Genetic analysis of two novel variants in a Chinese pedigree affected with intellectual disorder

Objective: To explore the clinical phenotype and genetic characteristics of two siblings with intellectual disability.

Methods: Clinical data and peripheral blood samples were collected from the proband, his younger sister and parents whom had presented at Wenzhou Central Hospital in February 2024. Low-coverage massively parallel copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were carried out for the family. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was performed on a fetus upon the couple's subsequent pregnancy. The study was approved by the Medical Ethics Committee of Wenzhou Central Hospital (Ethic No. L2024-07-001).

Results: The proband was a 12-year-old boy who had presented with mental retardation and language delay. His 10-year-old sister also manifested delayed mental and motor development. Whole exome sequencing revealed that the proband and his sister had respectively harbored a novel heterozygous c.3549_3550del (p.Glu1183Aspfs*29) variant of the TRIP12 gene and a novel heterozygous c.99del (p.Ser34Alafs*38) variant of the GRIN2B gene. Sanger sequencing confirmed that both variants had a de novo origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PS2_Supporting+PM2_Supporting). Neither variant was found to be carried by the fetus upon prenatal diagnosis.

Conclusions: Above variants probably underlay the mental disorders in the two siblings, and the concurrent occurrence of two novel pathogenic variants in a family has been extremely rare.