A novel de novo QRICH1 variant causing Ververi-Brady syndrome with infantile epileptic spasms syndrome: clinical and genetic analysis.

OBJECTIVE

This study aims to investigate the clinical phenotype and genetic etiology of a case of Ververi-Brady syndrome (VBS) with infantile epileptic spasms syndrome (IESS) caused by a novel de novo variant in the QRICH1 gene.

METHODS

Clinical data were retrospectively collected from a pediatric patient admitted to Hunan Children's Hospital on July 28, 2025, due to intermittent nodding episodes for 10 days. Trio-based whole-exome sequencing (trio-WES) was performed for the proband and his parents. Candidate variants were validated by Sanger sequencing and assessed for pathogenicity. Relevant literature was reviewed to summarize genotype-phenotype correlations.

RESULTS

The patient, a 5-month-and-22-day-old male infant, presented with facial dysmorphism, global developmental delay, and IESS. After treatment with adrenocorticotropic hormone (ACTH) and vigabatrin, seizures were fully controlled and developmental outcomes improved. Trio-WES identified a novel heterozygous frameshift variant in the QRICH1 gene (NM_198880.3: c.1282dup, p. Gln428Profs*27), which was de novo and absent in both parents. According to the ACMG/AMP guidelines, this variant was classified as pathogenic (PVS1 + PS2 + PM2_Supporting). A literature review identified 11 relevant articles, encompassing a total of 46 patients (including the present case) with 41 distinct QRICH1 variants: 10 missense, 11 nonsense, 17 frameshift, and 3 splicing mutations. Common clinical features included developmental delay, nonspecific facial dysmorphism, hypotonia, autism spectrum disorder, epilepsy, and scoliosis.

CONCLUSION

QRICH1 variants underlie Ververi-Brady syndrome. Here we describe a patient with QRICH1-related Ververi-Brady syndrome presenting with IESS. Combined treatment with ACTH and vigabatrin was followed by seizure freedom, electroencephalographic (EEG) improvement, and developmental gains in this patient. This report expands the genotypic and phenotypic spectrum of the disorder.