ClinVar

In a 23-year-old man (15DG1395), born of consanguineous parents, with neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA; 619989), Maddirevula et al. (2019) identified a homozygous c.706C-T transition (c.706C-T, NM_017736.3) in the THUMPD1 gene, resulting in a gln236-to-ter (Q236X) substitution. The mutation, which was found by exome sequencing of a cohort of over 2,500 patients with various mendelian phenotypes, was present in the heterozygous state at a low frequency (2 x 10(-5)) in gnomAD. Functional studies of the variant and studies of patient cells were not performed. In a follow-up study, Broly et al. (2022) found that patient 15DG1395 of Maddirevula et al., 2019 had a similarly affected brother who was homozygous for the Q236X mutation (referred to as family 2). Broly et al. (2022) also identified a homozygous Q236X mutation in an affected 8-year-old girl who was born of unrelated parents (family 3). The mutation segregated with the disorder in both families. Lymphoblastoid cells derived from 1 of the patients showed decreased THUMPD1 mRNA levels and absence of the full-length protein on Western blot analysis, suggesting that the mutant transcript is subject to nonsense-mediated mRNA decay. The mutation occurred in the second-to-last exon. Compared to controls, patient lymphoblasts showed no detectable N4-acetylcytidine (ac4C) modifications on small RNAs or tRNA(Ser). The findings were consistent with a loss of function.