QRICH1 – Ververi-Brady syndrome

Ververi-Brady syndrome is an autosomal dominant neurodevelopmental disorder characterized by short stature, microcephaly, speech delay, intellectual disability and dysmorphic features. Heterozygous loss-of-function variants in the glutamine-rich protein 1 gene QRICH1 have been implicated in its etiology. Clinical recognition has expanded since the initial description in 2018, with increasing reports of familial and de novo truncating variants.

Genetic evidence supports a strong gene–disease association. At least 14 probands across multiple unrelated families have been reported with heterozygous truncating or splice-disrupting QRICH1 variants, including a multi-generational mother–daughter pair segregating c.337C>T (p.Gln113Ter) (PMID:37211757), a de novo frameshift c.1788dup (p.Tyr597LeufsTer9) (PMID:37331002), and four unrelated individuals described in two cohorts (PMID:33738978; PMID:33009816). Segregation in a single family (2 affected relatives) and de novo occurrence in sporadic cases provide compelling evidence for haploinsufficiency as the pathogenic mechanism.

The variant spectrum is dominated by truncating alleles: nonsense (e.g., c.337C>T (p.Gln113Ter)), frameshift (c.1788dup (p.Tyr597LeufsTer9); c.1812_1813del (p.Glu605GlyfsTer25)), and canonical splice-site mutations, with only rare missense variants (p.Ser736Asn) reported (PMID:33009816). No common founder alleles have been identified to date, and population data indicate absence in control databases.

Functional studies corroborate the clinical findings. In vitro assays demonstrate that QRICH1 nonsense mutations (c.1606C>T (p.Arg536Ter)) lead to reduced protein expression and impaired hypertrophic differentiation in mouse epiphyseal chondrocytes following siRNA knockdown (PMID:30281152). Rescue experiments in primary cells restored growth-plate chondrocyte maturation, confirming haploinsufficiency as the disease mechanism.

No conflicting evidence has been reported that disputes the association with Ververi-Brady syndrome. Phenotypic variability includes seizures, atrial septal defects and hemangiomatosis, but core features of growth retardation, microcephaly, speech and motor delay remain consistent across cohorts.

Integration of genetic and experimental data establishes a strong ClinGen classification: autosomal dominant QRICH1 haploinsufficiency causes Ververi-Brady syndrome. Clinical exome sequencing should include QRICH1 for patients presenting with short stature, microcephaly and developmental delay. Early molecular diagnosis enables targeted surveillance for associated anomalies and informs genetic counseling.

References

• The American journal of case reports • 2023 • Mother and Daughter with Short Stature, Microcephaly, Mild Dysmorphic Features, and Learning Disabilities Due to Ververi-Brady Syndrome Associated with a New Variant of the QRICH1 Gene. PMID:37211757
• Molecular Genetics & Genomic Medicine • 2023 • A novel variant in the QRICH1 gene was identified in a patient with severe developmental delay. PMID:37331002
• American Journal of Medical Genetics Part A • 2021 • A case of Ververi-Brady syndrome due to QRICH1 loss of function and the literature review. PMID:33738978
• Clinical Genetics • 2021 • QRICH1 variants in Ververi-Brady syndrome-delineation of the genotypic and phenotypic spectrum. PMID:33009816
• Clinical Genetics • 2019 • QRICH1 mutations cause a chondrodysplasia with developmental delay. PMID:30281152

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