Postzygotic biallelic inactivation of FDFT1 underlies solitary lesion formation in porokeratosis of Mibelli.

BACKGROUNDPorokeratosis reflects clonal expansion of keratinocytes with biallelic inactivation of mevalonate-cholesterol biosynthesis pathway genes. In disseminated porokeratosis (DP), lesions arise through independent somatic second hits in carriers of heterozygous germline pathogenic variants, whereas porokeratosis of Mibelli (PM) is usually solitary, and its molecular basis remains incompletely defined.

OBJECTIVETo elucidate the molecular basis of solitary PM.

METHODSWe analyzed blood and lesional epidermis from seven patients with solitary PM within a 156-patient porokeratosis cohort using deep sequencing, copy-number/SNP profiling, and methylation analysis.

RESULTSSolitary PM plaques were larger and more irregular than the annular DP lesions. No pathogenic germline variants were detected in MVK, PMVK, MVD, FDPS, or FDFT1. Three patients had somatic biallelic genetic inactivation of FDFT1 through putative deleterious variants and/or focal microdeletions. The remaining four showed FDFT1 promoter hypermethylation with loss of heterozygosity (LOH) at the FDFT1 locus due to copy-neutral LOH or a monoallelic 8p deletion, consistent with early monoallelic epigenetic silencing, followed by genetic loss of the remaining active allele. In one patient, part of the plaque expanded centrifugally over 7.5 years.

CONCLUSIONSolitary PM can be driven by postzygotic, lesion-restricted, biallelic inactivation of FDFT1 through genetic or epigenetic mechanisms within a single epidermal clone, promoting clonal expansion. This model may explain the tendency toward solitary PM lesions. The low probability of acquiring postzygotic biallelic inactivation without germline predisposition may underlie solitary PM and suggest a low recurrence risk for offspring, unlike DP driven by germline heterozygosity.

Abstract from PubMed