BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous bone disorder 
characterized by recurrent fractures. Although most cases of OI have 
heterozygous mutations in COL1A1 or COL1A2 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 COL1A1 or COL1A2 heterozygous changes, although there were also a few cases 
with IFITM5 and WNT1 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,FKBP10,LEPRE1,PLOD2,PPIB,SERPINF1,TMEM38B, and WNT1. In addition, two 
patients born to consanguineous parents were found to have de novo COL1A1 
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 SCN9A,NTRK1, and SLC2A2, 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 SCN9A and NTRK1 in 
bone development.