Recessive mutations in SCYL2 cause a novel syndromic form of arthrogryposis in humans
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, microcephaly, brain malformation (absent corpus callosum), optic atrophy, limb fractures, profound global developmental delay, and early lethality. Whole-exome sequencing revealed a different homozygous truncating variant inSCYL2 in each of the two families. SCYL2 is a component of clathrin-coated vesicles, and deficiency of its mouse ortholog results in a severe neurological phenotype that largely recapitulates the phenot...
Source: Human Genetics - January 20, 2020 Category: Genetics & Stem Cells Source Type: research

Monogenic causes of non-obstructive azoospermia: challenges, established knowledge, limitations and perspectives
AbstractIt is estimated that one in 100 men have azoospermia, the complete lack of sperm in the ejaculate. Currently,  ~ 20% of azoospermia cases remain idiopathic. Non-obstructive azoospermia (NOA) is mostly explained by congenital factors leading to spermatogenic failure, such as chromosome abnormalities. The knowledge of the monogenic causes of NOA is very limited. High genetic heterogeneity due to the compl exity of spermatogenesis and testicular function, lack of non-consanguineous familial cases and confirmatory studies challenge the field. The reported monogenic defects cause syndromic NOA phenotypes p...
Source: Human Genetics - January 18, 2020 Category: Genetics & Stem Cells Source Type: research

Evaluating genetic causes of azoospermia: What can we learn from a complex cellular structure and single-cell transcriptomics of the human testis?
AbstractAzoospermia is a condition defined as the absence of spermatozoa in the ejaculate, but the testicular phenotype of men with azoospermia may be very variable, ranging from full spermatogenesis, through arrested maturation of germ cells at different stages, to completely degenerated tissue with ghost tubules. Hence, information regarding the cell-type-specific expression patterns is needed to prioritise potential pathogenic variants that contribute to the pathogenesis of azoospermia. Thanks to technological advances within next-generation sequencing, it is now possible to obtain detailed cell-type-specific expression...
Source: Human Genetics - January 16, 2020 Category: Genetics & Stem Cells Source Type: research

The genetic architecture of morphological abnormalities of the sperm tail
AbstractSpermatozoa contain highly specialized structural features reflecting unique functions required for fertilization. Among them, the flagellum is a sperm-specific organelle required to generate the motility, which is essential to reach the egg. The flagellum integrity is, therefore, critical for normal sperm function and flagellum defects consistently lead to male infertility due to reduced or absent sperm motility defined as asthenozoospermia. Multiple morphological abnormalities of the flagella (MMAF), also called short tails, is among the most severe forms of sperm flagellum defects responsible for male infertilit...
Source: Human Genetics - January 16, 2020 Category: Genetics & Stem Cells Source Type: research

Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD
AbstractSevere asthenozoospermia is a common cause of male infertility. Recent studies have revealed thatSPEF2 mutations lead to multiple morphological abnormalities of the sperm flagella (MMAF) without primary ciliary dyskinesia (PCD) symptoms in males, but PCD phenotype was also found in one female individual. Therefore, whether there is a phenotypic continuum ranging from infertile patients with PCD to MMAF patients with no or low noise PCD manifestations remains elusive. Here, we performed whole-exome sequencing in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families. We identified four novel bi...
Source: Human Genetics - January 16, 2020 Category: Genetics & Stem Cells Source Type: research

Susceptibility to infection in early life: a growing role for human genetics
AbstractThe unique vulnerability to infection of newborns and young infants is generally explained by a constellation of differences between early-life immune responses and immune responses at later ages, often referred to as neonatal immune immaturity. This developmental view, corroborated by robust evidence, offers a plausible, population-level description of the pathogenesis of life-threatening infectious diseases during the early-life period, but provides little explanation on the wide inter-individual differences in susceptibility and resistance to specific infections during the first months of life. In this context, ...
Source: Human Genetics - January 13, 2020 Category: Genetics & Stem Cells Source Type: research

Exon skipping induced by nonsense/frameshift mutations in DMD gene results in Becker muscular dystrophy
This study aims to find BMD cases with nonsense/frameshift mutations inDMD and to investigate the exon skipping rate of those nonsense/frameshift mutations. We searched for BMD cases with nonsense/frameshift mutations inDMD in the Japanese Registry of Muscular Dystrophy. For eachDMD mutation identified, we constructed minigene plasmids containing one exon with/without a mutation and its flanking intronic sequence. We then introduced them into HeLa cells and measured the skipping rate of transcripts of the minigene by RT-qPCR. We found 363 cases with a nonsense/frameshift mutation inDMD gene from a total of 1497 dystrophino...
Source: Human Genetics - January 9, 2020 Category: Genetics & Stem Cells Source Type: research

Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene
AbstractFragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5 ′ UTR of theFMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (>  200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due toFMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels ofFMR1-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clari...
Source: Human Genetics - January 9, 2020 Category: Genetics & Stem Cells Source Type: research

Loss of chromatin structural integrity is a source of stress during aging
AbstractDysfunction and dysregulation at multiple levels, from organismal to molecular, are associated with the biological process of aging. In a eukaryotic nucleus, multiple lines of evidence have shown that the fundamental structure of chromatin is affected by aging. Not only euchromatic and heterochromatic regions shift locations, global changes, such as reduced levels of histones, have been reported for certain aged cell types and tissues. The physiological effects caused by such broad chromatin changes are complex and the cell ’s responses to it can be profound and in turn influence the aging process. In this re...
Source: Human Genetics - January 3, 2020 Category: Genetics & Stem Cells Source Type: research

The X chromosome and male infertility
AbstractThe X chromosome is a key player in germ cell development, as has been highlighted for males in previous studies revealing that the mammalian X chromosome is enriched in genes expressed in early spermatogenesis. In this review, we focus on the X chromosome ’s unique biology as associated with human male infertility. Male infertility is most commonly caused by spermatogenic defects to which X chromosome dosage is closely linked; for example, any supernumerary X chromosome as in Klinefelter syndrome will lead to male infertility. Furthermore, because males normally only have a single X chromosome and because X-...
Source: Human Genetics - December 24, 2019 Category: Genetics & Stem Cells Source Type: research

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse an cestry. (Source: Human Genetics)
Source: Human Genetics - December 17, 2019 Category: Genetics & Stem Cells Source Type: research

A powerful fine-mapping method for transcriptome-wide association studies
AbstractTranscriptome-wide association studies (TWAS) have been recently applied to successfully identify many novel genes associated with complex traits. While appealing, TWAS tend to identify multiple significant genes per locus, and many of them may not be causal due to confounding through linkage disequilibrium (LD) among SNPs. Here we introduce a powerful fine-mapping method that prioritizes putative causal genes by accounting for local LD. We apply a weighted adaptive test with eQTL-derived weights to maintain high power across various scenarios. Through simulations, we show that our new approach yielded a well-contr...
Source: Human Genetics - December 16, 2019 Category: Genetics & Stem Cells Source Type: research

Alternative splicing in aging and longevity
AbstractAlternative pre-mRNA splicing increases the complexity of the proteome that can be generated from the available genomic coding sequences. Dysregulation of the splicing process has been implicated in a vast repertoire of diseases. However, splicing has recently been linked to both the aging process itself and pro-longevity interventions. This review focuses on recent research towards defining RNA splicing as a new hallmark of aging. We highlight dysfunctional alternative splicing events that contribute to the aging phenotype across multiple species, along with recent efforts toward deciphering mechanistic roles for ...
Source: Human Genetics - December 13, 2019 Category: Genetics & Stem Cells Source Type: research

Identifying common genome-wide risk genes for major psychiatric traits
AbstractMajor psychiatric traits are genetically inter-correlated with one another, but it not well known which genes play pleiotropic effects across different traits. We curated and compared genes identified from large-scale genome-wide association studies for seven psychiatric traits, including depression, bipolar disorder, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety and neuroticism. We then explored biological functions of the top pleiotropic genes. A total of 243 cross-trait genes were identified for the seven traits. Except for autism spectrum disorder, there was signific...
Source: Human Genetics - December 7, 2019 Category: Genetics & Stem Cells Source Type: research

Regulatory genome variants in human susceptibility to infection
AbstractGenome studies have accelerated the discovery of common and rare genetic variants associated with susceptibility to infection and with disease severity. Genome-wide association studies identified many common genetic variants associated with modest risk for infection. Over 80% of these common variants map to the non-coding genome and are thought to modulate the regulatory networks. Exome sequencing has rapidly expanded the number of recognized primary immunodeficiencies through the identification of rare coding variants. In contrast, less than 29 primary immunodeficiencies have causative rare variation mapped outsid...
Source: Human Genetics - December 5, 2019 Category: Genetics & Stem Cells Source Type: research

Editors ’ Note to: EDAR, LYPLAL1, PRDM16, PAX3, DKK1, TNFSF12, CACNA2D3, and SUPT3H gene variants influence facial morphology in a Eurasian population
(Source: Human Genetics)
Source: Human Genetics - December 5, 2019 Category: Genetics & Stem Cells Source Type: research

MS/MS in silico subtraction-based proteomic profiling as an approach to facilitate disease gene discovery: application to lens development and cataract
AbstractWhile the bioinformatics resource-tool iSyTE (integrated Systems Tool for Eye gene discovery) effectively identifies human cataract-associated genes, it is currently based on just transcriptome data, and thus, it is necessary to include protein-level information to gain greater confidence in gene prioritization. Here, we expand iSyTE through development of a novel proteome-based resource on the lens and demonstrate its utility in cataract gene discovery. We applied high-throughput tandem mass spectrometry (MS/MS) to generate a global protein expression profile of mouse lens at embryonic day (E)14.5, which identifie...
Source: Human Genetics - December 3, 2019 Category: Genetics & Stem Cells Source Type: research

Copy number variation profiling in pharmacogenes using panel-based exome resequencing and correlation to human liver expression
AbstractStructural variants including copy number variations (CNV) have gained widespread attention, especially in pharmacogenomics but for several genes functional relevance and clinical evidence are still lacking. Detection of CNVs in next-generation sequencing data is challenging but offers widespread applications. We developed a cohort-based CNV detection workflow to extract CNVs from read counts of targeted NGS of 340 genes involved in absorption, distribution, metabolism and excretion (ADME) of drugs. We applied our method to 150 human liver tissue samples and correlated identified CNVs to mRNA expression levels. In ...
Source: Human Genetics - November 30, 2019 Category: Genetics & Stem Cells Source Type: research

Mx genes: host determinants controlling influenza virus infection and trans-species transmission
AbstractThe human MxA protein, encoded by the interferon-inducibleMX1 gene, is an intracellular influenza A virus (IAV) restriction factor. It can protect transgenic mice from severe IAV-induced disease, indicating a key role of human MxA for host survival and suggesting that natural variations inMX1 may account for inter-individual differences in disease severity among humans. MxA also provides a robust barrier against zoonotic transmissions of avian and swine IAV strains. Therefore, zoonotic IAV must acquire MxA escape mutations to achieve sustained human-to-human transmission. Here, we discuss recent progress in the fie...
Source: Human Genetics - November 26, 2019 Category: Genetics & Stem Cells Source Type: research

Fondness for sugars of enteric viruses confronts them with human glycans genetic diversity
AbstractTogether, norovirus and rotavirus are responsible for the majority of gastroenteritis cases worldwide, leading to a large number of deaths of children in low-income countries. Both attach to glycans of the histo-blood group antigen type (HBGAs) widely expressed in the digestive tract of vertebrates, albeit with interspecies differences. In humans, their synthesis is performed by glycosyltransferases encoded by the highly polymorphicABO,FUT2 andFUT3 genes that are under long-term balanced selection. The combination of functional and null or weak alleles at these loci provides a diversity of glycan structures that de...
Source: Human Genetics - November 23, 2019 Category: Genetics & Stem Cells Source Type: research

The current and future impact of genome-wide sequencing on fetal precision medicine
AbstractNext-generation sequencing and other genomic technologies are transforming prenatal and reproductive screening and testing for fetal genetic disorders at an unprecedented pace. Original approaches of screening and testing for fetal genetic and genomic disorders were focused on a few more prevalent conditions that were easily diagnosable with pre-genomic era diagnostic tools. First, chromosomal microarray analysis and then next-generation sequencing brought technology capable of more detailed genomic evaluation to prenatal genetic screening and diagnosis. This has facilitated parallel introduction of a variety of ne...
Source: Human Genetics - November 21, 2019 Category: Genetics & Stem Cells Source Type: research

Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD)
AbstractPelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, a...
Source: Human Genetics - November 20, 2019 Category: Genetics & Stem Cells Source Type: research

Exploring the interactions between the human and viral genomes
AbstractOver the last decade, genome-wide association studies led to major advances in identifying human genetic variants associated with infectious disease susceptibility. On the pathogen side, comparable methods are now applied to identify disease-modulating pathogen variants. As host and pathogen variants jointly determine disease outcomes, the most recent development has been to explore simultaneously host and pathogen genomes, through so-called genome-to-genome studies. In this review, we provide some background on the development of genome-to-genome analysis and we detail the first wave of studies in this emerging fi...
Source: Human Genetics - November 15, 2019 Category: Genetics & Stem Cells Source Type: research

Maternal genetic diseases: potential concerns for mother and baby
AbstractWith advances in medical care, many women with genetic conditions previously known to decrease life expectancy are reaching childbearing age. Thus, it is important to understand the management of patients in the preconception, antepartum, and postpartum periods as they pose a unique challenge to the obstetrician. Most rare disorders lack well-established clinical guidelines for management in pregnancy. Existing data stem from case reports, case series, and expert opinion. We aim to summarize these recommendations and develop a clinical reference for managing reproductive age women with these conditions. We review r...
Source: Human Genetics - November 15, 2019 Category: Genetics & Stem Cells Source Type: research

Genetic and epigenetic Muller ’s ratchet as a mechanism of frailty and morbidity during aging: a demographic genetic model
AbstractMutation accumulation has been proposed as a cause of senescence. During this process, age-related genetic and epigenetic mutations steadily accumulate. Cascading deleterious effects of mutations might initiate a steady “accumulation of deficits” in cells, despite the existence of repair mechanisms, leading to cellular senescence and functional decline of tissues and organs, which ultimately manifest as frailty and disease. Here, we investigate several of these aspects in differentiating cell populations throug h modeling and simulation using the Moran birth–death (demographic) process, under seve...
Source: Human Genetics - November 11, 2019 Category: Genetics & Stem Cells Source Type: research

Genetics of leprosy: today and beyond
AbstractLeprosy is a chronic infectious disease of the skin and peripheral nerves that presents a strong link with the host genetic background. Different approaches in genetic studies have been applied to leprosy and today leprosy is  among the infectious diseases with the greatest number of genetic risk variants identified. Several leprosy genes have been implicated in host immune response to pathogens and point to specific pathways that are relevant for host defense to infection. In addition, host genetic factors are also inv olved in the heterogeneity of leprosy clinical manifestations and in excessive inflammatory...
Source: Human Genetics - November 11, 2019 Category: Genetics & Stem Cells Source Type: research

Considerations for whole exome sequencing unique to prenatal care
AbstractWhole exome sequencing (WES) is increasingly being used in the prenatal setting. The emerging data support the clinical utility of prenatal WES based on its diagnostic yield, which can be as high as 80% for certain ultrasound findings. However, detailed practice and laboratory guidelines, addressing the indications for prenatal WES and the surrounding technical, interpretation, ethical, and counseling issues, are still lacking. Herein, we review the literature and summarize the most recent findings and applications of prenatal WES. This review offers specialists and clinical genetic laboratorians a body of evidence...
Source: Human Genetics - November 7, 2019 Category: Genetics & Stem Cells Source Type: research

High-throughput transcriptome analysis reveals that the loss of Pten activates a novel NKX6-1/RASGRP1 regulatory module to rescue microphthalmia caused by Fgfr2 -deficient lenses
AbstractFGFR signaling is critical to development and disease pathogenesis, initiating phosphorylation-driven signaling cascades, notably the RAS-RAF-MEK-ERK and PI3  K-AKT cascades. PTEN antagonizes FGFR signaling by reducing AKT and ERK activation. Mouse lenses lacking FGFR2 exhibit microphakia and reduced ERK and AKT phosphorylation, widespread apoptosis, and defective lens fiber cell differentiation. In contrast, simultaneous deletion of bothFgfr2 andPten restores ERK and AKT activation levels as well as lens size, cell survival and aspects of fiber cell differentiation; however, the molecular basis of this &ldquo...
Source: Human Genetics - November 5, 2019 Category: Genetics & Stem Cells Source Type: research

Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype
We describe two similar heterozygous CNV deletions involving theFOXF1 enhancer and re-analyzeFOXF1 missense mutation, all associated with an unexpectedly mitigated disease phenotype. In one case, the deletion of the maternal allele of theFOXF1 enhancer caused pulmonary hypertension and histopathologically diagnosed MPV without the typical ACD features. In the second case, the deletion of the paternal enhancer resulted in ACDMPV rather than the expected neonatal lethality. In both cases,FOXF1 expression in lung tissue was higher than usually seen or expected in patients with similar deletions, suggesting an increased activi...
Source: Human Genetics - November 4, 2019 Category: Genetics & Stem Cells Source Type: research

The genetic landscape of the human solute carrier (SLC) transporter superfamily
In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entireSLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and ...
Source: Human Genetics - November 2, 2019 Category: Genetics & Stem Cells Source Type: research

Mutational signatures and mutagenic impacts associated with betel quid chewing in oral squamous cell carcinoma
In conclusion, consistent with the proposition that BQ chewing increases OSCC risk as a mutagen, our results unveil a BQ-associated mutational signature and indicate mutagenic impacts of BQ chewing on preferentially eliciting INDELs and SV-related breakpoints in OSCC genomes. (Source: Human Genetics)
Source: Human Genetics - November 2, 2019 Category: Genetics & Stem Cells Source Type: research

Expanded carrier screening: counseling and considerations
AbstractThe primary goal of carrier screening is to identify asymptomatic individuals who carry variants associated with genetic diseases, to inform about the risk of having a child with a genetic disease. Carrier screening can be accomplished through different approaches including ethnicity-based screening, pan-ethnic screening, and expanded carrier screening (ECS), and the decision to pursue carrier screening is voluntary. ECS takes a broad approach by screening for a large number of genetic diseases irrespective of ethnic background, and ideally is performed prior to conception. ECS has many benefits, including that it ...
Source: Human Genetics - November 2, 2019 Category: Genetics & Stem Cells Source Type: research

Widespread sex dimorphism in aging and age-related diseases
AbstractAlthough aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic...
Source: Human Genetics - November 1, 2019 Category: Genetics & Stem Cells Source Type: research

A novel homozygous RTEL1 variant in a consanguineous Lebanese family: phenotypic heterogeneity and disease anticipation
AbstractPhenotypic heterogeneity is often observed in patients with telomeropathies caused by pathogenic variants in telomere biology genes. However, the roles of recessive variants in these different phenotypes are not fully characterized. Our goal is to describe the biological roles of a novel homozygousRTEL1 variant identified in a consanguineous Lebanese family with unusual presentation of telomeropathies. A proband was screened for germline variants in telomere biology genes by whole exome sequencing. Leukocytes ’ telomere length was measured in the proband and eight relatives. We identified a novel homozygous p...
Source: Human Genetics - November 1, 2019 Category: Genetics & Stem Cells Source Type: research

Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair
AbstractPyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linkedPDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 ofPDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly p...
Source: Human Genetics - October 31, 2019 Category: Genetics & Stem Cells Source Type: research

First genome-wide association study of non-severe malaria in two birth cohorts in Benin
AbstractRecent research efforts to identify genes involved in malaria susceptibility using genome-wide approaches have focused on severe malaria. Here, we present the first GWAS on non-severe malaria designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Our study was performed on two cohorts of infants from southern Benin (525 and 250 individuals used as discovery and replication cohorts, respectively) closely followed from birth to 18 –24 months of age, with an assessment of a space- and time-dependent environmental risk of exposure. Both the recurrence of mild malar...
Source: Human Genetics - October 30, 2019 Category: Genetics & Stem Cells Source Type: research

Special issue on ‘Genetic epidemiology of complex diseases: impact of population history and modelling assumptions’
(Source: Human Genetics)
Source: Human Genetics - October 29, 2019 Category: Genetics & Stem Cells Source Type: research

Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses
In conclusion, we provide novel insights regarding the molecular basis of ATTRm and ATTRwt based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated withTTR gene variation. (Source: Human Genetics)
Source: Human Genetics - October 29, 2019 Category: Genetics & Stem Cells Source Type: research

Arteriovenous malformation associated with a HRAS mutation
We report a somaticHRAS mutation in a patient who has a facial AVM associated with subcutaneous adipose overgrowth. We performed whole exome sequencing on DNA from the affected tissue and found aHRAS mutation (p.Thr58_Ala59delinsValLeuAspVal). Mutant allelic frequency was 5% in whole tissue and 31% in isolated endothelial cells (ECs); the mutation was not present in blood DNA or non-ECs. Somatic mutations inHRAS can cause AVM. (Source: Human Genetics)
Source: Human Genetics - October 21, 2019 Category: Genetics & Stem Cells Source Type: research

A different view on fine-scale population structure in Western African populations
AbstractDue to its long genetic evolutionary history, Africans exhibit more genetic variation than any other population in the world. Their genetic diversity further lends itself to subdivisions of Africans into groups of individuals with a genetic similarity of varying degrees of granularity. It remains challenging to detect fine-scale structure in a computationally efficient and meaningful way. In this paper, we present a proof-of-concept of a novel fine-scale population structure detection tool with Western African samples. These samples consist of 1396 individuals from 25 ethnic groups (two groups are African American ...
Source: Human Genetics - October 19, 2019 Category: Genetics & Stem Cells Source Type: research

Legacy samples in Finnish biobanks: social and legal issues related to the transfer of old sample collections into biobanks
AbstractBiobank operations started officially in Finland in 2013 when the Biobank Act defining and regulating biobank operations came into force. Since then, ten biobanks have been established and they have started to collect new prospective samples with broad consent. The main corpus of biobank samples, however, consists of approximately 10 million “legacy samples”. These are old diagnostic or research samples that were transferred to biobanks in accordance with the Biobank Act. The focus of this article is on ambiguities concerning these legacy samples and their transfer in terms of legality, human rights, au...
Source: Human Genetics - October 16, 2019 Category: Genetics & Stem Cells Source Type: research

Mutant GNLY is linked to Stevens –Johnson syndrome and toxic epidermal necrolysis
AbstractStevens –Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions to drugs. Granulysin (GNLY) plays a key role in keratinocyte apoptosis during SJS/TEN pathophysiology. To determine if GNLY-encoding mutations might be related to the protein’s functional dis turbances, contributing to SJS/TEN pathogenesis, we performed direct sequencing of GNLY’s coding region in a group of 19 Colombian SJS/TEN patients. AGNLY genetic screening was implemented in a group of 249 healthy individuals. We identified the c.11G  >  A heterozygous sequence va...
Source: Human Genetics - October 14, 2019 Category: Genetics & Stem Cells Source Type: research

CRISPR/Cas9 facilitates genomic editing for large-scale functional studies in pluripotent stem cell cultures
AbstractPluripotent stem cell (PSC) cultures form an integral part of biomedical and medical research due to their capacity to rapidly proliferate and differentiate into hundreds of highly specialized cell types. This makes them a highly useful tool in exploring human physiology and disease. Genomic editing of PSC cultures is an essential method of attaining answers to basic physiological functions, developing in vitro models of human disease, and exploring potential therapeutic strategies and the identification of drug targets. Achieving reliable and efficient genomic editing is an important aspect of using large-scale PS...
Source: Human Genetics - October 12, 2019 Category: Genetics & Stem Cells Source Type: research

Characterization of GJB2 cis -regulatory elements in the DFNB1 locus
AbstractAlthough most disease-causing variants are within coding region of genes, it is now well established thatcis-acting regulatory sequences, depending on 3D-chromatin organization, are required for temporal and spatial control of gene expression. Disruptions of such regulatory elements and/or chromatin conformation are likely to play a critical role in human genetic disease. Hence, recurrent monoallelic cases, who present the most common hereditary type of nonsyndromic hearing loss (i.e.,DFNB1), carry only one identified pathogenic allele. This strongly suggests the presence of uncharacterized distalcis-acting element...
Source: Human Genetics - October 4, 2019 Category: Genetics & Stem Cells Source Type: research

Biallelic variants in AGMO with diminished enzyme activity are associated with a neurodevelopmental disorder
In this study, we identified rare nonsense, in frame deletion, and missense biallelic variants inAGMO in two unrelated individuals with neurodevelopmental disabilities. We assessed the activity of seven disease associatedAGMO variants including the four variants identified in our two affected individuals expressed in human embryonic kidney (HEK293T) cells. We demonstrated significantly diminished enzyme activity for all disease-associated variants, supporting the mechanism as decreased AGMO activity. Future mechanistic studies are necessary to understand how decreased AGMO activity leads to the neurologic manifestations. (...
Source: Human Genetics - September 25, 2019 Category: Genetics & Stem Cells Source Type: research

The significance of the placental genome and methylome in fetal and maternal health
AbstractThe placenta is a crucial organ for supporting a healthy pregnancy, and defective development or function of the placenta is implicated in a number of complications of pregnancy that affect both maternal and fetal health, including maternal preeclampsia, fetal growth restriction, and spontaneous preterm birth. In this review, we highlight the role of the placental genome in mediating fetal and maternal health by discussing the impact of a variety of genetic alterations, from large whole-chromosome aneuploidies to single-nucleotide variants, on placental development and function. We also discuss the placental methyl...
Source: Human Genetics - September 25, 2019 Category: Genetics & Stem Cells Source Type: research

Noninvasive prenatal testing: from aneuploidy to single genes
AbstractNoninvasive prenatal testing has undergone rapid advances in the last few years. Although researchers have long known about circulating pregnancy-based cell-free fragments of DNA in maternal plasma, it was the introduction of massively parallel sequencing that allowed noninvasive prenatal testing to become a widely used clinical test. This review will begin with an in-depth analysis of the use of noninvasive prenatal testing for aneuploidy, including common causes for inaccurate and/or discordant results. It will also review the ongoing expansion of noninvasive prenatal testing to include copy number variants and s...
Source: Human Genetics - September 25, 2019 Category: Genetics & Stem Cells Source Type: research

MDH1 deficiency is a metabolic disorder of the malate –aspartate shuttle associated with early onset severe encephalopathy
In conclusion, MDH1 deficiency is a new metabolic defect in the malate –aspartate shuttle characterized by a severe neurodevelopmental phenotype with elevated concentrations of glycerol-3-phosphate as a potential biomarker. (Source: Human Genetics)
Source: Human Genetics - September 19, 2019 Category: Genetics & Stem Cells Source Type: research

Long-read sequencing in deciphering human genetics to a greater depth
AbstractThrough four decades ’ development, DNA sequencing has inched into the era of single-molecule sequencing (SMS), or the third-generation sequencing (TGS), as represented by two distinct technical approaches developed independently by Pacific Bioscience (PacBio) and Oxford Nanopore Technologies (ONT). Historically, each generation of sequencing technologies was marked by innovative technological achievements and novel applications. Long reads (LRs) are considered as the most advantageous feature of SMS shared by both PacBio and ONT to distinguish SMS from next-generation sequencing (NGS, or the second-generatio...
Source: Human Genetics - September 19, 2019 Category: Genetics & Stem Cells Source Type: research

Rare variants in FANCA induce premature ovarian insufficiency
AbstractPremature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40  years of age. Recent advances emphasize the genetic heterogeneity of POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair and cytogenetic instability, have been demonstrated to be involved in meiosis and germ cell development. Here, we conducted whole-exome s equencing (WES) in 50 Han Chinese female patients with POI. Rare missense variants were identified inFANCA (Fanconi anemia complementation group A): c.1772G  >  A (p.R591Q) ...
Source: Human Genetics - September 18, 2019 Category: Genetics & Stem Cells Source Type: research