Novel Mutations Including Deletions of the Entire OFD1 Gene in 30 Families with Type 1 Orofaciodigital Syndrome: A Study of the Extensive Clinical Variability

Izak J. Bisschoff, Christine Zeschnigk, Denise Horn, Brigitte Wellek, Angelika Rieß, Maja Wessels, Patrick Willems, Peter Jensen, Andreas Busche, Jens Bekkebraten, Maya Chopra, Hanne Dahlgaard Hove, Christina Evers, Ketil Heimdal, Ann Sophie Kaiser, Erdmut Kunstmann, Kristina Lagerstedt Robinson, Maja Linné, Patricia Martin, James McGrathWinnie Pradel, Katrina E. Prescott, Bernd Roesler, Gorazd Rudolf, Ulrike Siebers-Renelt, Nataliya Tyshchenko, Dagmar Wieczorek, Gerhard Wolff, William B. Dobyns, Deborah J. Morris-Rosendahl

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)237-247
Number of pages11
JournalHuman mutation
Volume34
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Keywords

  • Ciliopathy
  • OFD1 mutation
  • Orofaciodigital syndrome

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    Bisschoff, I. J., Zeschnigk, C., Horn, D., Wellek, B., Rieß, A., Wessels, M., Willems, P., Jensen, P., Busche, A., Bekkebraten, J., Chopra, M., Hove, H. D., Evers, C., Heimdal, K., Kaiser, A. S., Kunstmann, E., Robinson, K. L., Linné, M., Martin, P., ... Morris-Rosendahl, D. J. (2013). Novel Mutations Including Deletions of the Entire OFD1 Gene in 30 Families with Type 1 Orofaciodigital Syndrome: A Study of the Extensive Clinical Variability. Human mutation, 34(1), 237-247. https://doi.org/10.1002/humu.22224