<i>COL4A1</i> and <i>COL4A2</i> Gene Duplication or Triplication as a Genetic Cause of Cerebral Small Vessel Disease in Adults.

Abstract

Cerebral small vessel disease (CSVD) is a major cause of stroke and vascular cognitive impairment, yet its mechanisms remain incompletely understood. While heterozygous point mutations in <i>COL4A1</i> and <i>COL4A2</i> are established monogenic cause of CSVD, the contribution of copy number gains involving these 2 genes has only recently been recognized. We aimed to define the clinical and radiological spectrum of <i>COL4A1/2</i> duplications and triplications in adults. We report 7 adult probands carrying duplications or triplications of <i>COL4A1</i> and <i>COL4A2</i>, in whom no pathogenic variants were identified in other known CSVD genes. Targeted high-throughput sequencing, quantitative multiplex polymerase chain reaction of short fluorescent fragments, and SNP arrays were used to confirm and characterize genomic rearrangements spanning the 13q33q34 region. Genomic rearrangements ranged from 328 kb to 11.8 Mb, involving complete or partial duplication/triplication of <i>COL4A1/2</i>. Patients presented heterogeneous cerebrovascular manifestations, including ischemic and hemorrhagic events, motor impairment, and cognitive decline. Brain magnetic resonance imaging consistently showed extensive white matter hyperintensities, lacunes (particularly in the pons), microbleeds, and, in some cases, saccular aneurysms or arterial dolichoectasia. Only 2 probands had a positive family history of CSVD. This large series confirms the pathogenicity of <i>COL4A1/2</i> duplications and triplications in adult-onset CSVD. Phenotypic variability likely reflects differences in duplication/triplication size, gene content, and modifying factors. Our findings highlight a distinct cerebral-only phenotype linked to gene dosage-related overexpression and underscore the importance of screening for copy number variations in patients with otherwise unexplained cerebral microangiopathy, even in the absence of a family history.