Vol.:(0123456789) 1 3 European Journal of Orthopaedic Surgery & Traumatology https://doi.org/10.1007/s00590-018-2343-3 ORIGINAL ARTICLE • UPPER LIMB - NERVE GRAFT Thumb duplication: molecular analysis of different clinical types Zisis Kyriazis 1  · Panagoula Kollia 2  · Ioanna Grivea 3  · Sokratis E. Varitimidis 1  · Pantelis Constantoulakis 4  · Zoe H. Dailiana 1,5 Received: 22 October 2018 / Accepted: 25 November 2018 © Springer-Verlag France SAS, part of Springer Nature 2018 Abstract Purpose 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. Results 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. Conclusion 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. Keywords Polydactyly · Thumb duplication · Gene · Mutation · Next-generation sequencing · Ciliopathy Introduction The development of the human limb bud starts during the end of the fourth week of intrauterine life. Approximately 4 weeks later, an interplay of genes and molecular fac- tors results in the development of a complete set of limbs with a well-defined appearance, function, and a specific number of digits. Proper positional signaling within the three-dimensional structure of the developing limb is of crucial importance for the future cell fate during embryo- genesis. Disturbances in these signaling pathways can result in a large number of congenital limb malformations, many of which were already described in the in mythology and antiquity [1–6]. Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10,000 live births [3]. Polydactyly can occur as an isolated disorder, in association with other hand and foot malforma- tions, or as a part of a syndrome, and is usually inherited as an autosomal dominant trait [3]. According to its ana- tomical location, polydactyly can be generally subdivided into pre- and postaxial forms. Polydactyly may be also clas- sified according the embryological findings (Winter and Tickle classification) [4] or the classification by Temtamy and McKusick widely used among geneticists [5]. Preaxial polydactyly refers to an excess of parts on the radial side of the limb, including thumb duplication, various forms of triphalangeal thumbs and index finger duplication. Thumb * Zoe H. Dailiana dailiana@med.uth.gr 1 Department of Orthopaedic Surgery, Medical School, University of Thessaly, Larissa, Greece 2 Department of Genetics and Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece 3 Department of Paediatrics, Medical School, University of Thessaly, Larissa, Greece 4 BioAnalytica-Genotypos, Athens, Greece 5 Iaso Thessalias, Larissa, Greece