TY - JOUR
T1 - Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome
AU - Bonnard, Carine
AU - Shboul, Mohammad
AU - Tonekaboni, Seyed Hassan
AU - Ng, Alvin Yu Jin
AU - Tohari, Sumanty
AU - Ghosh, Kakaly
AU - Lai, Angeline
AU - Lim, Jiin Ying
AU - Tan, Ene Choo
AU - Devisme, Louise
AU - Stichelbout, Morgane
AU - Alkindi, Adila
AU - Banu, Nazreen
AU - Yüksel, Zafer
AU - Ghoumid, Jamal
AU - Elkhartoufi, Nadia
AU - Boutaud, Lucile
AU - Micalizzi, Alessia
AU - Brett, Maggie Siewyan
AU - Venkatesh, Byrappa
AU - Valente, Enza Maria
AU - Attié-Bitach, Tania
AU - Reversade, Bruno
AU - Kariminejad, Ariana
N1 - Funding Information:
We would like to thank all families for their participation in this study. We thank Christine Bole and Patrick Nitschke from genomic and bioinformatics platforms in Imagine Institute, Necker-Enfants Malades hospital (Paris). This work was partly funded by a Strategic Positioning Fund on Genetic Orphan Diseases SPF2012/005 from the Agency for Science, Technology and Research (A*STAR) in Singapore and NMRC/CG/006/2013 from the National Medical Research Council, Ministry of Health, Singapore, as well as the European Research Council Starting Grant 260888.
Funding Information:
We would like to thank all families for their participation in this study. We thank Christine Bole and Patrick Nitschke from genomic and bioinformatics platforms in Imagine Institute, Necker-Enfants Malades hospital (Paris). This work was partly funded by a Strategic Positioning Fund on Genetic Orphan Diseases SPF2012/005 from the Agency for Science, Technology and Research (A*STAR) in Singapore and NMRC/CG/006/2013 from the National Medical Research Council, Ministry of Health , Singapore, as well as the European Research Council Starting Grant 260888 .
Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - C5orf42
KW - CPLANE1
KW - Joubert syndrome
KW - OFD6
KW - Oral-facial-digital syndrome
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U2 - 10.1016/j.ejmg.2018.03.012
DO - 10.1016/j.ejmg.2018.03.012
M3 - Article
C2 - 29605658
AN - SCOPUS:85045739422
SN - 1769-7212
VL - 61
SP - 585
EP - 595
JO - European Journal of Medical Genetics
JF - European Journal of Medical Genetics
IS - 10
ER -