113: Joint, Multifaceted Genomic Analysis Enables Diagnosis of Ultra-Rare Monogenic Presentations

Base by Base

️ Episode 113: Joint, Multifaceted Genomic Analysis Enables Diagnosis of Ultra-Rare Monogenic Presentations

In this episode of PaperCast Base by Base, we explore how the Undiagnosed Diseases Network (UDN) applied whole‑genome sequencing and new, well‑calibrated statistics to jointly analyze diverse, ultra‑rare monogenic cases across the consortium, yielding confirmed and putative diagnoses while enabling privacy‑preserving cross‑cohort discovery via shareable summary statistics.

Study Highlights:
The authors introduce RaMeDiES, a suite of analytical methods that detect gene‑level recurrence of deleterious de novo variants (RaMeDiES‑DN) and prioritize compound‑heterozygous configurations (RaMeDiES‑CH), with an individual‑level ranking (RaMeDiES‑IND) to surface single‑case recessive candidates. Using 4,236 individuals with harmonized whole‑genome data—including over a thousand complete trios—the framework integrates state‑of‑the‑art mutation‑rate models and variant effect scores, and extends to deep intronic splice‑altering variants supported by a massively parallel splicing reporter assay. The joint analysis recapitulates known diagnoses and uncovers new or strengthened gene–disease links, including de novo signals in KIF21A, BAP1, RHOA, KMT2B, histone H4 genes (H4C5), LRRC7 and ZNF865, and a compound‑heterozygous candidate in MED11 with RNA‑seq evidence of intron retention. Pathway‑level analysis within phenotype‑clustered patient groups highlights enriched biological modules such as the immunoproteasome (POMP/PSMB8) and a transmembrane signaling set containing CACNA1C, GABRA3 and HCN4, aligning with shared clinical features. The team releases an open browser of cohort findings and the open‑source RaMeDiES software to enable automated, de‑identified cross‑cohort analyses.

Conclusion:
This work shows that rigorous, summary‑statistic–based joint genomics can boost rare‑disease diagnosis and gene discovery while paving the way for scalable, privacy‑aware international meta‑analyses.

Reference:
Kobren, S. N., Moldovan, M. A., Reimers, R., Traviglia, D., Li, X., Barnum, D., Veit, A., Corona, R. I., Carvalho Neto, G. de V., Willett, J., Berselli, M., Ronchetti, W., Nelson, S. F., Martinez‑Agosto, J. A., Sherwood, R., Krier, J., Kohane, I. S., Undiagnosed Diseases Network, & Sunyaev, S. R. (2025). Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra‑rare monogenic presentations. Nature Communications, 16, 7267. https://doi.org/10.1038/s41467-025-61712-2

License:
This episode is based on an open‑access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
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Keywords: rare disease genomics, de novo recurrence, compound heterozygous, RaMeDiES, Undiagnosed Diseases Network

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