A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51

Najim Ameziane, Patrick May, Anneke Haitjema, Henri J. van de Vrugt, Sari E. van Rossum-Fikkert, Dejan Ristic, Gareth J. Williams, Jesper Balk, Davy Rockx, Hong Li, Martin A. Rooimans, Anneke B. Oostra, Eunike Velleuer, Ralf Dietrich, Onno B. Bleijerveld, A. F. Maarten Altelaar, Hanne Meijers-Heijboer, Hans Joenje, Gustavo Glusman, Jared RoachLeroy Hood, David Galas, Claire Wyman, Rudi Balling, Johan den Dunnen, Johan P. de Winter, Roland Kanaar, Richard Gelinas, Josephine C. Dorsman

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Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, 'FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility
Original languageEnglish
Article number8829
Pages (from-to)8829
JournalNature communications
Publication statusPublished - 2015

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