title: Goltz-Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap.
abstract: Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: May-Britt
authors.initials: MB
authors.lastname: Harmsen
authors.forename: Silvia
authors.initials: S
authors.lastname: Azzarello-Burri
authors.forename: M Mar
authors.initials: MM
authors.lastname: García González
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Peter
authors.initials: P
authors.lastname: Meinecke
authors.forename: Dietmar
authors.initials: D
authors.lastname: Müller
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Eva
authors.initials: E
authors.lastname: Rossier
authors.forename: Eva
authors.initials: E
authors.lastname: Seemanova
authors.forename: Christiane
authors.initials: C
authors.lastname: Spaich
authors.forename: Bernhard
authors.initials: B
authors.lastname: Steiner
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D000217:Acyltransferases; D017398:Alternative Splicing; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D004252:DNA Mutational Analysis; D005260:Female; D005489:Focal Dermal Hypoplasia / Q000150:complications / Q000235:genetics*; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008850:Microphthalmos / Q000150:complications / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D008565:Membrane Proteins; D000217:Acyltransferases; C491188:PORCN protein, human