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Exome sequencing identifies a mutation in OFD1 in a male with Joubert syndrome, orofaciodigital spectrum anomalies and complex polydactyly.

ABSTRACT: Orofaciodigital syndrome type 1 or oral-facial-digital syndrome type 1 (OFDS1, OMIM #311200) is an X-linked malformation syndrome caused by hemizygous mutations in the OFD1 (OMIM #300170) gene with presumed male lethality. Recently males with OFDS1 and mutations in OFD1 have been described. We report a 17-year-old male with molar tooth sign, small cerebellum with absence of the cerebellar vermis, complex polydactyly with a Y-shaped metacarpal, renal failure and craniofacial anomalies caused by a novel splice-mutation (c.1129+4A>T) in the OFD1 gene identified by exome sequencing.

SUBMITTER: Wentzensen IM

PROVIDER: S-EPMC4760119 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Exome sequencing identifies a mutation in OFD1 in a male with Joubert syndrome, orofaciodigital spectrum anomalies and complex polydactyly.

Wentzensen Ingrid M IM Johnston Jennifer J JJ Patton John H JH Graham John M JM Sapp Julie C JC Biesecker Leslie G LG

Human genome variation 20160204

Orofaciodigital syndrome type 1 or oral-facial-digital syndrome type 1 (OFDS1, OMIM #311200) is an X-linked malformation syndrome caused by hemizygous mutations in the OFD1 (OMIM #300170) gene with presumed male lethality. Recently males with OFDS1 and mutations in OFD1 have been described. We report a 17-year-old male with molar tooth sign, small cerebellum with absence of the cerebellar vermis, complex polydactyly with a Y-shaped metacarpal, renal failure and craniofacial anomalies caused by a ...[more]

PMID: 27081566

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Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral-facial-digital anomalies.

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Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations.

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Erratum: Mutation spectrum of Joubert syndrome and related disorders among Arabs.

Project description:[This corrects the article DOI: 10.1038/hgv.2014.20.].

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A novel non-sense variant in the OFD1 gene caused Joubert syndrome

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OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin.

Project description:We ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a "molar tooth sign," which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified. OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS.

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