275: MIPseq/WES of 11,555 CHD probands implicates 60 dominant genes with NOTCH1 cysteine‑altering and transmitted MYH6 missense variants

Sierant MC et al., Proc. Natl. Acad. Sci. U.S.A. 2025.122:e2420343122 - MIPseq and exome sequencing of 11,555 human congenital heart disease probands implicate 60 dominant CHD genes, with NOTCH1 cysteine‑altering and transmitted MYH6 missense variants driving distinct defects. Key terms: congenital heart disease, NOTCH1, MYH6, MIPseq, de novo mutations.

Study Highlights:
We analyzed 11,555 human CHD probands from PCGC and PHN using a 248‑gene MIPseq panel and whole‑exome sequencing. A meta‑analysis of de novo and very rare transmitted/unphased damaging variants identified 60 genes with significant burden, accounting for damaging variants in 10.1% of probands with similar DNM and transmitted contributions. Mechanistically, NOTCH1 missense mutations that introduce or remove cysteines in EGF domains were highly enriched in tetralogy of Fallot and conotruncal defects, while transmitted damaging MYH6 missense variants were overtransmitted and contributed to multiple CHD subtypes. Genes with cardiomyocyte‑restricted expression correlated with isolated CHD, whereas broadly brain‑expressed genes correlated with neurodevelopmental delay, supporting genotype‑informed risk assessment.

Conclusion:
Targeted genomic analysis of 11,555 CHD probands identifies 60 dominant genes accounting for 10.1% of cases and supports molecular diagnosis to stratify cardiac and neurodevelopmental risk.

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-30.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the study design (MIPseq), cohort composition, main genetic findings (60 genes, 10.1%), NOTCH1 cysteine-altering variants, MYH6 transmission findings, chromatin gene involvement, syndromic diagnoses, and cost reductions and future gene discovery projections.
- transcript topics: MIPseq methodology and cost reduction; Cohort assembly and the 248-gene panel; 60 significant CHD genes and 10.1% probands; NOTCH1 cysteine-altering variants in TOF/CTD (EGF domains, domain #5); MYH6 transmitted damaging variants and penetrance; Chromatin modifier genes and neurodevelopmental/EC phenotypes

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Study analyzed 11,555 CHD probands with a 248-gene MIPseq panel.
- 60 genes identified with significant burden of damaging variants; 10.1% of probands affected.
- Equal contributions from de novo and transmitted variants to CHD risk within the 60-gene set.
- NOTCH1 missense variants introducing/removing cysteines in EGF domains are enriched in TOF and CTD; cysteine-altering variants cluster in EGF domain #5.
- Transmitted damaging MYH6 missense variants enriched across multiple CHD phenotypes; risk ratio ~6; 2–3% of probands; ~1% of all trios.
- MYH6 is heart-restricted in expression; NDD risk among MYH6 carriers is low (~4%).

QC result: Pass.

Chapters

• (00:00:20) - Deadly heart defect: The genetics of congenital heart disease
• (00:03:05) - How 60 genes explain the cause of heart defect
• (00:07:03) - Heart defects and neurodevelopmental delay
• (00:10:24) - These are the hidden syndromes
• (00:14:21) - Dazzling Sound