Clinical Genetics最新文献

We identified an AMOTL1 variant in a patient that adds evidence supporting the clinical and molecular overlap between AMOTL1-related disorders and other syndromes affecting craniofacial, cardiac, and hepatic development. As more cases are identified, we propose naming this entity as AMOTL1-associated multiple congenital anomalies or craniofaciocardiohepatic syndrome (CFCHS).

The exponential growth of next-generation sequencing (NGS) data requires innovative bioinformatics approaches to unravel the genetic underpinnings of diseases. Hemiplegic migraine (HM), a debilitating neurological disorder with a genetic basis, is one such condition that warrants further investigation. Notably, the genetic heterogeneity of HM is underscored by the fact that approximately two-thirds of patients lack pathogenic variants in the known causal ion channel genes. In this context, we have developed PathVar, a novel bioinformatics algorithm that harnesses publicly available tools and software for pathogenic variant discovery in NGS data. PathVar integrates a suite of tools, including HaplotypeCaller from the Genome Analysis Toolkit (GATK) for variant calling, Variant Effect Predictor (VEP) and ANNOVAR for variant annotation, and TAPES for assigning the American College of Medical Genetics and Genomics (ACMG) pathogenicity labels. Applying PathVar to whole exome sequencing data from 184 HM patients, we detected 648 variants that are probably pathogenic in multiple patients. Moreover, we have identified several candidate genes for HM, many of which cluster around the Rho GTPases pathway. Future research can leverage PathVar to generate high quality, candidate pathogenic variants, which may enhance our understanding of HM and other complex diseases.

Rearrangements of the p-arm of Chromosome 8 can result in a spectrum of neurodevelopmental challenges, along with increased risk of epilepsy, structural brain and cardiac malformations, persisting developmental delays, and other health challenges. The majority of patients reported on in this sample are characterized by an inverted-duplication deletion rearrangement, but deletions, duplications, and mosaic ring changes in 8p result in similar phenotype. In this report, we add to the phenotypic and functional description of these patients according to their specific chromosomal rearrangement, share neuro-psychometric values, and propose surveillance care guidelines for caregivers and medical providers of patients with Chromosome 8p Syndromes. Observations from clinical experience with 24 patients seen at our 8p-dedicated Multi-Disciplinary Neurogenetics program are shared.

PTPRQ plays an important role in the development of inner ear hair cell stereocilia. While many autosomal recessive variants in PTPRQ have been identified as the pathogenic cause for nonsyndromic hearing loss (DFNB84A), so far only one autosomal dominant PTPRQ variant, c.6881G>A (p.Trp2294*), has been reported for late-onset, mild-to-severe hearing loss (DFNA73). By using targeted next-generation sequencing, this study identified a novel PTPRQ truncating pathogenic variant, c.3697del (p.Leu1233Phefs*11), from a Chinese Han family that co-segregated with autosomal dominant, postlingual, progressive hearing loss. A Ptprq-3700del knock-in mouse model was generated by CRISPR-Cas9 and characterized for its hearing function and inner ear morphology. While the homozygous knock-in mice exhibit profound hearing loss at all frequencies at the age of 3 weeks, the heterozygous mutant mice resemble the human patients in mild, progressive hearing loss from age 3 to 12 weeks, primarily affecting high frequencies. At this stage, the homozygous knock-in mice have a normal hair cell count but disorganized stereocilia. Cochlear proteosome analysis of the homozygous mutant mice revealed differentially expressed genes and pathways involved in oxidative phosphorylation, regulation of angiogenesis and synaptic vesicle cycling. Our study provides a valuable animal model for further functional studies of the pathogenic mechanisms underlying DFNA73.

Genomic repeat sequences are patterns of nucleic acids that exist in multiple copies throughout the genome. More than 60 Mendelian disorders are caused by the expansion or contraction of these repeats. Various specific methods for determining tandem repeat variations have been developed. However, these methods are highly specific to the genomic region being studied and sometimes require specialized tools. In this study, we have investigated the use of Optical Genome Mapping (OGM) as a diagnostic tool for detecting repeat disorders. We evaluated 19 patients with a prediagnosis of repeat disorders and explained the molecular etiology of 9 of them with OGM (5 patients with Facioscapulohumeral Muscular Dystrophy (FSHD), 2 patients with Friedreich's Ataxia (FA), 1 patient with Fragile X Syndrome (FXS), and 1 patient with Progressive Myoclonic Epilepsy 1A (EPM1A)). We confirmed OGM results with more widely used fragment analysis techniques. This study highlights the utility of OGM as a diagnostic tool for repeat expansion and contraction diseases such as FA, FXS, EPM1A, and FSHD.

Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The advent of next-generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL. After first excluding plausible variants in known deafness-causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL.

Empty follicle syndrome (EFS) is a disorder characterised by the unsuccessful retrieval of oocytes from matured follicles following ovarian stimulation for in vitro fertilisation (IVF). Genetic factors significantly contribute to this pathology. To date, an increasing number of genetic mutations associated with GEFS have been documented, however, some cases still remain unexplained by these previously reported mutations. Here, we identified a novel homozygous missense ZP1 variant (c.1096 C > T, p.Arg366Trp) in a female patient with GEFS from a consanguineous family who failed to retrieve any oocytes during two cycles of IVF treatment. We conducted a molecular dynamics simulation analysis on the mutant ZP1 model, revealing that the mutant ZP1 protein has an altered 3D structure, lower fluctuation, higher compactness and higher instability than wild-type ZP1. Immunostaining, immunoblotting and co-immunoprecipitation results showed that the homozygous missense mutation in ZP1 impaired protein secretion and weakened interactions between ZP1 and other ZP proteins, which may affect the ZP assembly. This study contributes to a more comprehensive understanding of the genetic aetiopathogenesis of GEFS.

Heterotaxy (HTX) is a group of clinical conditions with a shared pathology of dislocation of one or more organs along the left-right axis. The etiology of HTX is tremendously heterogeneous spanning environmental factors, chromosomal aberrations, mono/oligogenic variants, and complex inheritance. However, in the vast majority of cases, the etiology of HTX remains elusive. Here, we sought to describe the yield of genetic analysis and spectrum of variants in HTX in our highly consanguineous population. Twenty-four affected individuals, from 19 unrelated families, were consecutively recruited. Genetic analysis, with exome sequencing, genome sequencing, or multigene panel, detected 9 unique variants, 7 of which were novel, in 8 genes known to be implicated in autosomal recessive form of HTX (C1orf127, CCDC39, CIROP, DNAAF3, DNAH5, DNAH9, MMP21, and MNS1) providing a yield of 42.1%. Of note, 7 of the 9 variants were homozygous, while 2 were inherited in compound heterozygosity, including a heterozygous CNV deletion. A search for candidate genes in negative cases did not reveal a plausible variant. Our work demonstrates a relatively high yield of genetic testing in HTX in a consanguineous population with an enrichment of homozygous variants. The significant genetic heterogeneity observed herewith underscores the complex developmental mechanisms implicated in the pathogenesis of HTX and supports adopting a genome-wide analysis in the diagnostic evaluation of HTX.

Adult patients with undiagnosed genetic disorders suffer most from diagnostic delay and seldom appear in cohort studies investigating the diagnostic yield in medical genetic clinical practice. Here we present the results of the diagnostic activity performed in a referral center on 654 consecutive, unselected adult subjects presenting with molecularly unsolved conditions. More than 50% of the referred individuals were affected by syndromic or isolated intellectual disability. Different molecular approaches, including clinical/whole exome sequencing (CES/WES), chromosomal microarray analysis (CMA), and/or targeted gene or gene panel sequencing were used to analyze patients' DNA. Definitive diagnosis was obtained in over 30% of individuals. The most sensitive methodology was CES/WES, which allowed us to reach a diagnosis in over 50% of the 162 solved cases. Despite the great variety of clinical presentations, our results represent a reliable picture of the "real world" daily routine in an outpatient medical genetics clinic dedicated to diagnostic activity, and contribute to better understand the great value of a definitive molecular diagnosis in adults, either for the affected individuals and their families. This retrospective analysis demonstrates the importance of adopting a genomic-first approach within the diagnostic process for adults affected with unsolved rare conditions.

Variants in the SYNGAP1 gene leading to decreased SynGAP protein expression are critical for the pathogenesis of mental retardation type 5 (MRD5). This study aims to explore the relationship between SYNGAP1 genotype and clinical phenotype through an expanded sample size, thereby enhancing the understanding of the specific mechanisms underlying MRD5. Data from previously published cases of patients with SYNGAP1 mutations were collected, and the relationship between genotype and clinical phenotype was analyzed. A total of 246 MRD5 patients were included in the analysis. Among them, 98.7% (224/227) were diagnosed with intellectual disability (ID), 91.6% (208/227) with epilepsy, and 57.3% (137/239) with autism spectrum disorder (ASD). The clinical phenotypes of MRD5 patients were found to be associated with their genotypes. Variants located in exons 1 to 6 may correlate with milder ID and reduced risk of ASD, yet they are more likely to present as refractory epilepsy.