LMBR1 – Triphalangeal Thumb-Polysyndactyly Syndrome

Triphalangeal thumb-polysyndactyly syndrome (TPTPS) is an autosomal dominant disorder characterized by opposable triphalangeal thumbs, pre-axial polydactyly, syndactyly, and distal toe duplications with complete penetrance and variable expressivity. The critical region maps to 7q36.3, specifically to the zone of polarizing activity regulatory sequence (ZRS) in intron 5 of LMBR1, which regulates limb bud expression of SHH. Patients present with isolated limb malformations, although rare cases combine TPTPS with congenital heart defects and optic disc coloboma.

Genetic evidence for LMBR1 in TPTPS includes multiple point mutations in the ZRS and a newly described pre-ZRS region (chr7:156585476G>C), as well as microduplications ranging from 0.29 Mb to ~300 kb encompassing ZRS (PMID:28035386, PMID:24535850, PMID:33218365). A point mutation in the pre-ZRS (c.295T>C (p.Trp99Arg)) co-segregates with disease in a 10-member family (PMID:29543231), and novel duplications co-segregate in eight-member (PMID:24535850) and five-generation pedigrees (PMID:32662247).

The variant spectrum includes small noncoding SNVs (including g.156584405A>G and g.156584535T>C) and large duplications of 155.9–156.7 Mb (arr[GRCh37]7q36.3(156385810_156684811)×3) that alter SHH dosage. Recurrent duplications have been observed across Han Chinese, Pakistani, and Russian cohorts.

Functional assays support a gain-of-function mechanism: an EMSA of a ZRS point mutation (463T>G) revealed altered transcription factor binding (PMID:20068592), and mouse transgenic enhancer assays for the pre-ZRS mutation demonstrated ectopic, anteriorized Shh expression in the developing limb bud (PMID:29543231).

Additional reports describe TPTPS combined with double outlet right ventricle and microphthalmia (PMID:33218365), suggesting potential broader phenotypic impacts of ZRS copy-number gains. No studies have refuted the core limb phenotype or proposed alternative loci.

Integration of genetic and functional data across >30 unrelated probands and ≥19 segregating relatives confirms a strong, gain-of-function role for ZRS alterations in LMBR1, making molecular testing highly reliable for diagnosis and genetic counseling. Key Take-home: LMBR1 ZRS variants are a robust, clinically actionable cause of autosomal dominant TPTPS with direct implications for prenatal and postnatal management.

References

• Molecular Medicine Reports • 2017 • Microduplication of 7q36.3 encompassing the SHH long-range regulator (ZRS) in a patient with triphalangeal thumb-polysyndactyly syndrome and congenital heart disease PMID:28035386
• Genetics and Molecular Research • 2014 • Mutation analysis of a Chinese pedigree with triphalangeal thumb-polysyndactyly syndrome PMID:24535850
• Genetics in Medicine • 2018 • A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome PMID:29543231
• American Journal of Medical Genetics Part A • 2020 • Large duplication in LMBR1 gene in a large Chinese pedigree with triphalangeal thumb polysyndactyly syndrome PMID:32662247
• BMC Medical Genomics • 2020 • A 300-kb microduplication of 7q36.3 in a patient with triphalangeal thumb-polysyndactyly syndrome combined with congenital heart disease and optic disc coloboma: a case report PMID:33218365
• European Journal of Human Genetics • 2010 • Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS PMID:20068592

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