Novel PORCN mutations in focal dermal hypoplasia

Abstract

Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.

PORCN Mutations and Variants Identified in Patients with Focal Dermal Hypoplasia Through Diagnostic Gene Sequencing

“…Our diagnostic study detected this mutation in an additional 4 out of 53 unrelated probands. Combining previous studies and the current study, the c.1094G>A (p.R365Q) mutation was not detected in at least 680 control X chromosomes (Leoyklang et al, 2008;Bornholdt et al, 2009;Froyen et al, 2009;Maas et al, 2009). Interestingly, each of these nucleotides, c.178G and c.1094G, is part of a CpG dinucleotide and is therefore likely to represent a hotspot for PORCN gene mutations.…”

“…The p.G60R (c.178G>A) was reported previously as a mutation in one female patient (Wang et al, 2007) and was identified in three out of 53 unrelated female probands in our cohort. The c.1094G>A (p.R365Q) was identified previously as a mutation in four female patients (Leoyklang et al, 2008;Bornholdt et al, 2009;Froyen et al, 2009;Maas et al, 2009). Our diagnostic study detected this mutation in an additional 4 out of 53 unrelated probands.…”

“…Approximately 80% of FDH-causing mutations in PORCN are single-nucleotide substitutions, small deletions, or small insertions identifiable by sequence analysis of the PORCN coding region, while the remaining mutations are large genomic deletions that include PORCN (Grzeschik et al, 2007;Wang et al, 2007;Clements et al, 2008;Leoyklang et al, 2008;Bornholdt et al, 2009;Froyen et al, 2009;Harmsen et al, 2009;Maas et al, 2009); more recently, an intragenic deletion of four exons was identified in a female patient (Bornholdt et al, 2009). Ninety percent of affected individuals are women (Gorlin et al, 2001).…”

Co‐occurrence of severe Goltz–Gorlin syndrome and pentalogy of Cantrell – Case report and review of the literature

“…In 2007, mutations were reported in PORCN at Xp11.23 [Grzeschlik et al, 2007;Wang et al, 2007]. Over 100 different PORCN mutations have been reported [Lombardi et al, submitted for publication; Bornholdt et al, 2009;Clements et al, 2009;Froyen et al, 2009]. …”

Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia

“…19, 22 Froyen et al later identified PORCN variants and gene deletions in a cohort of patients with a clinical diagnosis of FDH. 23 FDH is characterized by phenotypic features, including longitudinal striation of the long bones, the combination of split hand with syndactyly and absence of rays (also termed 'lobster-claw hand'), as well as atrophy and linear pigmentation of the skin, herniation of fat through dermal defects and multiple papillomas of the mucous membranes or skin. Oral anomalies, in addition to lip papillomas, include hypoplastic teeth.…”