ADAMTSL2 – Ehlers–Danlos syndrome

ADAMTSL2 (HGNC:14631) variants have been implicated in autosomal dominant Ehlers–Danlos syndrome (Ehlers–Danlos syndrome). In a single-family case report, a novel heterozygous c.1261G>A (p.Gly421Ser) variant segregated with disease in the proband and his affected father in an autosomal dominant pattern (PMID:26879370). A subsequent series identified the same variant in five additional unrelated patients presenting with generalized joint hypermobility and tissue fragility, each with a positive family history consistent with autosomal dominant transmission (PMID:33369194).

Overall, six unrelated probands carry the ADAMTSL2 c.1261G>A (p.Gly421Ser) variant, with segregation confirmed in one pedigree. Bioinformatic analyses and protein modeling support a deleterious effect, but no dedicated functional assays have been performed in an EDS context and no truncating or splice variants have been reported for EDS. Additional functional and mechanistic studies are required to establish a definitive role of ADAMTSL2 in connective tissue integrity in Ehlers–Danlos syndrome.

References

• BMC musculoskeletal disorders • 2016 • Systematic data-querying of large pediatric biorepository identifies novel Ehlers-Danlos Syndrome variant. PMID:26879370
• American journal of medical genetics. Part A • 2021 • ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders. PMID:33369194

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