Identification of Novel HUWE1 Variants in Turner-Type X-Linked Intellectual Disability.
TL;DR
This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID and is of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.
Abstract
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.