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Novel Mutations Including Deletions of the Entire OFD1 Gene in 30 Families with Type 1 Orofaciodigital Syndrome: A Study of the Extensive Clinical Variability
Author(s) -
Bisschoff Izak J.,
Zeschnigk Christine,
Horn Denise,
Wellek Brigitte,
Rieß Angelika,
Wessels Maja,
Willems Patrick,
Jensen Peter,
Busche Andreas,
Bekkebraten Jens,
Chopra Maya,
Hove Hanne Dahlgaard,
Evers Christina,
Heimdal Ketil,
Kaiser AnnSophie,
Kunstmann Erdmut,
Robinson Kristina Lagerstedt,
Linné Maja,
Martin Patricia,
McGrath James,
Pradel Winnie,
Prescott Katrina E.,
Roesler Bernd,
Rudolf Gorazd,
SiebersRenelt Ulrike,
Tyshchenko Nataliya,
Wieczorek Dagmar,
Wolff Gerhard,
Dobyns William B.,
MorrisRosendahl Deborah J.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22224
Subject(s) - joubert syndrome , corpus callosum , ciliopathy , biology , hypoplasia , genetics , phenotype , mutation , cerebellar hypoplasia (non human) , agenesis of the corpus callosum , pathology , bioinformatics , gene , medicine , neuroscience , cerebellum , anatomy
OFD 1, 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 ( JBTS 10) and S impson– G olabi– B ehmel syndrome type 2 ( SGBS 2). We have studied 55 sporadic and six familial cases of suspected OFD 1. 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 MRI s 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.