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.
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Acknowledgements
We are grateful to the patients and their parents. The results summarized here are part of the MD thesis of May-Britt Harmsen at the University of Hamburg. We thank Inka Jantke for skillful technical assistance, Isabella Wimplinger for sequence analysis of HCCS and X chromosome inactivation analysis, Manuela Morleo and Brunella Franco for copy number analysis of HCCS exons, and Stephan Schneider for his constant support to obtain material from patient FDH5.
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Harmsen, MB., Azzarello-Burri, S., García González, M. et al. Goltz–Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap. Eur J Hum Genet 17, 1207–1215 (2009). https://doi.org/10.1038/ejhg.2009.40
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DOI: https://doi.org/10.1038/ejhg.2009.40
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