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A targeted NGS approach to identify a c.352C>G variant in the TWIST1 gene in an Albanian family with Saethre–Chotzen syndrome

Author(s): Elena Manara, Denisa Guraj, Francesca Fanelli, Paolo E Maltese, Anila Babameto-Laku, Natale Capodicasa , Sandro Michelini, Bruno Amato, Matteo Bertelli

A targeted next generation sequencing (NGS) approach analysing contemporaneously 20 different genes mainly involved in craniosynostosis was adopted to molecularly diagnose the family of a 2-years old girl affected by Saethre–Chotzen syndrome, a syndromic form of craniosynostosis. The identified pathogenic variant in the TWIST1 gene lies in a conserved residue (Arg118) that shifts from a positively charged amino acid to a non-polar amino acid and segregates in all the examined affected familial members, although with variable phenotypic expression. An accurate molecular diagnosis is of obvious value for the clinical management of individuals with isolated or syndromic craniosynostosis to define their medical needs, the recurrence risk and allow the identification of available therapeutic opportunity. Given the high number of associated genes, an NGS approach is the election choice to increase the yield of genetic diagnosis, leading to an expansion of the genotypic and phenotypic spectrum of these rare syndromes