title: A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51.
abstract: 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.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Najim
authors.initials: N
authors.lastname: Ameziane
authors.affiliation: Luxembourg Centre for Systems Biomedicine, House of Biomedicine, 7 Avenue des Hauts-Fourneaux, Esch/Alzette L-4362, Luxembourg.|Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109-5234, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: May
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Haitjema
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.|Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: van de Vrugt
authors.affiliation: Department of Genetics, Cancer Genomics Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.|Department of Radiation Oncology, Erasmus Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Sari E
authors.initials: SE
authors.lastname: van Rossum-Fikkert
authors.affiliation: Department of Genetics, Cancer Genomics Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.|Department of Radiation Oncology, Erasmus Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Dejan
authors.initials: D
authors.lastname: Ristic
authors.affiliation: Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Williams
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Jesper
authors.initials: J
authors.lastname: Balk
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Davy
authors.initials: D
authors.lastname: Rockx
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109-5234, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Rooimans
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Anneke B
authors.initials: AB
authors.lastname: Oostra
authors.affiliation: Department of Paediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225 Du¨sseldorf, Germany.
authors.forename: Eunike
authors.initials: E
authors.lastname: Velleuer
authors.affiliation: Deutsche Fanconi-Anämie-Hilfe e.V., Böckenweg 4, 59427 Unna, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dietrich
authors.affiliation: Mass Spectrometry and Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors.forename: Onno B
authors.initials: OB
authors.lastname: Bleijerveld
authors.affiliation: Mass Spectrometry and Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors.forename: A F
authors.initials: AF
authors.lastname: Maarten Altelaar
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Joenje
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109-5234, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Glusman
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109-5234, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Roach
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109-5234, USA.
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.affiliation: Luxembourg Centre for Systems Biomedicine, House of Biomedicine, 7 Avenue des Hauts-Fourneaux, Esch/Alzette L-4362, Luxembourg.|Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, Washington 98122, USA.
authors.forename: David
authors.initials: D
authors.lastname: Galas
authors.affiliation: Department of Genetics, Cancer Genomics Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.|Department of Radiation Oncology, Erasmus Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Claire
authors.initials: C
authors.lastname: Wyman
authors.affiliation: Luxembourg Centre for Systems Biomedicine, House of Biomedicine, 7 Avenue des Hauts-Fourneaux, Esch/Alzette L-4362, Luxembourg.
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.affiliation: Department of Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333ZA, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: den Dunnen
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.affiliation: Department of Genetics, Cancer Genomics Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.|Department of Radiation Oncology, Erasmus Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109-5234, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gelinas
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
mesh_terms: D017766:Acid Anhydride Hydrolases; D001483:Base Sequence; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005199:Fanconi Anemia / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011995:Recombination, Genetic; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes