Mosaic skin disorders - deep sequencing

Gene: PORCN

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 9 Mar 2022, 2:31 p.m. | Last Modified: 9 Mar 2022, 2:31 p.m.

Panel Version: 1.22

Green List (high evidence)

Comment on list classification: Promoting from grey to amber, but with a recommendation for a GREEN rating following GMS review.

Created: 24 Nov 2021, 5:03 p.m. | Last Modified: 24 Nov 2021, 5:03 p.m.

Panel Version: 1.15

Associated with Focal dermal hypoplasia #305600 (XLD) in OMIM. Focal dermal hypoplasia is characterized by patchy hypoplastic skin and digital, ocular and dental malformations (PMID: 17546030). It is predominantly seen in females (male lethality).

Large number of heterozygous variants in female cases with a FDH phenotype reported. In addition, there are 6 male cases reported (and suggestion of 2 female cases) where postzygotic mosaicism is observed.

PMID: 17546030 - Wang et al 2008 - following identification of a 219-kb region deletion covering 7 genes including PORCN in a girl with FDH, sequence analysis of PORCN identified heterozygous mutations (missense, nonsense, indels) in 10 out of 15 girls with confirmed or suspected FDH. Skewed X inactivation was identified in 3 of them. In 9 cases the variants were not detected in parental samples. In 1 case the mildly affected father appeared to be show somatic mosaicism for the variant. They also found de novo mosaic mutations in all 3 male index FDH cases studied but not in their parents. The males appeared to have normal XY copy numbers. A further female was found to have a near identical 219-kb deletion to the original index patient, together wit 100% skewing of XCI in PBL DNA. The authors note the absence of XCI skewing in some female individuals but postulate that this might be related to the tissue studied (PBL) and the temporal and tissue-specific expression pattern of PORCN.

PMID: 19309688 - Bornholdt et al 2009 - studied 24 unrelated patients (22 sporadic, 2 familial) with Goltz syndrome/focal dermal hypoplasia. 21 were female, 3 male. 3 patients had microdeletions eliminating PORCN, all of whom showed skewed XCI. 1 patient had a deletion of exons 1-4. A variety of nonsense, splice site and missense variants were also seen. For all male Goltz syndrome patients, the phenotype is a result of postzygotic mosaicism, a mixture of wildtype cells and cells with a mutated PORCN gene. This also seems to be the case for 2 of the female patients.

Created: 24 Nov 2021, 1:19 p.m. | Last Modified: 24 Nov 2021, 1:19 p.m.

Panel Version: 1.12

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Focal dermal hypoplasia, OMIM:305600

Publications

• 17546030
• 19309688

Green List (high evidence)

Sources: Other

Created: 9 Nov 2021, 10:52 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Focal dermal hypoplasia (https://omim.org/entry/305600)

Publications

• 17546030