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

Abstract

BackgroundOsteogenesis 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.MethodsMutation analysis was performed using a next‐generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES).ResultsPatients 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).ConclusionThis 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.

FAM46Amutations are responsible for autosomal recessive osteogenesis imperfecta

“…This patient had previously been screened for mutations using a NGS gene panel containing 16 OI genes with negative results 9. In addition, homozygosity mapping by SNP arrays in the proband and her two unaffected siblings showed no known OI genes being contained within patient-specific homozygous regions, strongly suggesting a novel recessive gene.…”

“…For patient 4, targeted NGS gene panel screening, SNP array-based homozygosity mapping and exome sequencing were conducted as previously described in the study by Caparros-Martin et al 9. Regions of homozygosity were established using 1 Mb of contiguous homozygous SNPs as the minimum size cut-off value.…”

Genetic approaches to metabolic bone diseases

“…duplication) may be indicated by increased numbers of different genotypes . SNP arrays may also help localize recessive disorders in the offspring of consanguineous parents by facilitating homozygosity mapping , whilst regions of LOH can also indicate uniparental isodisomy, which may be relevant to the diagnosis of imprinting disorders such as PHP1b .…”

Clinical Application of NGS Tools in the Diagnosis of Collagenopathies

“…Indeed, Caparros-Martin et al 12 analyzed 42 OI probands, all offspring parents, to determine the spectrum of mutated genes and variants detected for these cases. This work confirmed that COL1A1 mutations are responsible for the OI dominant form.…”