What question did this study set out to answer?

This study aims to identify rare protein-coding variants associated with non-syndromic cleft lip and palate (NSCLP) and understand their genetic contribution.

July 22, 2026Open Access

Genome-wide assessment of rare protein-coding variants identifies associations with non-syndromic cleft lip/palate

YYYao YuThe University of Texas MD Anderson Cancer Center GKGabriel J. KowalczykUniversity of Pittsburgh CHChad HuffThe University of Texas MD Anderson Cancer Center

Key Points

This study aims to identify rare protein-coding variants associated with non-syndromic cleft lip and palate (NSCLP) and understand their genetic contribution.
Analyzed short-read whole-genome sequencing data from 786 NSCLP cases and 2149 controls.
Conducted gene-based association testing, meta-analysis, functional prioritization, and effect-size estimation.
Performed pathway analyses to assess gene enrichment in relevant biological pathways.
Identified four novel candidate genes (SCT, MALRD1, GPR156, MYOCOS) with p-values < 10⁻⁴ indicating significant associations.
Replicated known associations robustly for ARHGAP29, FGF8, SKI, and TP63.
Estimated odds ratios for rare variants indicated a substantial increase in NSCLP risk, ranging from 2 to 4.

Abstract

Nonsyndromic cleft lip and palate (NSCLP) is a complex, multifactorial condition for which only about 25% of the genetic contribution has been identified. Although more than 60 genetic loci have been associated with NSCLP, a large portion of its heritability remains unexplained. Rare variants—often with stronger functional effects—are believed to account for some of this missing genetic risk. In this study, short-read whole-genome sequencing data from 786 NSCLP cases and 2149 controls were analyzed to identify genes enriched for rare protein-coding variants. Gene-based association testing, meta-analysis, functional prioritization, and effect-size estimation revealed several novel NSCLP candidate genes and confirmed associations with previously reported genes. The four novel candidate genes with the strongest association evidence were SCT, MALRD1, GPR156 , and MYOCOS , all with p -values < 10⁻⁴. Replication of known genes was most robust for ARHGAP29, FGF8, SKI , and TP63 . Pathway analyses showed significant enrichment of these genes in neuroactive ligand–receptor interactions, MAPK signaling, and other signal transduction pathways. Precise estimates of the risks conferred by the identified rare variants showed a substantial increase in NSCLP risk, with odds ratio point estimates between 2 and 4. These results provide strong support for a polygenic inheritance model in NSCLP, in which certain genes contribute varying levels of risk.

Ask AI

Helpful

Bookmark

View Full Paper