Ververi-Brady Syndrome

A number sign (#) is used with this entry because of evidence that Ververi-Brady syndrome (VERBRAS) is caused by heterozygous mutation in the QRICH1 gene (617387) on chromosome 3p21.

Description

Ververi-Brady syndrome is characterized by mild developmental delay, mildly impaired intellectual development and speech delay, and mild dysmorphic facial features. Affected individuals can usually attend mainstream schools with support, and may also show autistic features (summary by Ververi et al., 2018).

Clinical Features

Ververi et al. (2018) reported 3 unrelated children with developmental delay and variable additional features. All had variable and mild dysmorphic features, with common features including a prominent nose and wide mouth with thin upper lip. The first patient was noted to have delayed language acquisition and impaired social interaction around 2 years of age, and was diagnosed with autism spectrum disorder at 4.5 years. He was attending mainstream school with support at age 8. Dysmorphic features included flat malar region, long columella, smooth philtrum, protuberant lower lip, and mildly deformed toes. His overall growth was normal and he had no additional neurologic abnormalities. The second patient was a 12-year-old girl who showed delayed psychomotor development since infancy and had mild poor growth. She also attended a mainstream school, but had difficulty and was later home-schooled. She had an unsteady gait, leg pain after walking, frequent falls, intention tremor, decreased muscle tone and reflexes, and involuntary tongue movements. Dysmorphic features included ptosis and hypertelorism. The third patient was a 13-year-old Chinese girl who showed delayed walking and delayed speech acquisition in early childhood, but was able to attend a mainstream school with support. She had poor overall growth, microcephaly (-6 SD), and dysmorphic features, including brachycephaly, upslanting palpebral fissures, broad nose with broad nasal tip, low-set and cup-shaped ears, and transverse palmar creases. Two of the patients had mildly increased serum creatine kinase in the first years of life that later normalized.

Lui et al. (2019) identified 2 unrelated children, an 8-year-old girl and a 11 year-old boy, with features of Ververi-Brady syndrome, including short stature, irregular growth plates of the proximal phalanges, developmental delay, and mild dysmorphic facial features. The girl had a height of -2.5 SD, and the boy had a height within normal limits (-1.3 SD). Lui et al. (2019) suggested that QRICH1 mutations can cause a subtle chondrodysplasia and should be considered in the differential diagnosis of short stature. The authors presented evidence that the chondrodysplasia resulted from impaired growth plate chondrocyte hypertrophic differentiation, a process essential for normal linear growth.

Molecular Genetics

In 3 unrelated patients with Ververi-Brady syndrome (VERBRAS; 617982), Ververi et al. (2018) identified de novo heterozygous nonsense or frameshift mutations in the QRICH1 gene (617387.0001-617387.0003). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in haploinsufficiency.

In an 8-year-old girl with VERBRAS, Lui et al. (2019) identified a de novo heterozygous nonsense mutation in the QRICH1 gene (R536X; 617387.0004). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Lui et al. (2019) also identified an 11-year-old boy in the DECIPHER database (Firth et al., 2009) with features of VERBRAS syndrome and a de novo nonsense mutation in the QRICH1 gene (R511X). Neither variant was present in the gnomAD database. In vitro studies showed that the R536X variant resulted in decreased protein expression, suggesting haploinsufficiency.