Aug 2026· Clinica chimica acta; international journal of clinical chemistry· Vol 593, pp.
121279
· 0 citations· 11 references
Medicine
TL;DR
These findings expand the variant spectrum of COL5A2, improving molecular diagnosis of cEDS, and validate the pathogenicity of an unreported COL5A2 intronic variant in a Chinese family with cEDS.
Abstract
Background
Classical Ehlers-Danlos syndrome (cEDS), caused by pathogenic variants in COL5A2, is characterized by skin hyperextensibility, joint hypermobility and atrophic scarring. This study aimed to identify and validate the pathogenicity of an unreported COL5A2 intronic variant in a Chinese family with cEDS.
Methods
Trio-based whole exome sequencing (Trio-WES) was performed to screen for pathogenic variants, and the candidate variant was confirmed by Sanger sequencing. Minigene assays were then conducted to evaluate the functional consequences of key variants.
Results
A de novo COL5A2 (NM_000393.3) c.2499 + 4_2499 + 5insTAA variant was identified. Minigene assays demonstrated that this variant induced exon 37 skipping, resulting in an in-frame deletion. Based on ACMG guidelines, the variant was classified as pathogenic and considered the likely underlying etiology of cEDS in this family.
Conclusion
These findings expand the variant spectrum of COL5A2, improving molecular diagnosis of cEDS.
A previously unreported splice-site mutation in TACR3 that likely causes familial infertility by disrupting the neurokinin B/NK3R signaling pathway is identified and extended the mutational landscape of TACR3 and highlight its essential contribution to male reproductive endocrinology.
Mohammadreza Saberiyan, S. Kalantar, R. Mirfakhraie et al.· Reproductive Sciences· 0 citations
The co-occurrence of variants in AKAP4 and RNF220 may suggest an oligogenic etiology of NOA and contribute to the phenotypic variability associated with AKAP4 variants.
Razieh Ebrahimi Askari, A. Malcher, Fateme Sefid et al.· International Journal of Mol...· 0 citations
Background Autosomal dominant polycystic kidney disease (ADPKD) is most commonly caused by pathogenic variants in PKD1. Here, we reported the functional characterization of an intronic PKD1 variant identified in an ADPKD-affected family and its subsequent application in preimplantation genetic testing for monogenic disorders (PGT-M). Case presentation A three-generation ADPKD family was enrolled. Whole-exome sequencing revealed a heterozygous PKD1 c.7489 + 5G>A variant, which co-segregated with the disease and was initially classified as a variant of uncertain significance. A minigene assay demonstrated that the variant induced skipping of exon 18, leading to a frameshift (p.Arg2404Valfs*123), supporting its reclassification as pathogenic. The couple underwent PGT-M using trophectoderm biopsy, haplotype linkage analysis, and direct mutation detection. An unaffected pregnancy was achieved, and subsequent prenatal diagnosis confirmed the absence of the variant and a normal chromosomal karyotype. Conclusion We validated a pathogenic splicing variant in PKD1 and successfully applied PGT-M to prevent disease transmission, resulting in an unaffected pregnancy.
Qiong Pan, Yuefang Liu, Xueping Sun et al.· Frontiers in Genetics· 0 citations
A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.
Ying Zhao, Yi-Yang Fu, Shu-Ying Zhang et al.· Frontiers in Genetics· 0 citations
Background Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. Methods Candidate variants were identified and verified through trio whole‐exome sequencing (trio‐WES), copy number variation sequencing (CNV‐seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI‐C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype–phenotype spectrum was performed. Results Trio‐WES revealed a novel heterozygous variant in the C‐terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II‐2) and her foetus (III‐1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers–Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C‐terminal variants. Conclusions This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C‐terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.
Yujun Zhang, Huibing Liu, Ai-lan Yin et al.· Human Mutation· 0 citations
The identification of a pathogenic variant (PV) in one of the mismatch repair (MMR) genes confirms the diagnosis of Lynch syndrome (LS). Hence, the correct classification of MMR gene variants is of utmost importance for appropriate counselling, surveillance, and treatment of LS patients and their families. In 7/200 unrelated Tyrolean-suspected LS patients, we identified the rare variant MLH1:c.836T>G. Clinical and tumor data strongly indicate that this founder variant is associated with an increased risk for early-onset LS-associated tumors. We also demonstrate that the variant leads to aberrant mRNA splicing. However, the splice effect’s leakiness together with the small effect of the amino acid change p.(Val297Gly) encoded by the residual full-length transcripts in a functional assay preclude its formal classification as (likely) PV according to internationally accepted variant interpretation guidelines. The family histories of the carriers suggest that the obstacles to classify the variant as (likely) PV may be related with a reduced penetrance. Nonetheless, and despite the formal classification of MLH1:c.836T>G as a variant of uncertain significance, we show that carriers should undergo cancer surveillance and predictive testing should be offered to relatives. This variant illustrates the need for an improved classification framework for appropriate categorization of lower-penetrance alleles.
S. Horpaopan, E. Schamschula, H. Fiegl et al.· Biomolecules· 0 citations
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