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Biallelic variants in DNA2 cause microcephalic primordial dwarfism

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Original languageEnglish
JournalHuman Mutation
Early online date2 May 2019
Publication statusE-pub ahead of print - 2 May 2019


Microcephalic primordial dwarfism (MPD) is a group of rare single‐gene disorders characterised by 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 identification of four MPD individuals with biallelic variants in DNA2, which encodes an 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 binding by DNA2. Our findings support pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD‐disease gene.

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