title: Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability.
abstract: OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.
authors.affiliation: Institute of Human Genetics, University Clinic Freiburg, Freiburg, Germany.
authors.forename: Izak J
authors.initials: IJ
authors.lastname: Bisschoff
authors.forename: Christine
authors.initials: C
authors.lastname: Zeschnigk
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wellek
authors.forename: Angelika
authors.initials: A
authors.lastname: Rieß
authors.forename: Maja
authors.initials: M
authors.lastname: Wessels
authors.forename: Patrick
authors.initials: P
authors.lastname: Willems
authors.forename: Peter
authors.initials: P
authors.lastname: Jensen
authors.forename: Andreas
authors.initials: A
authors.lastname: Busche
authors.forename: Jens
authors.initials: J
authors.lastname: Bekkebraten
authors.forename: Maya
authors.initials: M
authors.lastname: Chopra
authors.forename: Hanne Dahlgaard
authors.initials: HD
authors.lastname: Hove
authors.forename: Christina
authors.initials: C
authors.lastname: Evers
authors.forename: Ketil
authors.initials: K
authors.lastname: Heimdal
authors.forename: Ann-Sophie
authors.initials: AS
authors.lastname: Kaiser
authors.forename: Erdmut
authors.initials: E
authors.lastname: Kunstmann
authors.forename: Kristina Lagerstedt
authors.initials: KL
authors.lastname: Robinson
authors.forename: Maja
authors.initials: M
authors.lastname: Linné
authors.forename: Patricia
authors.initials: P
authors.lastname: Martin
authors.forename: James
authors.initials: J
authors.lastname: McGrath
authors.forename: Winnie
authors.initials: W
authors.lastname: Pradel
authors.forename: Katrina E
authors.initials: KE
authors.lastname: Prescott
authors.forename: Bernd
authors.initials: B
authors.lastname: Roesler
authors.forename: Gorazd
authors.initials: G
authors.lastname: Rudolf
authors.forename: Ulrike
authors.initials: U
authors.lastname: Siebers-Renelt
authors.forename: Nataliya
authors.initials: N
authors.lastname: Tyshchenko
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolff
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Morris-Rosendahl
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009958:Orofaciodigital Syndromes / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: C115130:OFD1 protein, human; D011506:Proteins