A Rare Pathogenic Variant in the SERPINF1 Gene in Association with Early-Onset Severe Presentation of Autosomal Recessive Type of Osteogenesis Imperfecta VI: A Case Report

Abstract

Osteogenesis imperfecta (OI) refers to a group of genetic disorders with the typical clinical presentation of increased bone fragility. More than 90% of OI cases have an underlying genetic mutation in the collagen genes COL1A1 or COL1A2. However, there are now 22 different recognized OI subtypes based on the underlying gene implicated. OI type VI is caused by pathogenic variants in the serine proteinase inhibitor clade F (SERPINF1) gene. In this case study, the patient was a 4-year-old female, born in a consanguineous family, with a history of delayed gross motor milestones and recurrent fractures after trivial trauma since the age of 8 months. The results of skeletal surveys and bone scans indicated that the patient suffered from OI. To confirm the diagnosis, we performed a next-generation sequencing (NGS) analysis of genes implicated in OI using the TruSight One NGS Panel. Bioinformatics analysis showed the presence of a rare pathogenic variant in exon 7 of the SERPINF1 gene in a homozygous state (NM_002615.5:c.907C>T; NP_002606.3:p.Arg303Ter; ClinVar submission ID: SUB10491966). The variant results in the termination of the polypeptide chain at position 303. Targeted capillary sequencing confirmed the presence of this variant in a homozygous state in the patient and in heterozygous state for both parents. Additionally, the patient’s younger sibling, aged 10 months, harbored the variant in a homozygous state. The sibling started bisphosphonate therapy and did not suffer any fractures in over 2 years after initiating the therapy. The etiological genetic diagnosis helped provide genetic counseling to the family. This highlights the utility of NGS for the confirmation of a clinical analysis in cases where alterations in multiple genes can result in similar clinical presentation.

Keywords

• pathogenic variant
• rare mutation
• serpinf1
• truncating mutation
• osteogenesis imperfecta
• autosomal recessive