Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes.

Background: The of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause triphalangeal thumb (TPT) and polydactyly in affected families.

Objective: In this report, we describe two families with mild phenotypical presentation.

Methods: We performed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing.

Results: In family I, a novel 165A>G variant in the ZRS (g.156584405A>G, GRCh37/Hg19) was found. In family II, we identified a 295T>C variant in the ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who were presumed to be unaffected shared the variant in the ZRS with affected family members, suggesting reduced penetrance of the genotype. However, clinical examination of these unaffected family members revealed minor anomalies like broad thumbs and lack of thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that these ZRS variants are minimally disruptive for Sonic Hedgehog expression and therefore can result in subclinical phenotypes.

Conclusion: Our study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.