Skip to main content


Log in

C5orf42 is the major gene responsible for OFD syndrome type VI

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript


Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the “Joubert syndrome related disorders”. Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others


  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Alazami AM, Alshammari MJ, Salih MA, Alzahrani F, Hijazi H, Seidahmed MZ, Abu Safieh L, Aldosary M, Khan AO, Alkuraya FS (2012) Molecular characterization of Joubert syndrome in Saudi Arabia. Human mutation 33:1423–1428

    Article  CAS  PubMed  Google Scholar 

  • Bisschoff IJ, Zeschnigk C, Horn D, Wellek B, Riess A, Wessels M, Willems P, Jensen P, Busche A, Bekkebraten J, Chopra M, Hove HD, Evers C, Heimdal K, Kaiser AS, Kunstmann E, Robinson KL, Linne M, Martin P, McGrath J, Pradel W, Prescott KE, Roesler B, Rudolf G, Siebers-Renelt U, Tyshchenko N, Wieczorek D, Wolff G, Dobyns WB, Morris-Rosendahl DJ (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. Hum Mutat 34:237–247

    Article  CAS  PubMed  Google Scholar 

  • Brancati F, Dallapiccola B, Valente EM (2010) Joubert syndrome and related disorders. Orphanet J Rare Dis 5:20

    Article  PubMed Central  PubMed  Google Scholar 

  • Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, Hurd TW, Zhou W, Cluckey A, Gee HY, Ramaswami G, Hong CJ, Hamilton BA, Cervenka I, Ganji RS, Bryja V, Arts HH, van Reeuwijk J, Oud MM, Letteboer SJ, Roepman R, Husson H, Ibraghimov-Beskrovnaya O, Yasunaga T, Walz G, Eley L, Sayer JA, Schermer B, Liebau MC, Benzing T, Le Corre S, Drummond I, Janssen S, Allen SJ, Natarajan S, O’Toole JF, Attanasio M, Saunier S, Antignac C, Koenekoop RK, Ren H, Lopez I, Nayir A, Stoetzel C, Dollfus H, Massoudi R, Gleeson JG, Andreoli SP, Doherty DG, Lindstrad A, Golzio C, Katsanis N, Pape L, Abboud EB, Al-Rajhi AA, Lewis RA, Omran H, Lee EY, Wang S, Sekiguchi JM, Saunders R, Johnson CA, Garner E, Vanselow K, Andersen JS, Shlomai J, Nurnberg G, Nurnberg P, Levy S, Smogorzewska A, Otto EA, Hildebrandt F (2012) Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150:533–548

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Coene KL, Roepman R, Doherty D, Afroze B, Kroes HY, Letteboer SJ, Ngu LH, Budny B, van Wijk E, Gorden NT, Azhimi M, Thauvin-Robinet C, Veltman JA, Boink M, Kleefstra T, Cremers FP, van Bokhoven H, de Brouwer AP (2009) OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet 85:465–481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Darmency-Stamboul V, Burglen L, Lopez E, Mejean N, Dean J, Franco B, Rodriguez D, Lacombe D, Desguerres I, Cormier-Daire V, Doray B, Pasquier L, Gonzales M, Pastore M, Crenshaw ML, Huet F, Gigot N, Aral B, Callier P, Faivre L, Attie-Bitach T, Thauvin-Robinet C (2013) Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome. Eur J Med Genet

  • DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doss BJ, Jolly S, Qureshi F, Jacques SM, Evans MI, Johnson MP, Lampinen J, Kupsky WJ (1998) Neuropathologic findings in a case of OFDS type VI (Varadi syndrome). Am J Med Genet 77:38–42

    Article  CAS  PubMed  Google Scholar 

  • Figuera LE, Rivas F, Cantu JM (1993) Oral-facial-digital syndrome with fibular aplasia: a new variant. Clin Genet 44:190–192

    Article  CAS  PubMed  Google Scholar 

  • Gleeson JG, Keeler LC, Parisi MA, Marsh SE, Chance PF, Glass IA, Graham JM Jr, Maria BL, Barkovich AJ, Dobyns WB (2004) Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes. Am J Med Genet A 125:125–134 (discussion 117)

    Article  Google Scholar 

  • Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust EM, Brockman W, Fennell T, Giannoukos G, Fisher S, Russ C, Gabriel S, Jaffe DB, Lander ES, Nusbaum C (2009) Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol 27:182–189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gurrieri F, Franco B, Toriello H, Neri G (2007) Oral-facial-digital syndromes: review and diagnostic guidelines. Am J Med Genet A 143A:3314–3323

    Article  PubMed  Google Scholar 

  • Lee JE, Silhavy JL, Zaki MS, Schroth J, Bielas SL, Marsh SE, Olvera J, Brancati F, Iannicelli M, Ikegami K, Schlossman AM, Merriman B, Attie-Bitach T, Logan CV, Glass IA, Cluckey A, Louie CM, Lee JH, Raynes HR, Rapin I, Castroviejo IP, Setou M, Barbot C, Boltshauser E, Nelson SF, Hildebrandt F, Johnson CA, Doherty DA, Valente EM, Gleeson JG (2012a) CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat Genet 44:193–199

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee JH, Silhavy JL, Lee JE, Al-Gazali L, Thomas S, Davis EE, Bielas SL, Hill KJ, Iannicelli M, Brancati F, Gabriel SB, Russ C, Logan CV, Sharif SM, Bennett CP, Abe M, Hildebrandt F, Diplas BH, Attie-Bitach T, Katsanis N, Rajab A, Koul R, Sztriha L, Waters ER, Ferro-Novick S, Woods CG, Johnson CA, Valente EM, Zaki MS, Gleeson JG (2012b) Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science 335:966–969

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25:2078–2079

    Article  PubMed  Google Scholar 

  • McPherson E, Zaleski C, Mascola M (2006) Prenatal diagnosis of episodic tachypnea in an infant with OFD VI. Am J Med Genet A 140:2146–2149

    Article  PubMed  Google Scholar 

  • Mougou-Zerelli S, Thomas S, Szenker E, Audollent S, Elkhartoufi N, Babarit C, Romano S, Salomon R, Amiel J, Esculpavit C, Gonzales M, Escudier E, Leheup B, Loget P, Odent S, Roume J, Gerard M, Delezoide AL, Khung S, Patrier S, Cordier MP, Bouvier R, Martinovic J, Gubler MC, Boddaert N, Munnich A, Encha-Razavi F, Valente EM, Saad A, Saunier S, Vekemans M, Attie-Bitach T (2009) CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. Hum Mutat 30:1574–1582

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Poretti A, Brehmer U, Scheer I, Bernet V, Boltshauser E (2008) Prenatal and neonatal MR imaging findings in oral-facial-digital syndrome type VI. AJNR Am J Neuroradiol 29:1090–1091

    Article  CAS  PubMed  Google Scholar 

  • Poretti A, Vitiello G, Hennekam RC, Arrigoni F, Bertini E, Borgatti R, Brancati F, D’Arrigo S, Faravelli F, Giordano L, Huisman TA, Iannicelli M, Kluger G, Kyllerman M, Landgren M, Lees MM, Pinelli L, Romaniello R, Scheer I, Schwarz CE, Spiegel R, Tibussek D, Valente EM, Boltshauser E (2012) Delineation and diagnostic criteria of Oral-facial-digital syndrome type VI. Orphanet J Rare Dis 7:4

    Article  PubMed Central  PubMed  Google Scholar 

  • Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, Baye LM, Wen X, Scales SJ, Kwong M, Huntzicker EG, Sfakianos MK, Sandoval W, Bazan JF, Kulkarni P, Garcia-Gonzalo FR, Seol AD, O’Toole JF, Held S, Reutter HM, Lane WS, Rafiq MA, Noor A, Ansar M, Devi AR, Sheffield VC, Slusarski DC, Vincent JB, Doherty DA, Hildebrandt F, Reiter JF, Jackson PK (2011) Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145:513–528

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shaheen R, Faqeih E, Alshammari MJ, Swaid A, Al-Gazali L, Mardawi E, Ansari S, Sogaty S, Seidahmed MZ, Almotairi MI, Farra C, Kurdi W, Al-Rasheed S, Alkuraya FS (2012) Genomic analysis of Meckel-Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes. Eur J Human Genet EJHG

  • Srour M, Hamdan FF, Schwartzentruber JA, Patry L, Ospina LH, Shevell MI, Desilets V, Dobrzeniecka S, Mathonnet G, Lemyre E, Massicotte C, Labuda D, Amrom D, Andermann E, Sebire G, Maranda B, Rouleau GA, Majewski J, Michaud JL (2012a) Mutations in TMEM231 cause Joubert syndrome in French Canadians. J Med Genet 49:636–641

    Article  CAS  PubMed  Google Scholar 

  • Srour M, Schwartzentruber J, Hamdan FF, Ospina LH, Patry L, Labuda D, Massicotte C, Dobrzeniecka S, Capo-Chichi JM, Papillon-Cavanagh S, Samuels ME, Boycott KM, Shevell MI, Laframboise R, Desilets V, Maranda B, Rouleau GA, Majewski J, Michaud JL (2012b) Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am J Hum Genet 90:693–700

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stephan MJ, Brooks KL, Moore DC, Coll EJ, Goho C (1994) Hypothalamic hamartoma in oral-facial-digital syndrome type VI (Varadi syndrome). Am J Med Genet 51:131–136

    Article  CAS  PubMed  Google Scholar 

  • Thomas S, Legendre M, Saunier S, Bessieres B, Alby C, Bonniere M, Toutain A, Loeuillet L, Szymanska K, Jossic F, Gaillard D, Yacoubi MT, Mougou-Zerelli S, David A, Barthez MA, Ville Y, Bole-Feysot C, Nitschke P, Lyonnet S, Munnich A, Johnson CA, Encha-Razavi F, Cormier-Daire V, Thauvin-Robinet C, Vekemans M, Attie-Bitach T (2012) TCTN3 mutations cause Mohr-Majewski syndrome. Am J Hum Genet 91:372–378

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Toriello HV, Carey JC, Suslak E, Desposito FR, Leonard B, Lipson M, Friedman BD, Hoyme HE (1997) Six patients with oral-facial-digital syndrome IV: the case for heterogeneity. Am J Med Genet 69:250–260

    Article  CAS  PubMed  Google Scholar 

  • Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, Hildebrandt F, Otto EA, Held S, Diplas BH, Davis EE, Mikula M, Strom CM, Ben-Zeev B, Lev D, Sagie TL, Michelson M, Yaron Y, Krause A, Boltshauser E, Elkhartoufi N, Roume J, Shalev S, Munnich A, Saunier S, Inglehearn C, Saad A, Alkindy A, Thomas S, Vekemans M, Dallapiccola B, Katsanis N, Johnson CA, Attie-Bitach T, Gleeson JG (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 42:619–625

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Varadi V, Szabo L, Papp Z (1980) Syndrome of polydactyly, cleft lip/palate or lingual lump, and psychomotor retardation in endogamic gypsies. J Med Genet 17:119–122

    Article  CAS  PubMed  Google Scholar 

  • Wei Q, Zhang Y, Li Y, Zhang Q, Ling K, Hu J (2012) The BBSome controls IFT assembly and turnaround in cilia. Nat Cell Biol 14:950–957

    Article  PubMed Central  PubMed  Google Scholar 

Download references


We thank the families for their participation. We are grateful to the French Society of Fetal Pathology (SOFFOET) for participating in the study. This work was supported by grants from GIS-Institut des Maladies Rares and Fondation IMAGINE for high-throughput-sequencing, the French Ministry of Health (PHRC national 2010 and 2012), the Dijon University Hospital, Regional Council of Burgundy, the project ANR (2010 FOETOCILPATH N° BLAN 1122 01 to T.A.B.), and A*STAR Singapore for a Strategic Positioning Fund for Genetic Orphan Diseases. Finally, the authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

Conflict of interest

The authors declare no competing financial interest.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Christel Thauvin-Robinet.

Additional information

E. Lopez and C. Thauvin-Robinet contributed equally to this work.

L. Faivre and T. Attié-Bitach jointly directed this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 70 kb)

Supplementary material 2 (DOC 32 kb)

Supplementary material 3 (DOC 46 kb)

Supplementary material 4 (DOC 30 kb)

Supplementary Table 1: Primers for C5orf42 Sanger sequencing analysis.

Supplementary Table 2: exome analysis results of the cases 2, 5 and 6b, performed on the same platform.

Supplementary Table 3: Predicted effet of C5orf42 mutations identified in the individuals with OFD VI in this study.

Supplementary Table 4 : Analysis of 5 microsatellite markers at C5orf42 locus, showing that cases 6 and 7 share a common haplotype for D5S1994, D5S2021, D5S1964 and D5S2105 segregating with Ser1127Leu suggesting a founder effect for this mutation. No evidence was found for linkage disequilibrium around the Ile165ThrfsX17 mutation shared by cases 4 and 6.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lopez, E., Thauvin-Robinet, C., Reversade, B. et al. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet 133, 367–377 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: