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Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 816 trios
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Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 816 trios

Kelsey R. Robinson, Sarah W. Curtis, Justin E. Paschall, Terri H. Beaty, Azeez Butali, Carmen J. Buxó, David J. Cutler, Michael P. Epstein, Jacqueline T. Hecht, Lina Moreno Uribe, …
medRxiv
Cold Spring Harbor Laboratory Press, 1.1
03/04/2025
DOI: 10.1101/2025.03.03.25323233
PMCID: PMC11908282
PMID: 40093200
url
https://doi.org/10.1101/2025.03.03.25323233View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

De novo variants (DNs) are sporadically occurring variants that most commonly arise in the germline and are present in offspring but absent in both parents. As they are not under selective pressure, they may be enriched for disease-causing alleles and have been implicated in multiple rare genetic disorders. Cleft palate (CP) is a common craniofacial congenital anomaly occurring in ∼1 in 1700 live births. Genome-wide association studies for CP have found fewer than a dozen loci, while exome and targeted sequencing studies in family-based and case-control cohorts often lack statistical power to conclusively identify causal genes. Based on previous work by our group and others, deciphering the genetic architecture of CP and gene discovery efforts are complicated by the heterogeneous nature of the disorder. We aggregated sequence data for 816 case-parent trios with CP, representing all subtypes of CP and roughly evenly split between isolated and syndromic presentations. We hypothesized there would be a burden of DNs in CP probands and tested this hypothesis in the full cohort and various phenotypic subgroupings. We identified global enrichment of protein-altering DNs (1.36, p=2.39×10-22), and exome-wide significant (p<1.3×10-6) gene-specific enrichment for SATB2, MEIS2, COL2A1, ZC4H2, EFTUD2, KAT6B, and ANKRD11. We found a statistically significant higher enrichment of loss-of-function and missense DNs in syndromic (1.49, p=2.84×10-19) versus nonsyndromic probands (1.25, p=4.01×10-7) but no differences between CP subtypes. We also evaluated biological differences, identifying distinct enrichments across two single cell RNA sequencing datasets: mouse palate at the time of palate fusion and human embryos at post-conceptional weeks 3-5. Altogether, we show DNs are a contributor to CP risk, and that combined analysis can enhance our ability to find genetic associations that would otherwise be undetected.
 Genetic and Genomic Medicine

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