Clinical Genetics最新文献

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.

The cover image is based on the article Utility of Optical Genome Mapping in Repeat Disorders by Mehmet Burak Mutlu et al., https://doi.org/10.1111/cge.14633.

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.

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.

Recent advances in next generation sequencing (NGS) have positioned whole exome sequencing (WES) as an efficient first-tier method in genetic diagnosis. However, despite the diagnostic yield of 35%-50% in intellectual disability (ID) many patients still remain undiagnosed due to inherent limitations and bioinformatic short-comings. In this study, we reanalyzed WES data from 159 Iranian families showing recessively inherited ID. The reanalysis was conducted with an initial clinical re-evaluation of the patients and their families, followed by data reanalysis using two updated bioinformatic pipelines. In the first phase, the BWA-GATK pipeline was utilized for alignment and variant calling, with subsequent variant annotation by the ANNOVAR tool. This approach yielded causative variants in 17 families (10.6%). Among these, six genes (MAZ, ACTR5, AKTIP, MIX23, SERPINB12, and CDC25B) were identified as novel candidates potentially associated with ID, supported by bioinformatics functional annotation and segregation analysis. In the second phase, families with negative results were reassessed using the Illumina DRAGEN Bio-IT platform for variant-calling, and Ilyome, a newly developed web-based tool, for annotation. The second phase identified likely pathogenic variants in two additional families, increasing the total diagnostic yield to 11.9% which is consistent with other studies conducted on cohorts of patients with ID. In conclusion, identification of co-segregating variants in six novel candidate genes in this study, emphasizes once more on the potential of WES reanalysis to uncover previously unknown gene-disease associations. Notably, it demonstrates that systematic reanalysis of WES data using updated bioinformatic tools and a thorough review of the literature for new gene-disease associations while performing phenotypic re-evaluation, can improve diagnostic outcome of WES in recessively inherited ID. Consequently, if performed within a 1-3 year period, it can reduce the number of cases that may require other costly diagnostic methods such as whole genome sequencing.