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Background <p>Inherited retinal degenerations are a group of genetically heterogeneous disorders characterized by progressive photoreceptor degeneration. Despite the widespread use of targeted gene panels and exome sequencing, many cases remain genetically unresolved because structural and other complex variants may be missed. <i>CEP290</i> is a major cause of early-onset retinal degeneration, and although most pathogenic variants are sequence-level changes, structural rearrangements have increasingly been recognized through genome-wide sequencing approaches. This study aimed to identify the genetic cause in a child with early-onset retinal degeneration and to characterize the molecular mechanism of the underlying variant.</p> Methods <p>A 4-year-old boy with presumed rod-cone dystrophy underwent comprehensive clinical evaluation and trio whole-genome sequencing. Compound heterozygous <i>CEP290</i> variants, consisting of a maternally inherited splice-site variant and a paternally inherited large intragenic duplication, were identified and evaluated. The duplication breakpoint was subsequently characterized by structural variant analysis, gap-PCR, and Sanger sequencing, followed by analysis of breakpoint-associated microhomology, GC content, and repeat elements. Variants were interpreted according to ACMG/AMP and ClinGen recommendations, as appropriate.</p> Results <p>Trio-WGS detected compound heterozygous <i>CEP290</i> variants: a maternal splice-site variant c.6012–2&#xa0;A &gt; G and a paternal exons 31–53 tandem duplication (chr12:88050034–88089159dup). Gap-PCR and Sanger sequencing validated this rearrangement and defined a 7-bp junction microhomology (AAATTCT). Breakpoint analysis showed low GC and abundant repeats, supporting FoSTeS/MMBIR as the causal replicative mechanism. This duplication is predicted to alter <i>CEP290</i> transcripts, triggering frameshift, premature termination and C-terminal domain loss.</p> Conclusions <p>To our knowledge, this study represents the first breakpoint-resolved characterization of a pathogenic <i>CEP290</i> tandem duplication encompassing exons 31–53 identified in compound heterozygosity with a pathogenic splice-site variant in a patient with early-onset retinal degeneration. The duplication is predicted to disrupt the <i>CEP290</i> coding sequence, resulting in a frameshift, premature termination codon, and loss of the C-terminal functional domain. These findings expand the spectrum of pathogenic structural variants in <i>CEP290</i> and underscore the value of whole-genome sequencing and breakpoint-level analysis for resolving genetically unexplained inherited retinal disorders.</p>

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Breakpoint-level characterization of a novel CEP290 tandem duplication in trans with a pathogenic splice-site variant in a patient with Leber congenital amaurosis

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  • 发表日期：

    2026年7月21日

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  • Shumei Xu,
  • Jia Geng,
  • Wenyu Xiong,
  • Man Liu,
  • Chao Wang,
  • Xiaolu Wang,
  • Ting Tang,
  • Qian Zhang,
  • Huijun Yuan,
  • Yu Lu

摘要

Background

Inherited retinal degenerations are a group of genetically heterogeneous disorders characterized by progressive photoreceptor degeneration. Despite the widespread use of targeted gene panels and exome sequencing, many cases remain genetically unresolved because structural and other complex variants may be missed. CEP290 is a major cause of early-onset retinal degeneration, and although most pathogenic variants are sequence-level changes, structural rearrangements have increasingly been recognized through genome-wide sequencing approaches. This study aimed to identify the genetic cause in a child with early-onset retinal degeneration and to characterize the molecular mechanism of the underlying variant.

Methods

A 4-year-old boy with presumed rod-cone dystrophy underwent comprehensive clinical evaluation and trio whole-genome sequencing. Compound heterozygous CEP290 variants, consisting of a maternally inherited splice-site variant and a paternally inherited large intragenic duplication, were identified and evaluated. The duplication breakpoint was subsequently characterized by structural variant analysis, gap-PCR, and Sanger sequencing, followed by analysis of breakpoint-associated microhomology, GC content, and repeat elements. Variants were interpreted according to ACMG/AMP and ClinGen recommendations, as appropriate.

Results

Trio-WGS detected compound heterozygous CEP290 variants: a maternal splice-site variant c.6012–2 A > G and a paternal exons 31–53 tandem duplication (chr12:88050034–88089159dup). Gap-PCR and Sanger sequencing validated this rearrangement and defined a 7-bp junction microhomology (AAATTCT). Breakpoint analysis showed low GC and abundant repeats, supporting FoSTeS/MMBIR as the causal replicative mechanism. This duplication is predicted to alter CEP290 transcripts, triggering frameshift, premature termination and C-terminal domain loss.

Conclusions

To our knowledge, this study represents the first breakpoint-resolved characterization of a pathogenic CEP290 tandem duplication encompassing exons 31–53 identified in compound heterozygosity with a pathogenic splice-site variant in a patient with early-onset retinal degeneration. The duplication is predicted to disrupt the CEP290 coding sequence, resulting in a frameshift, premature termination codon, and loss of the C-terminal functional domain. These findings expand the spectrum of pathogenic structural variants in CEP290 and underscore the value of whole-genome sequencing and breakpoint-level analysis for resolving genetically unexplained inherited retinal disorders.