Ververi-Brady syndrome (QRICH mutations)

Inspired by a patient

Föhrenbach M, Jamra RA, Borkhardt A, Brozou T, Muschke P, Popp B, Rey LK, Schaper J, Surowy H, Zenker M, Zweier C, Wieczorek D, Redler S. QRICH1 variants in Ververi-Brady syndrome-delineation of the genotypic and phenotypic spectrum. Clin Genet. 2021 Jan;99(1):199-207. doi: 10.1111/cge.13853. Epub 2020 Nov 10. PMID: 33009816.

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.

Lui JC, Jee YH, Lee A, Yue S, Wagner J, Donnelly DE, Vogt KS, Baron J. QRICH1 mutations cause a chondrodysplasia with developmental delay. Clin Genet. 2019 Jan;95(1):160-164. doi: 10.1111/cge.13457. Epub 2018 Oct 26. PMID: 30281152; PMCID: PMC6353565.

Abstract

In many children with short stature, the etiology of the decreased linear growth remains unknown. We sought to identify the underlying genetic etiology in a patient with short stature, irregular growth plates of the proximal phalanges, developmental delay, and mildly dysmorphic facial features. Exome sequencing identified a de novo, heterozygous, nonsense mutation (c.1606C>T:p.R536X) in QRICH1. In vitro studies confirmed that the mutation impaired expression of the QRICH1 protein. SiRNA-mediated knockdown of Qrich1 in primary mouse epiphyseal chondrocytes caused downregulation of gene expression associated with hypertrophic differentiation. We then identified an unrelated individual with another heterozygous de novo nonsense mutation in QRICH1 who had a similar phenotype. A recently published study identified QRICH1 mutations in three patients with developmental delay, one of whom had short stature. Our findings indicate that QRICH1 mutations cause not only developmental delay but also a chondrodysplasia characterized by diminished linear growth and abnormal growth plate morphology due to impaired growth plate chondrocyte hypertrophic differentiation.

Ververi A, Splitt M, Dean JCS; DDD Study; Brady AF. Phenotypic spectrum associated with de novo mutations in QRICH1 gene. Clin Genet. 2018 Feb;93(2):286-292. doi: 10.1111/cge.13096. Epub 2017 Dec 21. PMID: 28692176.

Abstract

Rare de novo mutations represent a significant cause of idiopathic developmental delay (DD). The use of next-generation sequencing (NGS) has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present 3 unrelated children with de novo loss-of-function (LoF) mutations in QRICH1, diagnosed through trio-based exome sequencing. QRICH1 encodes the glutamine-rich protein 1, which contains 1 caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. All 3 children had speech delay, learning difficulties, a prominent nose and a thin upper lip. In addition, 2 of them had mildly raised creatine kinase (CK) and 1 of them had autism. Despite their small number, the patients had a relatively consistent pattern of clinical features suggesting the presence of a QRICH1-associated phenotype. LoF mutations in QRICH1 are suggested as a novel cause of DD.

Wang D, Wu J. A novel variant in the QRICH1 gene was identified in a patient with severe developmental delay. Mol Genet Genomic Med. 2023 Aug;11(8):e2227. doi: 10.1002/mgg3.2227. Epub 2023 Jun 18. PMID: 37331002; PMCID: PMC10422060.

Abstract

Background: 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.

Materials and methods: Whole exome sequencing, clinical examinations, and functional experiments were performed to identify the etiology of our patient.

Results: 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.

Conclusion: Our findings expand the QRICH1 variant spectrum in developmental disorders and provide evidence for the application of whole exome sequencing in Ververi-Brady syndrome.