SMARCAD1 and Absence of Fingerprints‐Congenital Milia Syndrome

Multiple independent studies have demonstrated a compelling association between SMARCAD1 (HGNC:18398) and absence of fingerprints‐congenital milia syndrome (MONDO_0007507). The disease is inherited in an autosomal dominant manner, and several families have been reported with recurrent splice site mutations in a skin‐specific isoform of SMARCAD1. In a large Chinese pedigree with a maximal LOD score of 3.01, whole‐genome sequencing identified a splice variant, c.378+1G>T (PMID:26932190), that co‐segregated with the disease phenotype across multiple affected individuals (PMID:26932190).

In addition to the Chinese cohort, independent reports from Canadian, Dutch, and other families have provided robust genetic evidence with additional donor splice site mutations such as c.378+5G>A and similar variants. These studies report a total of well over 10 unrelated probands and numerous affected relatives exhibiting congenital adermatoglyphia, congenital milia, and variable features such as hyperpigmentation, hypohidrosis, and ectodermal dysplasia (PMID:34909722, PMID:24664640). Such findings reinforce the consistency and reproducibility of the genotype‐phenotype correlation.

Detailed genetic evidence is supported by rigorous segregation analyses in which additional affected relatives across multi‐generation pedigrees consistently carry the pathogenic variant. Notably, the recurrent c.378+1G>T mutation, which was also implicated in isolated adermatoglyphia in other studies, underscores the molecular mechanism whereby aberrant splicing leads to haploinsufficiency of the skin‐specific SMARCAD1 isoform (PMID:26932190, PMID:30289605).

Functional assessments further substantiate the role of SMARCAD1 in the skin phenotype. In vitro minigene assays and RNA analyses have shown that these splice site mutations disrupt normal splicing and result in reduced expression of the skin‐specific transcript. Such experiments provide moderate functional evidence that the pathogenic mechanism is likely driven by loss‐of-function effects, which is consistent with the clinical presentation observed in affected individuals (PMID:21820097, PMID:24909267).

The convergence of genetic and experimental data from multiple, independent cohorts lends robust support to the disease association. Although some reports have explored potential associations with additional features such as cutaneous squamous cell carcinoma, the primary and recurrent finding remains the link between specific splice site mutations in SMARCAD1 and the core features of absence of fingerprints‐congenital milia syndrome.

In sum, the evidence demonstrates that mutations disrupting the donor splice site of the skin‐specific isoform of SMARCAD1 consistently result in a distinct autosomal dominant phenotype characterized by congenital adermatoglyphia, congenital milia, and additional ectodermal abnormalities. Importantly, the strength and consistency of the genetic evidence, together with in vitro functional assays, offer high clinical utility in diagnostic decision‑making and potential commercial applications.

Key Take‑home: SMARCAD1 splice site mutations are a robust molecular marker for absence of fingerprints‐congenital milia syndrome, facilitating targeted diagnostic and therapeutic strategies.

References

• European journal of human genetics • 2016 • Genome-wide linkage analysis and whole-genome sequencing identify a recurrent SMARCAD1 variant in a unique Chinese family with Basan syndrome PMID:26932190
• American journal of medical genetics. Part A • 2018 • Basan gets a new fingerprint: Mutations in the skin-specific isoform of SMARCAD1 cause ectodermal dysplasia syndromes with adermatoglyphia PMID:30289605
• JID innovations • 2021 • Two SMARCAD1 Variants Causing Basan Syndrome in a Canadian and a Dutch Family PMID:34909722
• 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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