@article{923dfadecb78448ab5807dc894c8892b,
title = "Biallelic variants in DNA2 cause microcephalic primordial dwarfism",
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.",
keywords = "DNA repair, DNA replication, DNA2, growth, microcephalic primordial dwarfism",
author = "{\v Z}ygimantė Tarnauskaitė and Bicknell, {Louise S.} and Marsh, {Joseph A.} and Murray, {Jennie E.} and Parry, {David A.} and Logan, {Clare V.} and Bober, {Michael B.} and {de Silva}, {Deepthi C.} and Duker, {Angela L.} and David Sillence and Carol Wise and Jackson, {Andrew P.} and Olga Murina and Reijns, {Martin A.M.}",
note = "Funding Information: The authors are grateful to the families for their participation in the research presented here. Authors are indebted to M. Hurles (Wellcome Trust Sanger Institute, UK) for collaboration on WES for P1 and P3, funded by the Wellcome Trust (WT098051). Authors thank S. Brown, A. Gallagher, and S. O'Neil for technical support, and T. Cooper for reagents. This study was supported by the Potentials Foundation (to C. W.). L. S. B. was supported by Medical Research Scotland. J. A. M. is supported by a Medical Research Council Career Development Award (MR/M02122X/1). The lab of A. P. J. is supported by the Medical Research Council, UK (MRC, U127580972) and the European Research Council (ERC), through ERC Starter Grant 281847; and now by the European Union's Horizon 2020 research and innovation programme ERC Advanced Grant (Grant agreement No: 788093). Publisher Copyright: {\textcopyright} 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.",
year = "2019",
doi = "10.1002/humu.23776",
language = "English (US)",
volume = "40",
pages = "1063--1070",
journal = "Human mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "8",
}