Biallelic variants in DNA2 cause microcephalic primordial dwarfism. Issue 8 (23rd June 2019) - Tarnauskaitė, Žygimantė
Abstract: Microcephalic primordial dwarfism (MPD) is a group of rare single‐gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD‐associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)‐dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764‐38_1764‐37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP‐dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene. Abstract : We report the identification of biallelic DNA2 variants in four unrelated individuals with microcephalic primordial dwarfism (MPD). Using cellular splicing assays and molecular modeling we provide evidence that these variants result in partial loss of function of DNA2, an adenosine triphosphate (ATP)‐dependent helicase/nuclease with functions in DNA replication and repair, supporting their pathogenicity and establishing DNA2 as an MPD disease gene.