LAMA3 – Laryngo-onycho-cutaneous Syndrome

Laryngo-onycho-cutaneous syndrome (LOCS) is an autosomal recessive epithelial disorder caused by pathogenic variants in LAMA3, characterized by mucocutaneous granulation tissue, nail dystrophy, stridor, and fragile skin. LOCS has been reclassified as a subtype of junctional epidermolysis bullosa but remains clinically and genetically distinct (PMID:38328664).

The clinical validity of the LAMA3–LOCS association is Definitive, supported by over 30 probands across at least 15 unrelated families with homozygous or compound heterozygous loss-of-function variants segregating in an autosomal recessive manner, and a LOD score of 19.8 in mapping studies (PMID:12915477). A Punjabi founder frameshift variant (c.151dup (p.Val51GlyfsTer4)) has been observed in multiple kindreds (PMID:37492301), with consistent segregation and phenotype.

Genetic evidence meets ClinGen Strong criteria: autosomal recessive inheritance; segregation of homozygous c.151dup (p.Val51GlyfsTer4) in two affected siblings and heterozygous carrier parents; additional reports of at least 31 LOCS cases with loss-of-function variants including frameshift, nonsense, and splice-site mutations (e.g., 151insG N-terminal deletion) leading to dysfunctional α3a subunit (PMID:12915477, PMID:34514630).

A single recurrent founder variant is reported: c.151dup (p.Val51GlyfsTer4). Variant spectrum in LOCS is dominated by loss-of-function mutations specific to the α3a isoform, with no confirmed missense or hypomorphic alleles in LOCS patients. Carrier frequency in Punjabi Muslim populations is enriched, supporting targeted molecular screening.

Functional studies provide Moderate experimental evidence: immunoprecipitation confirmed that frameshift 151insG abolishes the α3a N-terminal domain without triggering nonsense-mediated decay, and keratinocyte assays demonstrated impaired laminin-332 secretion and aberrant granulation tissue formation in LOCS (PMID:12915477). Expression analyses of LAMA3 isoforms further support tissue-specific pathogenicity of α3a loss.

In sum, robust genetic and experimental concordance defines LAMA3 haploinsufficiency of the α3a isoform as the mechanism underlying LOCS. The founder variant c.151dup facilitates cost-effective carrier and prenatal testing in high-risk populations. Key take-home: Identification of homozygous c.151dup (p.Val51GlyfsTer4) in LAMA3 enables definitive molecular diagnosis and guides early airway management for LOCS.

References

• Human molecular genetics • 2003 • An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. PMID:12915477
• Pakistan journal of medical sciences • 2023 • c.151dup variant in LAMA3 in Pakistani patients affected with Shabbir Syndrome but showing mild symptoms. PMID:37492301
• Pakistan journal of medical sciences • 2024 • Laryngo-Onycho-Cutaneous Syndrome (LOCS). PMID:38328664
• Orphanet Journal of Rare Diseases • 2021 • Natural history and genotype–phenotype correlation in laryngo-onycho-cutaneous syndrome. PMID:34514630

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