LSS – Hypotrichosis 14

Lanosterol synthase (LSS) is implicated in autosomal recessive Hypotrichosis 14, a disorder characterized by sparse scalp hair and variable midline anomalies. The clinical validity of this gene–disease relationship is classified as Moderate by ClinGen based on multiple unrelated probands and concordant functional models.

Inheritance is autosomal recessive. Two unrelated patients with congenital hypotrichosis and midline anomalies harbored biallelic LSS variants, including a missense change c.530G>A (p.Arg177Gln) and a second loss-of-function allele, consistent with recessive segregation (n = 2 probands) (PMID:32101538). The variant spectrum in these cases included missense and truncating alleles altering LSS enzymatic function.

Biochemical assays in affected individuals revealed an elevated (S)-2,3-epoxysqualene/lanosterol ratio in forehead sebum, confirming LSS enzymatic blockade (PMID:32101538). Epidermis-specific Lss knockout mice exhibited neonatal lethality due to barrier defects, and tamoxifen-induced knockout in adult skin recapitulated hypotrichosis, demonstrating tissue-specific loss-of-function pathogenesis.

No studies to date dispute the LSS–Hypotrichosis 14 association. The concordance of patient biochemical biomarkers, genetic segregation, and animal models provides robust experimental support for a haploinsufficiency mechanism.

Collectively, these data justify a Moderate ClinGen classification: multiple probands with biallelic variants and strong functional concordance. Key take-home: LSS genetic testing coupled with sebum biomarker analysis can confirm diagnosis and guide management of congenital hypotrichosis.

References

• PLoS Genetics • 2020 • Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. PMID:32101538

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