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Purpose <p>Patients referred with an osteogenesis imperfecta (OI) phenotype exhibit marked genetic heterogeneity, and a substantial proportion may harbor variants associated with early-onset osteoporosis (EOO) or OI-mimicking disorders rather than classical collagenopathies. This study aimed to define the genetic spectrum and non-<i>COL1A1/2</i> variant burden in a cohort clinically diagnosed with OI.</p> Methods <p>Ninety-eight unrelated patients referred with a clinical diagnosis of OI were analyzed using a targeted NGS panel on the DNBSEQ-400 platform and, when indicated, whole-exome sequencing. Variants were classified according to ACMG/AMP guidelines, and copy-number variants were assessed by microarray (Affymetrix&#xa0;CytoScan&#xa0;Optima, Thermo&#xa0;Fisher Scientific). Genes were categorized as <i>COL1A1/COL1A2</i>-related or non-collagen bone fragility genes.</p> Results <p>Seventy-two variants affecting 60 distinct loci were identified. While most pathogenic variants involved <i>COL1A1</i> and <i>COL1A2</i>, a substantial proportion of patients (approximately one-quarter) carried variants in non-collagen genes including <i>FKBP10, WNT1, P3H1, PLS3,</i> and <i>SERPINF1</i>, which are known to be associated with early-onset osteoporosis and OI-overlap phenotypes. Several of these variants were detected in the heterozygous state and were incompatible with classical autosomal-recessive OI, supporting an osteoporosis-predominant or modifier-based disease model.</p> Conclusions <p>A significant proportion of patients referred with an OI phenotype genetically represent early-onset osteoporosis or OI-overlap disorders rather than true collagenopathies. Comprehensive NGS-based testing, including copy-number analysis and non-<i>COL1A1/2</i> genes, enables accurate classification across the bone fragility spectrum and improves diagnostic yield.</p>

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Non-COL1A1/2 genetic burden and osteoporosis-overlap in patients referred with osteogenesis imperfecta phenotype

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • Fatma Nihal Ozturk,
  • Ece Keskin

摘要

Purpose

Patients referred with an osteogenesis imperfecta (OI) phenotype exhibit marked genetic heterogeneity, and a substantial proportion may harbor variants associated with early-onset osteoporosis (EOO) or OI-mimicking disorders rather than classical collagenopathies. This study aimed to define the genetic spectrum and non-COL1A1/2 variant burden in a cohort clinically diagnosed with OI.

Methods

Ninety-eight unrelated patients referred with a clinical diagnosis of OI were analyzed using a targeted NGS panel on the DNBSEQ-400 platform and, when indicated, whole-exome sequencing. Variants were classified according to ACMG/AMP guidelines, and copy-number variants were assessed by microarray (Affymetrix CytoScan Optima, Thermo Fisher Scientific). Genes were categorized as COL1A1/COL1A2-related or non-collagen bone fragility genes.

Results

Seventy-two variants affecting 60 distinct loci were identified. While most pathogenic variants involved COL1A1 and COL1A2, a substantial proportion of patients (approximately one-quarter) carried variants in non-collagen genes including FKBP10, WNT1, P3H1, PLS3, and SERPINF1, which are known to be associated with early-onset osteoporosis and OI-overlap phenotypes. Several of these variants were detected in the heterozygous state and were incompatible with classical autosomal-recessive OI, supporting an osteoporosis-predominant or modifier-based disease model.

Conclusions

A significant proportion of patients referred with an OI phenotype genetically represent early-onset osteoporosis or OI-overlap disorders rather than true collagenopathies. Comprehensive NGS-based testing, including copy-number analysis and non-COL1A1/2 genes, enables accurate classification across the bone fragility spectrum and improves diagnostic yield.