Triphalangeal thumbs (TPTs) are regularly caused by mutations in the ZRS in LMBR1. Phenotypic variability can be present in TPT-families. However, recent observations suggest an increased occurrence of severe phenotypes in the Dutch TPT-population. Therefore, the aim of this study is to investigate the progression of the clinical severity of TPT-phenotype through generations. Index patients from a Dutch TPT-population were identified. A 105C>G mutation in the ZRS has previously been confirmed in this population. Questionnaires regarding family occurrence and phenotypes were distributed. Subsequently, families were visited to validate the phenotype. Both occurrence and inheritance patterns of the TPT-phenotype were analyzed through multiple generations. One hundred seventy patients with TPT were identified from 11 families. When considering all 132 segregations (parent-to-child transmission), 54% of the segregations produced a stable phenotype, 38% produced a more severe phenotype while only 8% of the phenotype was less severe when compared to the affected parents. Overall, 71% of the index patients had a more severe phenotype compared to their great-grandparent. Although all family members share an identical mutation in the ZRS (105C>G), it does not explain the wide phenotypic range of anomalies. Our observational study provides better estimations for counseling and provides new insights in the long-range regulation of SHH by the ZRS-enhancer. In the current study, we provide evidence that the assumed variability in TPT-phenotype is not random, but in fact it is more likely that the expression becomes more severe in the next generation. Therefore, we observe a pattern that resembles phenotypic anticipation in TPT-families.

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Keywords Genetic enhancer element, Genetic variation, Hedgehog proteins, Polydactyly, Thumb abnormalities
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Journal American Journal of Medical Genetics. Part A
Baas, M, Potuijt, J.W. (Jacob W.P.), Hovius, S.E.R, Hoogeboom, A.J.M, Galjaard, R-J.H, & van Nieuwenhoven, C.A. (2017). Intrafamilial variability of the triphalangeal thumb phenotype in a Dutch population: Evidence for phenotypic progression over generations?. American Journal of Medical Genetics. Part A. doi:10.1002/ajmg.a.38398