QRICH1 variants in Ververi-Brady syndrome-delineation of the genotypic and phenotypic spectrum.

Martin Zenker,Petra Muschke,Arndt Borkhardt,Triantafyllia Brozou,Silke Redler,Jörg Schaper,Christiane Zweier,Melanie Föhrenbach,Bernt Popp,Linda K. Rey,Rami Abou Jamra,Harald Surowy,Dagmar Wieczorek

doi:10.1111/cge.13853

Abstract

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.

Highlights

Recent findings revealed de novo QRICH1 variants in five patients of which one derived from the DECIPHER database with the hallmarks delayed speech, learning difficulties and dysmorphic signs.[1,2,3] a whole exome sequencing (WES) study provided encouraging evidence for involvement of QRICH1 in autism spectrum disorder (ASD).[4]
Trio-based WES identified a de novo heterozygosity for the variant at position QRICH1 NM_017730.3:c.2207G > A; p. (Ser736Asn). This variant has not been reported before in the dbSNP8 and gnomAD9 variant databases (Supplemental Table 2, Supplemental Figure 1), and it is to our knowledge the first reported missense mutation related to Ververi-Brady syndrome (VBS)
The mutation is located in the YcfA/nrd intein domain of QRICH110 and bioinformatic prediction tools uniformly point toward a potential damaging effect on the protein structure (Supplemental Table 3), indicating a likely impact on the functionality of the domain (Supplemental Figure 1)

Summary

Introduction

Recent findings revealed de novo QRICH1 (glutamine rich 1) variants in five patients of which one derived from the DECIPHER database with the hallmarks delayed speech, learning difficulties and dysmorphic signs.[1,2,3] a whole exome sequencing (WES) study provided encouraging evidence for involvement of QRICH1 in autism spectrum disorder (ASD).[4]. Cases, expanding the phenotypic and genotypic spectrum of individuals with QRICH1 variants/Ververi-Brady syndrome (VBS)

Methods

Results

Conclusion