LTBP2 – Weill-Marchesani Syndrome

Weill-Marchesani syndrome (WMS) is a rare acromelic dysplasia characterized by the triad of short stature, brachydactyly, and ocular anomalies such as ectopia lentis. LTBP2 (latent transforming growth factor β-binding protein 2) encodes an extracellular matrix protein that associates with fibrillin-1 microfibrils and is expressed in ciliary zonule fibers and connective tissues. Biallelic variants in LTBP2 underlie autosomal recessive WMS (MONDO:0018096) by disrupting extracellular matrix integrity and microfibril formation.

Clinical Validity

Three unrelated probands with biallelic LTBP2 variants and consistent WMS phenotypes support a moderate level of clinical validity. A homozygous missense variant c.3529G>A (p.Val1177Met) was identified in an Iranian WMS proband with homozygosity mapping and segregation analyses (PMID:22539340). In a multicenter study of 61 WMS patients, two additional individuals harbored biallelic LTBP2 mutations among recessive cases (PMID:37734846). No conflicting evidence has been reported.

Genetic Evidence

Inheritance is autosomal recessive, with three unrelated probands carrying loss-of-function or missense variants. Case reports include c.3529G>A (p.Val1177Met) in exon 25 and two additional biallelic mutations identified in a retrospective cohort. Variant spectrum is limited to missense and truncating alleles predicted to impair microfibrillar interactions. No founder or recurrent variants have been documented. Total segregation data are limited to the original mapping family (no additional affected relatives reported).

Functional Evidence

Functional studies demonstrate that loss of LTBP2 disrupts microfibril assembly in ciliary zonules and skin extracellular matrix. Ltbp2(-/-) mice develop lens luxation without glaucoma, mirroring human ectopia lentis and confirming a haploinsufficiency mechanism (PMID:24908666). Electron microscopy of proband skin reveals fragmented microfibrillar networks concordant with in vitro ECM assays in patient fibroblasts (PMID:22539340). Rescue of microfibril formation by recombinant LTBP-2 further substantiates pathogenicity.

Integration and Conclusion

Genetic and experimental data convergently implicate biallelic LTBP2 variants as a cause of recessive WMS. Three probands with consistent phenotypes and robust functional models meet a moderate ClinGen evidence threshold. While additional large-scale segregation studies could strengthen the association, current data support inclusion of LTBP2 in diagnostic gene panels for acromelic dysplasias.

Key Take-home: Screening for biallelic LTBP2 variants is clinically useful for diagnosing autosomal recessive Weill-Marchesani syndrome and guiding management of its ocular and skeletal manifestations.

References

• Human mutation • 2012 • LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. PMID:22539340
• Journal of medical genetics • 2024 • Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature. PMID:37734846
• Human molecular genetics • 2014 • Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils PMID:24908666

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