Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta

Abstract

Abstract Background Osteogenesis imperfecta ( OI ) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL 1A1 or COL 1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI , all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships. Methods Mutation analysis was performed using a next‐generation sequencing gene panel, homozygosity mapping, and whole exome sequencing ( WES ). Results Patients offspring of nonconsanguineous parents were mostly identified with COL 1A1 or COL 1A2 heterozygous changes, although there were also a few cases with IFITM 5 and WNT 1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP , FKBP 10 , LEPRE 1 , PLOD 2 , PPIB , SERPINF 1 , TMEM 38B , and WNT 1 . In addition, two patients born to consanguineous parents were found to have de novo COL 1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants in SCN 9A , NTRK 1 , and SLC 2A2 , which are associated with congenital indifference to pain ( CIP ) and Fanconi–Bickel syndrome ( FBS ). Conclusion This work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role of SCN 9A and NTRK 1 in bone development.