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Background <p>Pathogenic variants in the <i>COL4A1</i> gene, which encodes a key structural component of the vascular basement membrane, compromise vascular integrity and contribute to a broad spectrum of cerebrovascular disorders.&#xa0;<i>COL4A1</i>-related intracerebral hemorrhage (ICH) demonstrates a distinct bimodal age distribution, characterized by early-onset (perinatal/childhood) and late-onset (adulthood) presentations.Although early-onset phenotypes have been extensively characterized, late-onset intracerebral hemorrhage linked to <i>COL4A1</i> mutations remains underrecognized, frequently obscured by coexisting vascular risk factors.</p> Method <p>We reported two probands with late-onset intracerebral hemorrhage associated with <i>COL4A1</i>. Structural modeling was performed to assess the potential impact of these variants on collagen stability. Additionally, we reviewed 27 previously published cases to evaluate the association between <i>COL4A1</i> mutations and ICH.</p> Results <p>We identified two probands with heterozygous <i>COL4A1</i> missense variants: c.2086G &gt; A (p.Gly696Ser) and a novel c.3110C &gt; T (p.Pro1037Leu). Notably, the patient with the Pro1037Leu variant remained asymptomatic until experiencing a hemorrhagic event.Structural modeling suggests that these variants may induce subtle conformational changes that impair collagen stability. A review of 27 published cases further supports the notion that such intrinsic structural abnormalities, in combination with vascular risk factors (e.g., arterial hypertension), may increase susceptibility to intracerebral hemorrhage.</p> Conclusion <p>The results underscore the importance of considering genetic testing in patients with unexplained or recurrent intracerebral hemorrhage, particularly those with a positive family history or syndromic features. While disease-specific therapies are currently lacking, early molecular diagnosis and rigorous control of modifiable risk factors may improve long-term outcomes and support informed genetic counseling.</p>

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Late-onset intracerebral hemorrhage associated with COL4A1 variants: clinical and genetic perspectives

  • 期刊论文

  • 发表日期：

    2026年1月3日

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  • Xinting Zhuang,
  • Shuyan Xu,
  • Chaohan Chen,
  • Ying Wang,
  • Fangwei Hu,
  • Bin Cai

摘要

Background

Pathogenic variants in the COL4A1 gene, which encodes a key structural component of the vascular basement membrane, compromise vascular integrity and contribute to a broad spectrum of cerebrovascular disorders. COL4A1-related intracerebral hemorrhage (ICH) demonstrates a distinct bimodal age distribution, characterized by early-onset (perinatal/childhood) and late-onset (adulthood) presentations.Although early-onset phenotypes have been extensively characterized, late-onset intracerebral hemorrhage linked to COL4A1 mutations remains underrecognized, frequently obscured by coexisting vascular risk factors.

Method

We reported two probands with late-onset intracerebral hemorrhage associated with COL4A1. Structural modeling was performed to assess the potential impact of these variants on collagen stability. Additionally, we reviewed 27 previously published cases to evaluate the association between COL4A1 mutations and ICH.

Results

We identified two probands with heterozygous COL4A1 missense variants: c.2086G > A (p.Gly696Ser) and a novel c.3110C > T (p.Pro1037Leu). Notably, the patient with the Pro1037Leu variant remained asymptomatic until experiencing a hemorrhagic event.Structural modeling suggests that these variants may induce subtle conformational changes that impair collagen stability. A review of 27 published cases further supports the notion that such intrinsic structural abnormalities, in combination with vascular risk factors (e.g., arterial hypertension), may increase susceptibility to intracerebral hemorrhage.

Conclusion

The results underscore the importance of considering genetic testing in patients with unexplained or recurrent intracerebral hemorrhage, particularly those with a positive family history or syndromic features. While disease-specific therapies are currently lacking, early molecular diagnosis and rigorous control of modifiable risk factors may improve long-term outcomes and support informed genetic counseling.