Key result
Long-read genome sequencing detected 1.60-fold more deletions, 7.73-fold more duplications, and 1.64-fold more insertions compared to short-read sequencing in genotype-elusive congenital heart disease patients.
Why the study?
Congenital heart disease is the most common birth defect, but short-read genome sequencing often leaves many patients genotype-elusive.
Does long-read genome sequencing improve the detection of genetic variants compared to short-read genome sequencing in genotype-elusive congenital heart disease patients?
Observational (n=43)
No
Does long-read genome sequencing improve the detection of genetic variants compared to short-read genome sequencing in genotype-elusive congenital heart disease patients?
Long-read genome sequencing improves the detection of complex structural variants and tandem repeat expansions in congenital heart disease patients who remain genotype-elusive after short-read sequencing.
May support long-read GS for additional variant detection in genotype-elusive CHD; leaves open impact on diagnostic yield and outcomes.
Congenital heart disease (CHD) is the most common birth defect. We performed Illumina short-read genome sequencing (GS) of 1,101 probands, which identified a genetic cause in 16% of cases. We performed PacBio long-read GS in 43 genotype-elusive patients. Paired analysis revealed higher detection with long-read GS of single nucleotide variants, deletions, duplications, and insertions as well as fewer false-positives for indels and inversions. Long-read GS had higher coverage of nine CHD genes, but a low sequencing depth (<10×) in intragenic regions of four of these genes. Long-read GS was better able to resolve complex structural variants and the size of large repeat expansions in 59 known disease-causing regions. This included a complex de novo structural variant upstream of ZEB2 that was only resolved with long-read GS in a patient with extra-cardiac phenotype overlapping Mowat-Wilson syndrome. Long-read GS may provide an option in CHD patients who remain genotype-elusive on short-read GS.
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Lesurf et al. (2025) conducted an observational in Congenital heart disease (n=43). Long-read genome sequencing vs. Short-read genome sequencing was evaluated on Detection of structural variants (deletions, duplications, insertions, inversions). Long-read genome sequencing detected 1.60-fold more deletions, 7.73-fold more duplications, and 1.64-fold more insertions compared to short-read sequencing in genotype-elusive congenital heart disease patients.
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