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.
OBJECTIVE
To characterize the clinical phenotypes and identify the genetic etiology in four unrelated families affected by Turner-type X-linked intellectual disability (XLID).
METHODS
Peripheral blood samples were collected from four probands and their parents. Genomic DNA was extracted, and a comprehensive genetic analysis was performed using trio-based Whole Exome Sequencing (WES) combined with low-pass Copy Number Variation sequencing (CNV-seq). Candidate variants were subsequently validated via Sanger sequencing.
RESULTS
Genetic analysis identified distinct variants in the HUWE1 across the four families. Specifically, a hemizygous c.10034A>T (p.Lys3345Met) variant was identified in the proband of Family 1; a heterozygous c.9209G>A (p.Arg3070His) variant in Family 2; a heterozygous c.12688T>C (p.Phe4230Leu) variant in Family 3; and a hemizygous c.9070G>A (p.Ala3024Thr) variant in Family 4. According to the ACMG guidelines, all four variants were classified as "Likely Pathogenic" based on the following criteria: PS2 + PM2_Supporting + PP2 + PP3. Notably, the c.10034A>T (p.Lys3345Met), c.12688T>C (p.Phe4230Leu), and c.9070G>A (p.Ala3024Thr) are novel variants that have not been previously reported. All probands were clinically diagnosed with Turner-type XLID.
CONCLUSIONS
This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID. These findings are of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.
Jingjing Zhang, Jing He, H. Pan et al.· European Journal of Medical...· 0 citations