A novel ACVR1 mutation detected by whole exome sequencing in a family with an unusual skeletal dysplasia Maryam Rafati a, b, c , Faezeh Mohamadhashem a, d , Azadeh Hoseini a, b , Fatemeh Hoseininasab a , Saeed Reza Ghaffari a, b, c, * a Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran b Comprehensive Genetic Center, Hope Generation Foundation, Tehran, Iran c Gene Clinic, Tehran, Iran d Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran article info Article history: Received 10 January 2016 Received in revised form 18 April 2016 Accepted 11 May 2016 Available online 13 May 2016 Keywords: Whole exome sequencing ACVR1 Skeletal dysplasia Fibrodysplasia ossificans progressiva FOP variant abstract “Disorganized Development of Skeletal Component” (DDSC) is a group of genetic skeletal dysplasia, caused by mutations in 9 genes including ACVR1 . The most known ACVR1-related disorder is fibrodys- plasia ossificans progressiva (FOP). FOP variants are frequently encountered with diagnostic challenges due to overlapping clinical manifestations and variable severity. Application of high throughput sequencing methods can overcome these limitations by simultaneous investigation of the entire ACVR1 gene together with other genes involved in disorders with similar manifestations. A 33-year-old man with an unusual skeletal dysplasia and no previous clinical diagnosis is presented in this study. Whole exome sequencing detected a novel c.737T>A (p.Phe246Tyr) mutation in ACVR1 gene. Detailed targeted variant analysis in 226 known genes associated with genetic skeletal disorders together with more specific targeted analysis in 9 genes associated with DDSC ruled out the involvement of other investi- gated genes. Proband’s phenotypically normal father and brother had the same mutation in whom subsequent investigations showed subclinical radiographic findings. The clinical manifestations, the disease course, and the molecular findings of involvement of ACVR1 gene in this family are suggestive of “FOP variant” or an unusual ACVR1-related skeletal dysplasia. Moreover, this report has demonstrated the critical role of the next generation sequencing technique in characterizing such a rare disorder with variable and even no clinical manifestations, providing the opportunity for effective preventive measures such as preimplantation genetic diagnosis. © 2016 Elsevier Masson SAS. All rights reserved. 1. Introduction “Disorganized Development of Skeletal Component” (DDSC) is a group of genetic skeletal dysplasia causing abnormal development of skeletal components such as exostoses, ecnhondromas, and ectopic calcification (Warman et al., 2011). Nine genes including ACVR1 have been reported to be associated with DDSC. The most known ACVR1-related disorder is Fibrodysplasia ossificans pro- gressiva (FOP) which involves one of every two million people (Gregson et al., 2011; Miao et al., 2012). It is inherited in an auto- somal dominant mode of inheritance. Most cases arise sporadically with only a few reported familial cases (Morales-Piga et al., 2012; Shore et al., 2006). Patients with “classic” features of FOP, develop heterotopic ossification of tendons, ligaments, skeletal muscles and/or fascia, usually in childhood with no smooth or cardiac muscle involvement. Heterotopic ossification is usually triggered by minor trauma and viral illness and occurs following a period of soft tissue swelling and inflammation (Gregson et al., 2011). Congenital great toe malformations are the earliest most recognizable feature of ‘classic’ FOP. However, in 2009, Kaplan et al. reported on patients with clinical features unusual for FOP. These atypical FOP patients included two classes: “FOP-plus” (classic defining features of FOP * Corresponding author. 21, Shabahang Building, 26, Dr Gharib Street, Keshavarz Blvd, Tehran, 1419783517, Iran. E-mail address: saeed@ghaffari.org (S.R. Ghaffari). Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg http://dx.doi.org/10.1016/j.ejmg.2016.05.007 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved. European Journal of Medical Genetics 59 (2016) 330e336