Neuropediatrics 2015; 46 - FV03-09
DOI: 10.1055/s-0035-1550669

Oral-Facial-Digital Syndrome Type VI: is C5orf42 Really the Major Gene?

A. Poretti 1, 2, M. Romani 3, F. Mancini 3, A. Micalizzi 3, E. Miccinilli 3, M. Steinlin 4, N. Wolf 5, E. Boltshauser 1, E. Valente 3
  • 1Abteilung für Neuropädiatrie Universitäts-Kinderklinik, Zürich, Switzerland
  • 2Russell H. Morgan Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, United States
  • 3Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, Roma, Italy
  • 4Abtelung für Neuropädiatrie, Universitätsklinik für Kinderheilkunde Bern, Bern, Switzerland
  • 5Department of Child Neurology, VU University Medical Center and Neuroscience Campus, Amsterdam, The Netherlands

Aims: Oral-facial-digital type VI syndrome (OFDVI) is a rare phenotype of Joubert syndrome (JS). It is defined by the “molar tooth sign” with at least one of the followings: (1) tongue hamartoma and/or additional lingual frenula and/or upper lip notch; (2) mesoaxial polydactyly; and (3) hypothalamic hamartoma. Recently, C5orf42 was suggested as the major OFDVI gene, being mutated in 9 (12 patients) of the 11 families (82%). In this study, we aimed to (1) elucidate the prevalence of C5orf42 mutations in our cohort of OFDVI patients and (2) verify if C5orf42 is the major gene associated with OFDVI.

Methods: We sequenced C5orf42 in 313 JS patients including 17 OFDVI patients. All children underwent simultaneous target sequencing of 50 ciliopathy genes, including C5orf42 and other 21 JS genes. A comparison of clinical features in C5orf42 mutated versus nonmutated OFDVI patients from this study and the literature was made by Fisher exact test. We reviewed the clinical phenotype of all C5orf42 mutated JS patients reported so far.

Results: We identified pathogenic C5orf42 mutations in 28 of 313 JS patients (9%). Only 2 of 17 OFDVI patients (12%) carried mutations in C5orf42, whereas 1 patient was mutated in OFD1. The comparison of clinical features in C5orf42 mutated (n = 14) versus nonmutated (n = 17) OFDVI patients showed that preaxial and mesoaxial polydactyly, hypothalamic hamartoma, and other congenital defects predict C5orf42 mutations, while tongue hamartomas are more common in nonmutated patients. A total of 58 C5orf42 mutated JS patients have been reported so far: 66% with JS phenotype whereas 24% with OFDVI. Polydactyly was present in approximately 50% of all mutated patients.

Conclusion: C5orf42 is a major contributor to the pathogenesis of JS and seems to play a major role in limb development. Mutations in C5orf42 account only for OFDVI patients with preaxial and mesoaxial polydactyly, hypothalamic hamartoma and other congenital defects, while the genotype of OFDVI patients with oral-facial involvement remains to be identified.

Keywords: Joubert syndrome, cerebellum, malformation, ciliopathy.