Clinical Genetics最新文献

Bainbridge-Ropers Syndrome (BRPS) is a genetic condition resulting from truncating variants in the ASXL3 gene. The clinical features include neurodevelopmental and language impairments, behavioral issues, hypotonia, feeding difficulties, and distinctive facial features. In this retrospective study, we analyzed 22 Spanish individuals with BRPS, aiming to perform a detailed clinical and molecular description and establish a genotype-phenotype correlation. We identified 19 ASXL3 variants, nine of which are novel. We documented recurrence in nontwin siblings due to parental mosaicism. The predominant prenatal finding was intrauterine growth restriction (35%) followed, after birth, by feeding difficulties (90.5%), hypotonia (85.7%), and gastroesophageal reflux disease (82.4%). Later in life, intellectual disability, language impairment, autism spectrum disorder (75%), and joint laxity (73.7%) were noted. Individuals with variants in the 3' mutational cluster region (MCR) of exon 12 exhibited more perinatal feeding problems, and those with variants in the 5' MCR of exon 11 displayed lower percentiles in height and occipitofrontal circumference, as well as higher frequency of arched eyebrows. This study is the first characterization of a Spanish BRPS cohort, with more than 50 clinical features analyzed, representing the most detailed phenotypic analysis to date.

Intellectual and developmental disabilities (IDD) are clinically and genetically heterogeneous disorders of global concern. While whole exome sequencing (WES) is used to identify single nucleotide variants (SNVs) and small insertions/deletions (Indels) in IDD patients, its detection rate is limited. This study evaluated the value of integrating copy number variation (CNV) analysis into traditional SNV/Indel analysis based on trio-WES. One hundred eighty seven patients with IDD in 140 families from southwest China were incorporated into the study cohort. The overall diagnostic rate was 40.11% (75/187), with 33.16% (62/187) from SNV/Indel analysis and 6.95% (13/187) from CNV analysis. SNV/Indel analysis identified 52 variants in 42 genes, including 30 novel and 22 reported variants; CNV analysis identified 11 CNVs, comprising 1 repeat and 10 deletions, with sizes ranging from 1313 to 55 184 kb. 39.29% (55/140) families benefited from this study for their clinical diagnosis, treatment, and reproduction. Furthermore, our strategy, with an incremental cost-effectiveness ratio (ICER) of $2546.22/diagnosis, had demonstrated significant advantages in terms of cost-effectiveness and detection speed compared to previous methods. In general, by incorporating SNV/Indel and CNV analysis based on trio-WES, a robust, cost-effective, and time-saving approach for diagnosing IDD has been developed.

Focal facial dermal dysplasia (FFDD) type IV is a rare inherited facial defect caused by biallelic variants in CYP26C1. This study reports two novel Belgian FFDD type IV cases, both homozygous for a recurrent CYP26C1 frameshift variant, with a common 700 kb haplotype, indicating a founder effect.

Split-hand/foot malformation syndrome (SHFM) is a congenital limb malformation that is both clinically and genetically heterogeneous. Variants in WNT10B are known to cause an autosomal recessive form of SHFM. Here, we report a patient born to unrelated parents who was found to be a compound heterozygote for missense variants in WNT10B: c.994C>T, p.(Arg332Trp) and c.638T>G, p.(Phe213Cys). The variants were identified using long-read PacBio sequencing, which enabled phasing and confirmed that they were located on different alleles. The maternally inherited variant p.(Arg332Trp) has been previously reported, whereas the paternally inherited variant p.(Phe213Cys) is novel and absent from the gnomAD database. Our findings highlight the utility of long-read haplotype phasing, which provides valuable insights in determining the biallelic nature of variants in recessive disorders when parental DNA samples are unavailable.

In 2021, the Indian Undiagnosed Diseases Program was initiated for patients without a definite diagnosis despite extensive evaluation in four participating sites. Between February 2021 and March 2023, a total of 88 patients were recruited and underwent deep phenotyping. A uniform methodology for data re-analysis was implemented as the first step prior to conducting additional genomic testing. The largest cohort was of 38 patients with neurodevelopmental disorders (NDD). A genetic diagnosis was achieved in 24 of the 88 patients (27.2%), including 7 cases within the NDD cohort. Factors contributing to the increased diagnostic yield included: (a) identification of a novel disease association in DAAM2 gene, and (b) limitations of the standard analysis pipeline, particularly for synonymous variants in SELENOI and KIAA0753 genes, non-frameshift variant in GLRX5 gene, low-coverage variant in GJC2 gene, large deletions in PCNT and PHKG2 genes, and intronic variants in VPS33B and FBN1. Improved phenotyping led to a diagnosis in three cases, while genomic variants missed in the previous bioinformatics analysis were identified in 12 cases. The study also contributed to the development of enhanced bioinformatics scripts for variant prioritization and more refined literature search for novel disease associations. It highlights the importance of incorporating data reanalysis into clinical workflows before pursuing advanced diagnostic tests, particularly in resource-limited settings where healthcare expenses are often borne out of pocket.

The pathogenicity of cholestatic liver diseases (CLDs) remains insufficiently characterized, hindering definitive diagnosis and timely treatment. The aim of this study was to improve the pathogenicity prediction of novel bile acid (BA) transporter variants in patients with CLDs. We analyzed the clinical characteristics and genetic profiles of a CLD cohort (n = 57) using multiple in silico tools and in vitro functional assays. We identified 78 unique variants in four BA transporter genes. The predominant defects were associated with ABCC2 (57/78, 73.1%), with the most frequent being missense variants (39/78, 50.0%). Using in silico tools, we identified 47 novel variants: 12 mis-splicing, 21 deleterious missense, and 23 with altered protein stability. Of the 34 novel variants in ABCC2 identified through in vitro functional assays, seven incurred aberrant splicing, 11 missense variants resulted in MRP2 reduction, 9 missense variants resulted in abnormal N-glycosylation, 18 variants altered MRP2 localization, and 26 variants reduced organic anion transport activity. These findings indicate that a multidisciplinary approach, integrating bioinformatics and experimental data, significantly enhances the accuracy of genetic-based CLD diagnosis. It serves as a foundational study for BA transport variants pathogenicity reclassification and expands the mutation spectrum of CLDs in China.

Timeline and genetic analysis of a 55-year-old female with a family history of gastric cancer and multiple myeloma, who was diagnosed with AML and a germline CEBPA variant.

An increasing number of autosomal recessive forms of adenomatous polyposis have been described, but some in very few cases. Here, we describe a rare case of biallelic germline pathogenic variants in the MLH3 gene, implicating it as a potential cause of early colorectal cancer. The patient, a 47-year-old woman, presented with rectal bleeding, leading to the discovery of a malignant rectal tumor and adenomas during colonoscopy. Histopathological examination confirmed adenocarcinoma without microsatellite instability, and genetic testing identified two likely pathogenic frameshift variants in MLH3 located in trans. These findings contribute to the expanding knowledge of MLH3-related polyposis and colorectal cancer and underscore the need for further research into the gene's broader implications, including its potential role in cancer and infertility pathways.

Oligoasthenoteratozoospermia (OAT) is a frequent but severe type of male infertility. As one of the most multifaceted male infertility resulting from sperm problems, its genetic etiology remains unknown in most cases. In this review, we systematically sort out the latest literature on clinical reports and animal models leading to OAT, summarise the expression profiles of causative genes for OAT, and highlight the important role of the protein transport system during spermiogenesis, spermatid cell-specific genes, Golgi and acrosome-related genes, manchette-related genes, HTCA-related genes, and axoneme-related genes in OAT development. These causative genes would be instrumental in genetic etiological screening, genetic counseling, and pre-implantation genetic testing of patients with clinical OAT.

Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder associated with 1/3000 to 1/5000 live births. We report a consanguineous family with multiple affected members with AMC and identified a recessive mutation in the highly conserved splice donor site, resulting in the mis-splicing of the affected exons. SENP7 is a deSUMOylase that is critical for sarcomere assembly and skeletal muscle contraction by regulating the transcriptional program in the skeletal muscle. This is a reported case of an affected family with a noncoding, splice site SENP7 variant, expanding the spectrum of SENP7 as a causative gene in rare cases of lethal AMC.