title: Whole exome sequencing reveals uncommon mutations in the recently identified Fanconi anemia gene SLX4/FANCP.
abstract: Fanconi anemia (FA) is a rare genetic disorder characterized by congenital malformations, progressive bone marrow failure (BMF), and susceptibility to malignancies. FA is caused by biallelic or hemizygous mutations in one of 15 known FA genes, whose products are involved in the FA/BRCA DNA damage response pathway. Here, we report on a patient with previously unknown mutations of the most recently identified FA gene, SLX4/FANCP. Whole exome sequencing (WES) revealed a nonsense mutation and an unusual splice site mutation resulting in the partial replacement of exonic with intronic bases, thereby removing a nuclear localization signal. Immunoblotting detected no residual SLX4 protein, which was consistent with abrogated interactions with XPF/ERCC1 and MUS81/EME1. This cellular finding did not result in a more severe clinical phenotype than that of previously reported FA-P patients. Our study additionally exemplifies the versatility of WES for the detection of mutations in heterogenic disorders such as FA.
authors.affiliation: Department of Human Genetics, University of Wuerzburg, Wuerzburg, Germany. beatrice.schuster@biozentrum.uni-wuerzburg.de
authors.forename: Beatrice
authors.initials: B
authors.lastname: Schuster
authors.forename: Kerstin
authors.initials: K
authors.lastname: Knies
authors.forename: Chantal
authors.initials: C
authors.lastname: Stoepker
authors.forename: Eunike
authors.initials: E
authors.lastname: Velleuer
authors.forename: Richard
authors.initials: R
authors.lastname: Friedl
authors.forename: Birgit
authors.initials: B
authors.lastname: Gottwald-Mühlhauser
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
mesh_terms: D001483:Base Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics; D045522:Recombinases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D022821:RNA Splice Sites; D045522:Recombinases; C542319:SLX4 protein, human