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

Abstract

BackgroundThe 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.ObjectiveIn this report, we describe two families with mild phenotypical presentation.MethodsWe performed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing.ResultsIn 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.ConclusionOur study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.

A large, ten‐generation family with autosomal dominant preaxial polydactyly/triphalangeal thumb: Historical, clinical, genealogical, and molecular studies

“…At least 20 different SNVs have been reported within the ZRS region in patients with triphalangeal thumb and related diseases: C105 A165 (Potuijt et al, 2020), C287 (VanderMeer et al, 2012), T295 (Furniss et al, 2008), G297 (Albuisson et al, 2011), A305 (Lettice et al, 2003), T323 (Lettice et al, 2003), T334 (Albuisson et al, 2011), C396 (Semerci et al, 2009) and present report, C402 (VanderMeer et al, 2014), G404, A406 (Norbnop et al, 2014; Zhao et al, 2016), A417 (Vanlerberghe et al, 2015) (in mosaic), T428 (Wu et al, 2016), C446 (Xu et al, 2020), T463 (Farooq et al, 2010), T603 (Laurell et al, 2012), a 13 bp insertion (Laurell et al, 2012), C619 (Al‐Qattan et al, 2012), C621 (Gurnett et al, 2007), A739 (Gurnett et al, 2007) (Figure 6). Recently, some other pathogenic changes at the so‐called pre‐ZRS region (pZRS), a region approximately 800 bp upstream from the ZRS, have been related to an indistinguishable similar phenotype (Potuijt et al, 2018; Xiang et al, 2017) to those having a pathogenic variant within the ZRS region (Figure 6).…”

ZPA Regulatory Sequence Variants in Chinese Patients With Preaxial Polydactyly: Genetic and Clinical Characteristics

“…We found that the proband harbored the compound heterozygote of ZRS (ZRS474C > G and ZRS619C > T). Given that Jacob et al ( 23 ) reported ZRS variant carriers with minor anomalies and underlined the importance of accurate clinical examination in mild triphalangeal thumb families, we carefully checked the phenotypes of her family members with one ZRS variant and did not find any limb defects (cannot completely exclude the possibility of an extremely subtle anomaly) ( 23 ). We reasoned that PPD in this family was attributed to combinedly acting by these two variants.…”

Prenatal diagnosis of triphalangeal thumb-polysyndactyly syndrome by ultrasonography combined with genetic testing: A case report

“…These mild anomalies might not cause evident aesthetic or functional problems, so the report will indicate that the individual is as unaffected. Consequently, the width, number of flexion folds, strength, and digital opposition of the thumb and whether the lunula of the thumb is duplicated should be evaluated when investigating the patient’s history[ 19 ].…”