QRICH1 encodes the glutamine-rich protein 1, which contains one caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. However, the function of the QRICH1 gene was largely unknown. Recently, several studies have reported de novo variants in QRICH1, and the variants have been associated with Ververi-Brady syndrome characterized by developmental delay, nonspecific facial dysmorphism, and hypotonia.
Whole exome sequencing, clinical examinations, and functional experiments were performed to identify the etiology of our patient.
Here, we added another patient with severe growth retardation, atrial septal defect, and slurred speech. Whole exome sequencing identified a novel truncation variant in the QRICH1 gene (MN_017730.3: c.1788dupC, p.Tyr597Leufs*9). Furthermore, the functional experiments confirmed the effect of genetic variation.
Our findings expand the QRICH1 variant spectrum in developmental disorders and provide evidence for the application of whole exome sequencing in Ververi-Brady syndrome.

Ververi-Brady syndrome (VBS), first reported in 2018, is characterized by intellectual disability, speech delay, and mild dysmorphic facial features. VBS has been linked to de novo loss-of-function variants in the glutamine-rich protein 1 (QRICH1) on chromosome 3p21 and was reported until lately in only five individuals. Four additional cases have just been described substantiating the notion that children with VBS are mildly dysmorphic, mildly to moderately intellectually disabled, have linear growth shortage, are picky eaters, and have notable attention and social behavioral deficits. We describe a new patient and review the clinical and genetic information, on all previously reported VBS cases. The child here reported is noted for maladaptive behavior, sensory hypersensitivity, and slow linear growth. He is mainly hyperactive, distractible, impulsive, and inattentive. His speech, initially delayed, is fair and his verbal comprehension age adequate.

Ververi-Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss-of-function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail.