Focal facial dermal dysplasia, type IV, is caused by mutations in CYP26C1

Anne M. Slavotinek, Pavni Mehrotra, Irina Nazarenko, Paul Ling Fung Tang, Richard Lao, Don Cameron, Ben Li, Catherine Chu, Chris Chou, Ann L. Marqueling, Mani Yahyavi, Kelly Cordoro, Ilona Frieden, Tom Glaser, Trine Prescott, Marie Anne Morren, Koen Devriendt, Pui Yan Kwok, Martin Petkovich, Robert J. Desnick

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35 Scopus citations


Focal facial dermal dysplasia (FFDD) Type IV is a rare syndrome characterized by facial lesions resembling aplasia cutis in a preauricular distribution along the line of fusion of the maxillary and mandibular prominences. To identify the causative gene(s), exome sequencing was performed in a family with two affected siblings. Assuming autosomal recessive inheritance, two novel sequence variants were identified in both siblings in CYP26C1-a duplication of seven base pairs, which was maternally inherited, c.844_851dupCCATGCA, predicting p.Glu284fsX128 and a missense mutation, c.1433G>A, predicting p.Arg478His, that was paternally inherited. The duplication predicted a frameshift mutation that led to a premature stop codon and premature chain termination, whereas the missense mutation was not functional based on its in vitro expression in mammalian cells. The FFDD skin lesions arise along the sites of fusion of the maxillary and mandibular prominences early in facial development, and Cyp26c1 was expressed exactly along the fusion line for these facial prominences in the first branchial arch in mice. Sequencing of four additional, unrelated Type IV FFDD patients and eight Type II or III TWIST2-negative FFDD patients revealed that three of the Type IV patients were homozygous for the duplication, whereas none of the Type II or III patients had CYP26C1 mutations. The seven base pairs duplication was present in 0.3% of healthy controls and 0.3% of patients with other birth defects. These findings suggest that the phenotypic manifestations of FFDD Type IV can be non-penetrant or underascertained. Thus, FFDD Type IV results from the loss of function mutations in CYP26C1.

Original languageEnglish
Article numberdds477
Pages (from-to)696-703
Number of pages8
JournalHuman Molecular Genetics
Issue number4
StatePublished - Feb 2013


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