Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations
bioRxiv the preprint server for biology(2024)
摘要
Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform “N-of-1” analyses on individual patients. The increasing sizes of ultra-rare, “N-of-1” disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development.[1][1],[2][2] The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale N-of-1 analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We apply existing and introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We make our gene-level findings and variant-level information across the cohort available in a public-facing browser ( ). These results show that N-of-1 efforts should be supplemented by a joint genomic analysis across cohorts.
### Competing Interest Statement
The authors have declared no competing interest.
[1]: #ref-1
[2]: #ref-2
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