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.

Setleis syndrome due to inheritance of the 1p36.22p36.21 duplication: evidence for lack of penetrance

“…7 In patients with FFDD4, exome sequencing identified mutations in the CYP26C1 gene, which encodes an enzyme involved in retinoic acid metabolism. 12 The studies reported here further extend the genetic and phenotypic heterogeneity of FFDD3. In addition to the homozygous TWIST2 mutations leading to the loss-of-function of transcription factor, 1p36.22p36.21 duplication in FFDD3 BH Lee et al a microduplication or triplication at 1p36.22p36.21 was recently reported that alters the dosage and presumably the expression of genes located in the region.…”

“…In the last few years, the genetic etiologies of FFDD3 and FFDD4 have been identified. 3,12 In FFDD3, recessive TWIST2 mutations were found in patients from five unrelated families, all having normal intelligence. [3][4][5][6] In addition, de novo duplications or triplication of genomic region, 1p36.22p36.21, were found in three unrelated patients who had the typical FFDD3 manifestations and developmental delay or intellectual disabilities.…”

Enzymology of retinoic acid biosynthesis and degradation

“…Of the three CYP26 genes, CYP26C1 is the least conserved, and its physiological function remains poorly understood. A frameshift mutation in human CYP26C1 has been recently linked to focal facial dermal dysplasia type IV, a rare syndrome characterized by facial lesions resembling aplasia cutis ( 135 ).…”

Expansion of phenotype and genotypic data in CRB2-related syndrome

“…For the second patient, sequencing of CRB2 only was performed using Sanger sequencing. 18 For the third and fourth patients, homozygosity mapping was performed using the human GeneChip Mapping 10K 2.0 SNP genotyping array (Affymetrix, Santa Clara, CA, USA) on the third patient only, followed by identity-by-descent mapping using HomozygosityMapper. 19 Whole exome sequencing (WES) was undertaken using the SureSelect exome kit v3 (Agilent, Mississauga, ON, USA) and sequenced on a SOLiD 5500xl (ThermoFisher, Burlington, ON, USA).…”