A novel ACVR1 mutation detected by whole exome sequencing in a family with an unusual skeletal dysplasia

作者：Rafati Maryam; Mohamadhashem Faezeh; Hoseini Azadeh; Hoseininasab Fatemeh; Ghaffari Saeed Reza^*

来源：European Journal of Medical Genetics, 2016, 59(6-7): 330-336.

DOI：10.1016/j.ejmg.2016.05.007

• Whole exome sequencing
• ACVR1
• Skeletal dysplasia
• Fibrodysplasia ossificans progressiva
• FOP variant

"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 fibrodysplasia 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 investigated 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.

• 出版日期2016-6