Thumb duplication: molecular analysis of different clinical types
Molecular analysis of different types of thumb duplication and identification of new suspected gene mutations.
Materials and methods
In a series of patients operated for polydactyly, DNA was extracted from blood samples collected preoperatively. Among these, the samples of two patients with thumb duplication (Wassel types III and IV) were initially selected for molecular analysis. The method of Clinical Exome Solution was used for the study of the phenotype-involved genes. Next-generation sequencing (NGS) was performed on a NextSeq-500 Platform (Illumina), and Sophia DDM® SaaS algorithms were used for the bioinformatics analysis of the data.
In total, 8—including 4 new—mutations were detected in CEP290 (1 mutation), RPGRIP1 (2 mutations), TMEM216 (2 mutations), FBN1 (1 mutation), CEP164 (1 mutation), and MEGF8 (1 mutation) genes. NGS revealed 3 mutated genes in the patient with Wassel III thumb duplication and 5 mutated genes in the patient with Wassel IV duplication. The molecular analysis revealed that the patients had 2 mutated genes in common, but they only shared one common mutation.
The new detected mutations are most probably associated with thumb duplication, as they belong to genes with already described mutations causing ciliopathies, often including polydactyly in their phenotype. Recognition of these mutations will be helpful to prenatal diagnosis, operative treatment strategy prediction, and possible future experimental applications in gene therapy.
KeywordsPolydactyly Thumb duplication Gene Mutation Next-generation sequencing Ciliopathy
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
This study was approved by the institutional review board and follows the ethical principles for medical research involving human subjects of the World Medical Association Declaration of Helsinki.
- 4.Winter RM, Tickle C (1993) Syndactylies and polydactylies: embryological overview and suggested classification. Eur J Hum Genet 1:96–104Google Scholar
- 5.Temtamy S (1985) The genetics of hand malformations: updated. Congenit Anom 25(1):73–92. https://doi.org/10.1111/j.1741-4520.1985.tb00636.x Google Scholar
- 8.Marzke M, Marzke RF (2000) Evolution of the human hand: approaches to acquiring, analysing and interpreting the anatomical evidence. J Anat 197:121–140. https://doi.org/10.1046/j.1469-7580.2000.19710121.x Google Scholar
- 9.Ezaki M (1990) Radial polydactyly. Hand Clin 6:577–588Google Scholar
- 10.Faust KC, Kimbrough T, Oakes JE, Edmunds JO, Faust DC (2015) Polydactyly of the hand. Am J Orthop 44:127–134Google Scholar
- 11.Goldfarb CA (2006) Reconstruction of radial polydactyly. Tech Hand Up Extrem Surg 10:265–270. https://doi.org/10.1097/01.bth.0000236988.88911.4b Google Scholar
- 12.Jia ZW, Bai DM, Long JT, Guo XS, Tian Y, Zhang LQ, Liu BB, Ren L (2013) Optimal surgical timing and treatment of thumb duplication in children. Zhonghua Zheng Xing Wai Ke Za Zhi 29:336–340Google Scholar
- 16.Miura T (1982) Duplicated thumb. Plastic Reconstr Surg 69:470–481Google Scholar
- 17.Cohen MS (1998) Thumb duplication. Hand Clin 14:17–27Google Scholar
- 19.Coene K, Mans D, Boldt K, Gloeckner J, Van Reeuwijk J, Bolat E, Roosing S, Letteboer S, Peters T, Cremers F (2011) The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. Hum Mol Genet 20:3592–3605. https://doi.org/10.1093/hmg/ddr280 Google Scholar
- 20.Valente EM, Logan C, Mougou-Zerelli S, Ho Lee J, Silhavy J, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K et al (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 42:619–625. https://doi.org/10.1038/ng.594 Google Scholar
- 21.Adès LC, Haan EA, Colley AF, Richard RI (1996) Characterisation of four novel fibrillin-1 (FBN1) mutations in Marfan syndrome. J Med Genet 33:665–671Google Scholar
- 23.Twigg S, Lloyd D, Jenkins D, Elçioglu N, Cooper C, Al-Sannaa N, Annagür A, Gillessen-Kaesbach G, Hüning I, Knight S, Goodship S, Keavney B et al (2012) Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. Am J Hum Genet 91:897–905. https://doi.org/10.1016/j.ajhg.2012.08.027 Google Scholar
- 24.Slaats GG, Ghosh AK, Falke LL, Le Corre S, Shaltiel IA, Van de Hoek G, Klasson TD, Stokman MF, Logister I, Verhaar MC, Goldschmeding R, Nguyen TQ, Drummond IA, Hildebrandt F, Giles RH (2014) Nephronophthisis-associated CEP164 regulates cell cycle progression, apoptosis and epithelial-to-mesenchymal transition. PLoS Genet 10:e1004594. https://doi.org/10.1371/journal.pgen.1004594 Google Scholar