title: Focal facial dermal dysplasia, type IV, is caused by mutations in CYP26C1.
abstract: 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.
authors.affiliation: Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143-0316, USA. slavotia@peds.ucsf.edu
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
authors.forename: Pavni
authors.initials: P
authors.lastname: Mehrotra
authors.forename: Irina
authors.initials: I
authors.lastname: Nazarenko
authors.forename: Paul Ling-Fung
authors.initials: PL
authors.lastname: Tang
authors.forename: Richard
authors.initials: R
authors.lastname: Lao
authors.forename: Don
authors.initials: D
authors.lastname: Cameron
authors.forename: Ben
authors.initials: B
authors.lastname: Li
authors.forename: Catherine
authors.initials: C
authors.lastname: Chu
authors.forename: Chris
authors.initials: C
authors.lastname: Chou
authors.forename: Ann L
authors.initials: AL
authors.lastname: Marqueling
authors.forename: Mani
authors.initials: M
authors.lastname: Yahyavi
authors.forename: Kelly
authors.initials: K
authors.lastname: Cordoro
authors.forename: Ilona
authors.initials: I
authors.lastname: Frieden
authors.forename: Tom
authors.initials: T
authors.lastname: Glaser
authors.forename: Trine
authors.initials: T
authors.lastname: Prescott
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Morren
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Pui-yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Martin
authors.initials: M
authors.lastname: Petkovich
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072500:Cytochrome P450 Family 26; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000201:enzymology / Q000235:genetics*; D000090303:Focal Facial Dermal Dysplasias; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D006801:Humans; D051379:Mice; D018895:Microsatellite Repeats; D020125:Mutation, Missense
chemical_list: D003577:Cytochrome P-450 Enzyme System; C482075:CYP26C1 protein, human; D000072500:Cytochrome P450 Family 26