Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders.
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ABSTRACT:
SUBMITTER: Oud MS
PROVIDER: S-EPMC8373475 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:STUDY QUESTION: What are the causative genetic variants in patients with male infertility due to severe sperm motility disorders?
SUMMARY ANSWER: We identified high confidence disease-causing variants in multiple genes previously associated with severe sperm motility disorders in 9 out of 21 patients (43%). We also identified variants in novel candidate genes in 8 additional patients (38%).
WHAT IS KNOWN ALREADY: Severe sperm motility disorders are a form of male infertility characterised by vital, but immotile sperm often in combination with a spectrum of structural abnormalities of the sperm flagellum. Examples of this spectrum of disorders include dysplasia of the fibrous sheath / multiple morphological abnormalities of the sperm flagella (DFS-MMAF) and severe forms of asthenozoospermia associated to non-specific structural defects. These disorders frequently recur in families and may include chronic respiratory disease. As such, genetic causes are suspected and many genes have recently been reported. Currently, depending on the clinical sub-categorisation, up to 50% of causality in patients with severe sperm motility disorders can be explained by pathogenic variants in at least 21 known genes.
STUDY DESIGN, SIZE, DURATION: We performed exome sequencing in patients with severe sperm motility disorders from two different clinics, aiming to identify the underlying genetic defects and establishing a diagnostic yield in both.
PARTICIPANTS/MATERIALS, SETTING, METHOD: Two groups of infertile men, one from Argentina (n= 9) and one from Australia (n=12), with clinically defined sperm motility disorders were included. All patients in the Argentine cohort were diagnosed with DFS-MMAF, based on transmission electron microscopy. Exome sequencing was performed in all 21 patients and variants with an allele frequency of <1% in the gnomAD population were prioritised and interpreted.
MAIN RESULTS AND ROLE OF CHANCE: In 9/21 patients (43%), we identified pathogenic variants in known sperm motility disorder genes: CFAP43 (3 patients); CFAP44 (2 patients), QRICH2 (2 patients), DNAH1 (1 patient) and DNAH6 (1 patient). The diagnostic rate did not differ markedly between the Argentinian and the Australian cohort (44% and 42%, respectively). Furthermore, we identified patients with variants in the novel candidate sperm motility genes CFAP58, DNAH12, DRC1, MDC1, PACRG, SSPL2C and TPTE2. One patient presented with two possibly damaging variants in four candidate genes and it remains unclear which variants were responsible for the severe sperm motility defect in this patient.
LIMITATIONS, REASONS FOR CAUTION: In this study, we described patients with potential bi-allelic variants in known and novel candidate genes for severe sperm motility disorders. Due to unavailability of parental DNA, we have not assessed de novo or maternally inherited dominant variants and could not phase the mutations to establish in all cases that the mutations occur on both alleles.
WIDER IMPLICATIONS OF THE FINDINGS: Our results confirm an important role for five known genes for sperm motility and we demonstrate that exome sequencing is an effective method to diagnose patients with severe sperm motility defects (9/21 diagnosed; 43%). Furthermore, our analysis revealed seven novel candidate genes for severe sperm motility disorders. Genome-wide sequencing of additional patient cohorts and re-analysis of exome data of currently unsolved cases may reveal additional variants in these novel candidate genes.
| EGAS00001005018 | EGA
Project description:We investigated hearing impairment (HI) in 51 families from Ghana with at least two affected members that were negative for GJB2 pathogenic variants. DNA samples from 184 family members underwent whole-exome sequencing (WES). Variants were found in 14 known non-syndromic HI (NSHI) genes [26/51 (51.0%) families], five genes that can underlie either syndromic HI or NSHI [13/51 (25.5%)], and one syndromic HI gene [1/51 (2.0%)]. Variants in CDH23 and MYO15A contributed the most to HI [31.4% (16/51 families)]. For DSPP, an autosomal recessive mode of inheritance was detected. Post-lingual expression was observed for a family segregating a MARVELD2 variant. To our knowledge, seven novel candidate HI genes were identified (13.7%), with six associated with NSHI (INPP4B, CCDC141, MYO19, DNAH11, POTEI, and SOX9); and one (PAX8) with Waardenburg syndrome. MYO19 and DNAH11 were replicated in unrelated Ghanaian probands. Six of the novel genes were expressed in mouse inner ear. It is known that Pax8-/- mice do not respond to sound, and depletion of Sox9 resulted in defective vestibular structures and abnormal utricle development. Most variants (48/60; 80.0%) have not previously been associated with HI. Identifying seven candidate genes in this study emphasizes the potential of novel HI genes discovery in Africa.
| S-EPMC9019055 | biostudies-literature
Project description:Vitiligo is an autoimmune complex pigmentation disease characterized by non-pigmented patches on the surface of the skin that affect approximately 0.5-2% population worldwide. The exact etiology is still unknown; however, vitiligo is hypothesized to be a multifactorial and genetically heterogeneous condition. Therefore, the current study is designed to investigate the anthropometric presentation and genetic spectrum of vitiligo in fifteen consanguineous Pakistani families. The clinical evaluation of participating individuals revealed varying degrees of disease severity, with 23 years as the average age of disease onset. The majority of the affected individuals had non-segmental vitiligo (NSV). Whole exome sequencing analysis revealed clustering of rare variants of known vitiligo-associated genes. For instance, in the affected individuals of family VF-12, we identified three novel rare variants of PTPN22 (c.1108C>A), NRROS (c.197C>T) and HERC2 (c.10969G>A) genes. All three variants replaced evolutionarily conserved amino acid residues in encoded proteins, which are predicted to impact the ionic interactions in the secondary structure. Although various in silico algorithms predicted low effect sizes for these variants individually, the clustering of them in affected individuals increases the polygenic burden of risk alleles. To our knowledge, this is the first study that highlights the complex etiology of vitiligo and genetic heterogeneity in multiplex consanguineous Pakistani families.
| S-EPMC10218579 | biostudies-literature
Project description:BACKGROUND:Deafness is a highly heterogenous disorder with over 100 genes known to underlie human non-syndromic hearing impairment. However, many more remain undiscovered, particularly those involved in the most common form of deafness: adult-onset progressive hearing loss. Despite several genome-wide association studies of adult hearing status, it remains unclear whether the genetic architecture of this common sensory loss consists of multiple rare variants each with large effect size or many common susceptibility variants each with small to medium effects. As next generation sequencing is now being utilised in clinical diagnosis, our aim was to explore the viability of diagnosing the genetic cause of hearing loss using whole exome sequencing in individual subjects as in a clinical setting. METHODS:We performed exome sequencing of thirty patients selected for distinct phenotypic sub-types from well-characterised cohorts of 1479 people with adult-onset hearing loss. RESULTS:Every individual carried predicted pathogenic variants in at least ten deafness-associated genes; similar findings were obtained from an analysis of the 1000 Genomes Project data unselected for hearing status. We have identified putative causal variants in known deafness genes and several novel candidate genes, including NEDD4 and NEFH that were mutated in multiple individuals. CONCLUSIONS:The high frequency of predicted-pathogenic variants detected in known deafness-associated genes was unexpected and has significant implications for current diagnostic sequencing in deafness. Our findings suggest that in a clinic setting, efforts should be made to a) confirm key sequence results by Sanger sequencing, b) assess segregations of variants and phenotypes within the family if at all possible, and c) use caution in applying current pathogenicity prediction algorithms for diagnostic purposes. We conclude that there may be a high number of pathogenic variants affecting hearing in the ageing population, including many in known deafness-associated genes. Our findings of frequent predicted-pathogenic variants in both our hearing-impaired sample and in the larger 1000 Genomes Project sample unselected for auditory function suggests that the reference population for interpreting variants for this very common disorder should be a population of people with good hearing for their age rather than an unselected population.
| S-EPMC6123954 | biostudies-literature
Project description:BackgroundPolycystic ovary syndrome (PCOS) is a complex genetic trait, the pathogenesis of which is governed by an interplay of genetic and epigenetic factors. However, the aetiology of PCOS is not fully understood.AimsThe objective of this study was to investigate the genetic causes of PCOS by identifying rare variants in genes implicated in its pathophysiology.Settings and designThis was a hospital-based observational study.Materials and methodsWe used whole-exome sequencing for 52 PCOS women to identify the rare variants in genes related to PCOS pathogenesis. Subsequently, we analysed these variants using in silico prediction software to determine their functional effects. We then assessed the relationship between these variants and the clinical outcomes of the patients.Statistical analysis usedStudent's t-test and Fisher's exact test were used to compare clinical parameters and frequency differences amongst PCOS patients with and without variants.ResultsA total of four rare exonic variants in obesity- and hyperinsulinaemia-related genes including UCP1 (p.Thr227Ile), UCP2 (p.Arg88Cys), IRS1 (p.Ser892Gly) and GHRL (p.Leu72Met) were identified in eight patients. Significant differences were observed between the patients carrying variants and those without variants. PCOS patients with identified variants exhibited significantly higher average body mass index and fasting insulin levels of PCOS subjects with identified variants compared to those without variants (P < 0.05). Additionally, there were significant differences in the variant frequencies of four variants when compared to the population database (P < 0.05).ConclusionThis study shows a prevalence of rare variants in obesity and hyperinsulinaemia-related genes in a cohort of PCOS women, thereby underscoring the impact of the identified rare variants on the development of obesity and associated metabolic derangements in PCOS women.
| S-EPMC10841935 | biostudies-literature
Project description:Triploidy is a relatively common cause of miscarriage; however, recurrent triploidy has rarely been reported. A healthy 34-year-old woman was ascertained because of 18 consecutive miscarriages with triploidy found in all 5 karyotyped losses. Molecular results in a sixth loss were also consistent with triploidy. Genotyping of markers near the centromere on multiple chromosomes suggested that all six triploid conceptuses occurred as a result of failure to complete meiosis II (MII). The proband's mother had also experienced recurrent miscarriage, with a total of 18 miscarriages. Based on the hypothesis that an inherited autosomal-dominant maternal predisposition would explain the phenotype, whole-exome sequencing of the proband and her parents was undertaken to identify potential candidate variants. After filtering for quality and rarity, potentially damaging variants shared between the proband and her mother were identified in 47 genes. Variants in genes coding for proteins implicated in oocyte maturation, oocyte activation or polar body extrusion were then prioritized. Eight of the most promising candidate variants were confirmed by Sanger sequencing. These included a novel change in the PLCD4 gene, and a rare variant in the OSBPL5 gene, which have been implicated in oocyte activation upon fertilization and completion of MII. Several variants in genes coding proteins playing a role in oocyte maturation and early embryonic development were also identified. The genes identified may be candidates for the study in other women experiencing recurrent triploidy or recurrent IVF failure.
| S-EPMC4381034 | biostudies-literature
Project description:BackgroundRetinitis pigmentosa (RP) is the most common form of inherited retinal degeneration, but genetic defects in nearly half of families remain unresolved. This study aims to identify novel genes associated with RP based on whole exome sequencing (WES) data from 552 probands with RP.MethodsBiallelic loss-of-function (LoF) variants were selected from the WES data of 552 probands with RP and compared with that of 4728 in-house controls and the gnomAD database. Expression analysis and knockout mice model or knockdown zebrafish model were performed to confirm the association of a few candidate genes with RP.FindingsUnique biallelic LoF variants in ENSA, DACT2, DDR1, and CCDC188 were identified in four probands with RP, but were absent in 4728 in-house controls and were extremely rare in the gnomAD database. The expression of ENSA was enriched in the rod outer segments of human retina, and significant reduced responses of rods and cones were detected in Ensa knockout mice compared to wild-type mice by electroretinogram. The DACT2 transcript showed the highest expression in human retina and knockdown of dact2 in zebrafish resulted in photoreceptor disc membrane disarrangement.InterpretationThis study suggests that ENSA is likely a novel gene for RP and DACT2 is a potentially candidate gene for RP. Further studies are expected to evaluate the association between mutations in the other two genes and RP. To our knowledge, mutations in these genes have not been reported to be associated with RP before.
| S-EPMC7248430 | biostudies-literature
Project description:High myopia [refractive error ≤ -6 diopters (D)] is a heterogeneous condition, and without clear accompanying features, it can be difficult to pinpoint a genetic cause. This observational study aimed to evaluate the utility of whole exome sequencing (WES) using an eye disorder gene panel in European patients with high myopia. Patients with high myopia were recruited by ophthalmologists and clinical geneticists. Clinical features were categorized into isolated high myopia, high myopia with other ocular involvement or with systemic involvement. WES was performed and an eye disorder gene panel of ~500 genes was evaluated. Hundred and thirteen patients with high myopia [mean (SD) refractive error - 11.8D (5.2)] were included. Of these, 53% were children younger than 12 years of age (53%), 13.3% were aged 12-18 years and 34% were adults (aged > 18 years). Twenty-three out of 113 patients (20%) received a genetic diagnosis of which 11 patients displayed additional ocular or systemic involvement. Pathogenic variants were identified in retinal dystrophy genes (e.g. GUCY2D and CACNA1F), connective tissue disease genes (e.g. COL18A1 and COL2A1), non-syndromic high myopia genes (ARR3), ocular development genes (e.g. PAX6) and other genes (ASPH and CNNM4). In 20% of our high myopic study population, WES using an eye gene panel enabled us to diagnose the genetic cause for this disorder. Eye genes known to cause retinal dystrophy, developmental or syndromic disorders can cause high myopia without apparent clinical features of other pathology.
| S-EPMC9523556 | biostudies-literature
Project description:Congenital scoliosis (CS) is a lateral curvature of the spine characterized by the presence of vertebral anomalies. Pathogenic genetic variants in the TBX6 gene are one of the causes of CS. However, since many clinically diagnosed cases of CS are without known TBX6 gene variations, this study aims to uncover new genes related to disease susceptibility of CS by exome sequencing (ES). This study employed ES in a cohort of 5 Japanese patients with CS and their healthy parents or a sister for a total of 16 samples among 5 families. Variant interpretation was performed using SIFT, PolyPhen-2, Mutation Taster, and CADD. Four de novo variants were identified by ES and confirmed by Sanger sequencing: 1 frameshift variant ( SHISA3 ) and 3 missense variants ( AGBL5 , HDAC4 , and PDE2A ). ES also uncovered 1 homozygous variant in the MOCOS gene. All of these variants were predicted to be deleterious by SIFT, PolyPhen-2, Mutation Taster, and/or CADD. The number of de novo variants identified in this study was exactly what would be expected by chance. Additional functional studies or gathering matched patients using Gene Matcher are needed.
| S-EPMC9578779 | biostudies-literature
Project description:BackgroundMitochondrial disorders are difficult to diagnose due to extreme genetic and phenotypic heterogeneities.MethodsWe explored the utility of targeted next-generation sequencing for the diagnosis of mitochondrial disorders in 148 patients submitted for clinical testing. A panel of 447 nuclear genes encoding mitochondrial respiratory chain complexes, and other genes inducing secondary mitochondrial dysfunction or that cause diseases which mimic mitochondrial disorders were tested.ResultsWe identified variants considered to be possibly disease-causing based on family segregation data and/or variants already known to cause disease in twelve genes in thirteen patients. Rare or novel variants of unknown significance were identified in 45 additional genes for various metabolic, genetic or neurogenetic disorders.ConclusionsPrimary mitochondrial defects were confirmed only in four patients indicating that majority of patients with suspected mitochondrial disorders are presumably not the result of direct impairment of energy production. Our results support that clinical and routine laboratory ascertainment for mitochondrial disorders are challenging due to significant overlapping non-specific clinical symptoms and lack of specific biomarkers. While next-generation sequencing shows promise for diagnosing suspected mitochondrial disorders, the challenges remain as the underlying genetic heterogeneity may be greater than suspected and it is further confounded by the similarity of symptoms with other conditions as we report here.
| S-EPMC3827825 | biostudies-literature