Palmoplantar keratodermas

Gene: PERP

Green List (high evidence)

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

Created: 6 Dec 2024, 12:38 p.m. | Last Modified: 6 Dec 2024, 12:38 p.m.

Panel Version: 3.27

Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in Palmoplantar keratodermas, as identified from both monoallelic and biallelic variants from at least nine different families from multiple ethnicities, and supported by results from mouse models.

Heterozygous variants in PERP gene has been identified in five families (p.Tyr153* (c.459C>G, c.459C>A) and p.Trp151* (c.452G>A, c.453G>A)). These cause Olmsted syndrome-2 (OLMS-2, MIM# 619208), which is characterised by mutilating hyperkeratotic skin lesions, primarily on the palms and soles, but also extending onto dorsal surfaces of the hands and feet and distal extremities. However, two unrelated patients of Chinese ancestry identified with heterozygous mutation c.459C>A (p.Tyr153*) had more severe clinical manifestations such as more generalized lesions, alopecia universalis, intolerable itching, congenital hypotrichosis, and growth retardation.

Homozygous variants in PERP gene has been identified in four different families. p.Ser38Leufs*52 and p.Gly156Arg (c.466G>A) variants cause Erythrokeratodermia variabilis et progressiva-7 (EKVP7, MIM# 619209), which is characterised by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet (transgrediens) and erythematous annular skin lesions. p.Leu30Pro (c.89T > C) and p.Gly156Arg (c.466G > C) variants cause ichthyosis (MONDO:0019269), palmoplantar keratoderma and dystrophic toe nails.

The association of PERP to OMS2 and EKVP7 has also been documented in OMIM, however the association to ichthyosis from a recent study from two unrelated multiplex consanguineous Iranian families has not yet been documented in OMIM.

The gene-disease association phenotypes from homozygous EKVP7 patients were supported by similar observations from Perp-/- mice. In addition, the functional analysis of patient- and control-derived keratinocytes revealed a deleterious effect on intracellular localisation of PERP.

Created: 9 Dec 2022, 5:56 p.m. | Last Modified: 9 Dec 2022, 5:56 p.m.

Panel Version: 2.1

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; Ichthyosis, MONDO:0019269; Alopecia universalis; Congenital hypotrichosis

Publications

• 31898316
• 30321533
• 31361044
• 34265120
• 34863005
• 32593191

Red List (low evidence)

This gene was part of an initial gene list collated by Thomas Cullup, GOSH and Veronica Kinsler, UCL, 25.Jan.2019 on behalf of the GMS Skin Specialist Test Group. Gene Symbol submitted: PERP; Suggested initial gene rating: Red; Evidence for inclusion: PMID:30321533; Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none provided.

Created: 28 Jan 2019, 10:47 a.m.

Publications

• 30321533