Intrafamilial variability of the triphalangeal thumb phenotype in a Dutch population: Evidence for phenotypic progression over generations?
Autor: | Jacob W P Potuijt, A. Jeannette M. Hoogeboom, Robert-Jan H. Galjaard, Christianne A. van Nieuwenhoven, Steven E.R. Hovius, Martijn Baas |
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Přispěvatelé: | Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Adult Male Triphalangeal thumb Population 030105 genetics & heredity Biology 03 medical and health sciences Genetic variation Genetics medicine Inheritance Patterns Humans Hedgehog Proteins education Child Genetics (clinical) education.field_of_study thumb abnormalities Polydactyly Membrane Proteins genetic enhancer element Original Articles polydactyly medicine.disease Phenotype Pedigree Enhancer Elements Genetic Thumb Mutation (genetic algorithm) Anticipation (genetics) Mutation genetic variation Female Original Article Hand Deformities Congenital |
Zdroj: | American Journal of Medical Genetics Part A, 173(11), 2898-2905. Wiley-Liss Inc. American Journal of Medical Genetics. Part a |
ISSN: | 1552-4825 |
Popis: | 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. |
Databáze: | OpenAIRE |
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