ClinVar Genomic variation as it relates to human health

Hearing impairment (present) , Failure to thrive (present) , Nephrotic syndrome (present) , Posteriorly rotated ears (present) , Large forehead (present) , Decreased circulating antibody concentration (present) , Global developmental delay (present) , Macrocephaly (present) , Depressed nasal bridge (present) , Abnormality of the palmar creases (present) , Recurrent bronchitis (present) , Cow milk allergy (present) , Deeply set eye (present) (less)

In 2 patients from the same German family (family 1) with short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF; 617763), Di Donato et al. (2016) identified a homozygous c.89G-T transversion (c.89G-T, NM_014285.5) in exon 1 of the EXOSC2 gene, resulting in a gly30-to-val (G30V) substitution at a conserved residue in the NT domain. The G30V substitution was predicted to disrupt EXOSC2 protein interaction with EXOSC4 (606491). An unrelated patient from another German family (family 2) with a similar disorder was compound heterozygous for G30V and a c.593G-A transition in exon 7, resulting in a gly198-to-asp (G198D; 602238.0002) substitution at a conserved residue in the KH domain. The G198D variant was predicted to alter the beta-hairpin structure of the protein and possibly interfere with RNA recruiting and binding. The mutations, which were found by whole-exome sequencing, segregated with the disorder in both families. The G30V variant was found in heterozygous state in 1 of 1,000 local German control individuals (frequency of 0.0005) and at a low frequency in the ExAC database (0.00002), whereas G198D was not found in the German controls. Neither variant was found in the 1000 Genomes Project database. Functional studies of the variants and studies of patient cells were not performed. By Western blot and immunoprecipitation analyses, Yang et al. (2020) showed that the G198D mutation, but not the G30V mutation, decreased EXOSC2 protein stability and impaired its interactions with other RNA exosome components. Moreover, the G198V mutant protein was nonfunctional and was associated with compromised cell proliferation, as expression of the G198V mutant did not rescue decreased cell proliferation in EXOSC2-deficient keratinocytes. RNA-sequencing analysis identified several deregulated RNAs in SHRF patient B-lymphoblasts and EXOSC2-knockout primary cultured keratinocytes, indicating that EXOSC2 regulates RNA metabolism. Subsequent in vitro analysis revealed an autophagy defect in EXOSC2-deficient human cells. (less)