Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome

Carine Bonnard, Mohammad Shboul, Seyed Hassan Tonekaboni, Alvin Yu Jin Ng, Sumanty Tohari, Kakaly Ghosh, Angeline Lai, Jiin Ying Lim, Ene Choo Tan, Louise Devisme, Morgane Stichelbout, Adila Alkindi, Nazreen Banu, Zafer Yüksel, Jamal Ghoumid, Nadia Elkhartoufi, Lucile Boutaud, Alessia Micalizzi, Maggie Siewyan Brett, Byrappa VenkateshEnza Maria Valente, Tania Attié-Bitach, Bruno Reversade, Ariana Kariminejad

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22 Scopus citations


Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.
Original languageEnglish (US)
Pages (from-to)585-595
Number of pages11
JournalEuropean Journal of Medical Genetics
Issue number10
StatePublished - Oct 1 2018
Externally publishedYes

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