SMARCAD1 – Palmoplantar Keratoderma-Sclerodactyly Syndrome

Palmoplantar keratoderma-sclerodactyly syndrome, also known as Huriez syndrome, is an autosomal dominant genodermatosis characterized by scleroatrophic hands and feet, hypoplastic nails, palmoplantar keratoderma and predisposition to cutaneous squamous cell carcinoma. Genetic and clinical convergence with Basan syndrome and isolated adermatoglyphia implicates allelic variation in SMARCAD1 as the underlying cause. The gene SMARCAD1 encodes a helicase with a skin-specific short isoform critical for dermatoglyph development and epidermal homeostasis.

Deep sequencing in three unrelated families (Croatia, Netherlands, Germany) identified heterozygous splice-donor variants disrupting the first exon–intron boundary of the skin-specific SMARCAD1 isoform in seven affected individuals ([PMID:35212137]). These variants segregated with disease across three pedigrees, establishing autosomal dominant inheritance. Clinically, all patients exhibited adermatoglyphia (HP:0007455), hypoplastic nails (HP:0001792) and palmoplantar keratoderma (HP:0000982).

Prior functional studies demonstrate that heterozygous donor splice-site mutations (e.g., c.378+1G>T) cause aberrant splicing of the skin-specific transcript in minigene assays, leading to reduced RNA stability ([PMID:21820097]). Global gene expression analyses in patient and SMARCAD1-knockdown keratinocytes reveal dysregulation of epidermal differentiation–associated genes ([PMID:24909267]). These data support a haploinsufficiency mechanism, as loss of the short isoform perturbs key pathways governing dermatoglyph formation and keratinocyte function.

However, one reported variant (c.378+3A>T) failed to show splicing defects in vitro despite co-segregation with Basan syndrome in a small pedigree ([PMID:24664640]). This discrepancy may reflect context-dependent splicing efficiency, alternative regulatory elements or assay limitations, warranting further mechanistic studies.

The convergence of genotype and phenotype across Huriez syndrome, Basan syndrome and isolated adermatoglyphia supports a shared allelic spectrum attributable to SMARCAD1 skin-specific isoform haploinsufficiency. Splice-site variants consistently lead to decreased transcript levels, disrupt epidermal differentiation gene networks and manifest as palmoplantar keratoderma, scleroatrophy and nail hypoplasia. The clinical overlap underscores the utility of SMARCAD1 analysis in unexplained ectodermal dysplasias involving dermatoglyph abnormalities. While current data yield a strong gene–disease association, expanded cohorts and transcript quantification are needed to refine genotype–phenotype correlations. This integration informs genetic counseling, directs molecular diagnostics and suggests surveillance for cutaneous malignancy in affected individuals. Key take-home: Heterozygous splice-donor mutations in the skin-specific SMARCAD1 isoform are a robust biomarker for palmoplantar keratoderma-sclerodactyly syndrome with direct diagnostic and prognostic relevance.

References

• American journal of medical genetics. Part A • 2022 • Huriez syndrome: Additional pathogenic variants supporting allelism to SMARCAD syndrome. PMID:35212137
• American journal of human genetics • 2011 • A mutation in a skin-specific isoform of SMARCAD1 causes autosomal-dominant adermatoglyphia. PMID:21820097
• The British journal of dermatology • 2014 • Mutations in SMARCAD1 cause autosomal dominant adermatoglyphia and perturb the expression of epidermal differentiation-associated genes. PMID:24909267
• American journal of medical genetics. Part A • 2014 • Analysis of two candidate genes for Basan syndrome. PMID:24664640

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