Biallelic variants in VARS in a family with two siblings with intellectual disability and microcephaly: case report and review of the literature

Abstract

Two male siblings ages 15 and 10 yr old had similar features of intellectual disability, developmental delay, severe speech impairment, microcephaly, prematurity, and transient elevation of liver enzymes in infancy. Exome sequencing revealed one novel (c.65C>A; p.Ala22Asp) and one ultra-rare (c.3214T>C; p.Phe1072Leu) predicted damaging missense variant in trans in the gene encoding cytoplasmic valyl-tRNA synthetase (VARS). Biallelic variants in VARS have previously been associated with a neurodevelopmental disorder characterized by microcephaly, seizures, and cortical atrophy (NDMSCA; MIM #617802). Although our patients have no history of seizures or cortical atrophy, we suggest that the biallelic variants in VARS p.Ala22Asp and p.Phe1072Leu in this family are likely pathogenic and associated with NDMSCA, expanding the clinical phenotype of the condition.

Keywords: absent speech; appendicular hypotonia; intellectual disability, moderate; microcephaly; premature birth following premature rupture of fetal membranes.

Figure 1.

Distribution of reported VARS variants in the literature and ClinVar over 2D representation of VARS domains given on InterPro for P26640 (SYVC_HUMAN) and the mutated residues’ sequence alignment across species. Mutated residues are shown in bold black font for previously reported variants and in bold red font for variants reported in our study. HUMAN (P26640); Homo sapiens, PANTR (H2QSM5); Pan troglodytes (chimpanzee), MACMU (G7MRK4); Rhesus macaque; MOUSE (G3UY93); Mus musculus; CANLF (E2RTJ7), Canis lupus familiaris (dog); LOXAF (G5E7F5), African elephant; RAT (Q04462), Rattus norvegicus. ^†This variant is deposited into ClinVar but not reported in any publication.