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<p>Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and variable skeletal deformities. While <i>SP7</i> variants typically underlie autosomal recessive OI, a single heterozygous <i>SP7</i> variant has recently been reported to cause autosomal dominant OI. Given the limited family-based genetic studies of OI in Malaysian populations, its inheritance patterns and molecular spectrum remain poorly defined. Here, we investigated a three-generation Malaysian family with three individuals (the 7-year-old proband, her 8-year-old brother, and 34-year-old mother) presenting with lower limb bowing, impaired fracture healing, despite preserved lumbar spine areal bone mineral density. Three affected individuals and seven unaffected relatives were recruited for clinical evaluation and genetic analysis. Targeted sequencing and whole-exome sequencing (WES) revealed a heterozygous <i>SP7</i> missense variant, NM_001173467.2:c.1019A&gt;C (p.Glu340Ala), initially classified as a variant of uncertain significance, in all affected individuals. Variant evaluation using in silico tools (CADD-Phred, 27.2; REVEL, 0.812; PROVEAN, 0.887), protein stability modeling (ΔΔG<sup>Stability</sup> = –1.05&#xa0;kcal/mol), and conservation analysis across orthologs predicted a deleterious effect. The variant met six ACMG/AMP criteria (PS3, PM1, PM2, PP1, PP2, PP4) and was reclassified as pathogenic. Sanger sequencing confirmed variant presence in all affected individuals and absence in unaffected relatives, with Fisher’s exact test demonstrating a significant association with the disease (<i>p</i> = 0.0083). This study represents the first family-based genetic investigation of OI in Malaysia and provides independent evidence that <i>SP7</i>-related OI can manifest as autosomal dominant disease with preserved bone mineral density and defective fracture healing. This supports a haploinsufficiency mechanism with important implications for genetic diagnosis and counseling. </p>

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Preserved bone mineral density in autosomal dominant SP7-related osteogenesis imperfecta: a case report of the p.Glu340Ala variant

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • Hui Wen Teh,
  • Yee Lin Lee,
  • Nurul Huda Musa,
  • Karuppiah Thilakavathy

摘要

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and variable skeletal deformities. While SP7 variants typically underlie autosomal recessive OI, a single heterozygous SP7 variant has recently been reported to cause autosomal dominant OI. Given the limited family-based genetic studies of OI in Malaysian populations, its inheritance patterns and molecular spectrum remain poorly defined. Here, we investigated a three-generation Malaysian family with three individuals (the 7-year-old proband, her 8-year-old brother, and 34-year-old mother) presenting with lower limb bowing, impaired fracture healing, despite preserved lumbar spine areal bone mineral density. Three affected individuals and seven unaffected relatives were recruited for clinical evaluation and genetic analysis. Targeted sequencing and whole-exome sequencing (WES) revealed a heterozygous SP7 missense variant, NM_001173467.2:c.1019A>C (p.Glu340Ala), initially classified as a variant of uncertain significance, in all affected individuals. Variant evaluation using in silico tools (CADD-Phred, 27.2; REVEL, 0.812; PROVEAN, 0.887), protein stability modeling (ΔΔGStability = –1.05 kcal/mol), and conservation analysis across orthologs predicted a deleterious effect. The variant met six ACMG/AMP criteria (PS3, PM1, PM2, PP1, PP2, PP4) and was reclassified as pathogenic. Sanger sequencing confirmed variant presence in all affected individuals and absence in unaffected relatives, with Fisher’s exact test demonstrating a significant association with the disease (p = 0.0083). This study represents the first family-based genetic investigation of OI in Malaysia and provides independent evidence that SP7-related OI can manifest as autosomal dominant disease with preserved bone mineral density and defective fracture healing. This supports a haploinsufficiency mechanism with important implications for genetic diagnosis and counseling.