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C5orf42 is the major gene responsible for OFD syndrome type VI

Abstract

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.

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Acknowledgments

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

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

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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.

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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). https://doi.org/10.1007/s00439-013-1385-1

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Keywords

  • Polydactyly
  • Microphthalmia
  • C5orf42 Mutation
  • C5orf42 Gene
  • Hypothalamic Hamartoma