SMARCAD1 – Isolated Congenital Adermatoglyphia

Isolated congenital adermatoglyphia is characterized by lifelong absence of dermatoglyphs (fingerprints and palmoplantar ridges) and follows an autosomal-dominant inheritance with complete penetrance. Linkage analysis localized the phenotype to 4q22, implicating a skin-specific short isoform of SMARCAD1.

Sequencing in one large kindred identified a heterozygous splice-site transversion, c.1281+665G>T, predicted to abolish the conserved donor site of the noncoding exon unique to the skin-specific SMARCAD1 transcript; this variant segregated with disease across all affected relatives (PMID:21820097).

A second study of six unrelated patients uncovered three additional heterozygous splice-site mutations (c.378+2T>C, c.378+5G>C and c.378+1G>A) at the same donor junction, all predicted to result in haploinsufficiency of the skin-specific isoform (PMID:24909267).

The variant spectrum in isolated adermatoglyphia is restricted to single-nucleotide substitutions at this conserved splice donor site; no coding missense or structural variants have been reported. A representative pathogenic allele is c.1281+665G>T (p.?) (PMID:21820097).

Functional assessment using a minigene assay demonstrated aberrant exon skipping and decreased RNA stability of the short SMARCAD1 transcript, confirmed by RT-PCR in patient cells; global expression profiling of SMARCAD1-deficient keratinocytes revealed dysregulation of epidermal differentiation-associated genes, supporting a haploinsufficiency mechanism (PMID:21820097, PMID:24909267).

Together, robust segregation in multiple pedigrees, a consistent splice-site mutation spectrum, and concordant functional data establish a Strong clinical validity for heterozygous SMARCAD1 variants in Isolated Congenital Adermatoglyphia. Key take-home: splice-site disruption of a skin-specific SMARCAD1 isoform causes autosomal-dominant adermatoglyphia, informing molecular diagnosis of fingerprint absence.

References

• 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

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