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

Compound heterozygosity in CEP290: a maternal splice site variant c.6012-2A>G and a paternal tandem duplication of exons 31-53; a 7-bp junction microhomology, low GC content and abundant repeats support a FoSTeS/MMBIR replicative mechanism, with predicted frameshift, premature termination codon and loss of the C-terminal domain.

Many inherited retinal degenerations remain unresolved despite targeted panels and exome sequencing, because structural and other complex variants can be missed. In a 4-year-old boy with presumed rod-cone dystrophy, trio whole-genome sequencing identified compound heterozygous CEP290 variants: a maternal splice site variant c.6012-2A>G and a paternal intragenic duplication of exons 31-53. The duplication was validated by gap-PCR and Sanger sequencing, with a 7-bp junction microhomology, low GC content and abundant repeat elements, supporting a FoSTeS/MMBIR replicative mechanism. The authors predict that this duplication alters CEP290 transcripts, causing a frameshift, premature termination and loss of the C-terminal functional domain.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A single case, but an instructive illustration of why an exome fails in retinal dystrophy: the second allele was an intragenic duplication, invisible without WGS and breakpoint-level analysis. The takeaway reflex is that an isolated heterozygote in a strongly suggestive recessive gene such as CEP290 here justifies actively searching for a structural variant in trans. The transcriptional consequence remains predicted rather than demonstrated on RNA, which limits the strength of the proposed classification.

Analysis by Dr Thibaut Benquey