Cells Source Type: research

The necdin interactome: evaluating the effects of amino acid substitutions and cell stress using proximity-dependent biotinylation (BioID) and mass spectrometry
AbstractPrader –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 ofNdn in mice causes defects in the formation and function of the nervous system. Necdin is a member of the melanoma-associated antigen gene (MAGE) protein family. The functions of MAGE proteins depend highly on their interactions with other proteins, and in particular MAGE proteins interact with E3 ubiquitin ligases and deubiquitinases to form...
Source: Human Genetics - June 11, 2020 Category: Genetics & Stem Cells Source Type: research

Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis
In conclusion, we report that bi-allelic pathogenic variants inRPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies. (Source: Human Genetics)
Source: Human Genetics - June 8, 2020 Category: Genetics & Stem Cells Source Type: research

DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation
AbstractIn humans, pathogenic variants in theDHH 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 humanDHH pathogenic variants involved in recessive complete or partial gonadal dysgenesis, on protein processing and sub-cellular localization. We found that a subset of variants was unable to perform self-cleavage, which correlated albeit not perfectly with an altered subcellular localization of the resulting proteins. For the...
Source: Human Genetics - June 5, 2020 Category: Genetics & Stem Cells Source Type: research

Rare variant association testing in the non-coding genome
We describe the few studies that have considered variants from the non-coding genome in association tests and how they managed to define testing units and select qualifying variants. (Source: Human Genetics)
Source: Human Genetics - June 4, 2020 Category: Genetics & Stem Cells Source Type: research

Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East
AbstractAutozygosity-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, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with su...
Source: Human Genetics - June 2, 2020 Category: Genetics & Stem Cells Source Type: research

The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications
AbstractAn 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 8p inv-dup-del cases harbored a large copy-number-neutral region between the duplication and deletion in common. Although the other non-recurrent cases did not appear to have this copy-number-neutral region, refi...
Source: Human Genetics - June 2, 2020 Category: Genetics & Stem Cells Source Type: research

The human genetic determinism of life-threatening infectious diseases: genetic heterogeneity and physiological homogeneity?
Abstract 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 an infinite diversity of circumstances. This is neatly illustrated by the extraordinarily high level of interindividual clinical variability in human infections, even for a given pathogen, ranging from a total absence ...
Source: Human Genetics - May 27, 2020 Category: Genetics & Stem Cells Source Type: research

Low-pass genome sequencing: a validated method in clinical cytogenetics
In this study, by using data from 50 samples with high read-depth GS (30 ×) and the reported clinically significant CNVs, we first demonstrated the optimal read-amount and the most cost-effective read-length for CNV analysis to be 15 million reads and single-end 50 bp (equivalent to a read-depth of 0.25-fold), respectively. In addition, we showed that CNVs at mosaic le vels as low as 30% are readily detected, furthermore, CNVs larger than 2.5 Mb are also detectable at mosaic levels as low as 20%. Herein, by conducting a retrospective back-to-back comparison study of low-pass GS versus routine CMA for 5...
Source: Human Genetics - May 25, 2020 Category: Genetics & Stem Cells Source Type: research

Correction to: Genetic algorithms identify individuals with high risk of severe liver disease caused by schistosomes
In the original article publication, the affiliation of the author Ana  Coutinho is incorrect. (Source: Human Genetics)
Source: Human Genetics - May 22, 2020 Category: Genetics & Stem Cells Source Type: research

ATP1A3 mutation as a candidate cause of  autosomal dominant cone-rod dystrophy
AbstractCone-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 theATP1A3 gene, encoding the α3 subunit of Na+, K+-ATPase, as a novel gene associated with adCORD. Using whole-exome sequencing (WES), we found a candidate mutation ofATP1A3 that co-segregated with the disease in an analysis of two affected patients and one healthy relative in an adCORD family. According to our ...
Source: Human Genetics - May 21, 2020 Category: Genetics & Stem Cells Source Type: research

Human genetic dissection of papillomavirus-driven diseases: new insight into their pathogenesis
AbstractHuman 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 basis of interindividual clinical variability in the course of HPV infections of the skin and mucosae. Typical epidermodysplasia verruciformis (EV) is characterized by β-HPV-driven flat wart-like and pityriasis-lik...
Source: Human Genetics - May 20, 2020 Category: Genetics & Stem Cells Source Type: research

De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome
We report truncating de novo variants in specific exons ofFBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function ofFBRSL1 is largely unknown. Interestingly, mutations in theFBRSL1 paralogueAUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined humanFBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short ...
Source: Human Genetics - May 18, 2020 Category: Genetics & Stem Cells Source Type: research

Autoantibodies against cytokines: phenocopies of primary immunodeficiencies?
AbstractAnti-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 diso rders. So far, autoantibodies to interferon (IFN)-γ, GM-CSF, to a group of TH-17 cytokines and to IL-6 have been found to be causative or closely associated with susceptibility to infection. This review compare...
Source: Human Genetics - May 17, 2020 Category: Genetics & Stem Cells Source Type: research

Minding the gap in HIV host genetics: opportunities and challenges
AbstractGenome-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. Recently, there has been a concerted effort to address this gap that leads to health care (disease prevention, diagnosis, treatment) disparities with marginal improvement. As precision medicine becomes more utilized, non...
Source: Human Genetics - May 14, 2020 Category: Genetics & Stem Cells Source Type: research

Identifying disease-causing mutations in genomes of single patients by computational approaches
AbstractOver 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 of the remaining genes based on disease genomics and physiological knowledge. This review provides a pipeline including all these steps, describes popular software for each step of the analysis, and proposes a general f...
Source: Human Genetics - May 13, 2020 Category: Genetics & Stem Cells Source Type: research

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
AbstractDevelopmental 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 variant selection thanks to rapid parental segregation. We performed a second step trio-ES (not only focusing on genes involved in human disorders) analysis in 70 patients with negative results after solo-cES. All ca...
Source: Human Genetics - May 12, 2020 Category: Genetics & Stem Cells Source Type: research

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 )
This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such asTFAM, involved in mtDNA transcription, replication, and packaging, andGGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome. (Source: Human Genetics)
Source: Human Genetics - May 12, 2020 Category: Genetics & Stem Cells Source Type: research

SZDB2.0: an updated comprehensive resource for schizophrenia research
AbstractDuring 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 an updated version of a comprehensive database for schizophrenia research, SZDB2.0 (, which accompanies significant data expansion and feature improvements, as well as functionality optimization. Compa...
Source: Human Genetics - May 8, 2020 Category: Genetics & Stem Cells Source Type: research

A comparative analysis of genetic hearing loss phenotypes in European/American and Japanese populations
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 variants in one of three genes (KCNQ4,TECTA,WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in a...
Source: Human Genetics - May 7, 2020 Category: Genetics & Stem Cells Source Type: research