Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing

Area of Science:

• Genetics
• Developmental Biology
• Human Malformations

Background:

• Nonsyndromic cleft palate only (nsCPO) is a common birth defect with a significant genetic component, but its underlying causes are largely unknown.
• Current research has identified only one common genetic variant (in GRHL3) associated with nsCPO, highlighting the need to explore other genetic factors.
• Understanding the genetic etiology of nsCPO is crucial for diagnosis, counseling, and potential therapeutic strategies.

Purpose of the Study:

• To identify rare genetic variants contributing to the risk of nonsyndromic cleft palate only (nsCPO).
• To explore the role of whole-exome sequencing (WES) in discovering novel genetic factors for nsCPO.
• To investigate candidate genes for their involvement in facial development and nsCPO pathogenesis.

Main Methods:

• Whole-exome sequencing (WES) was performed on affected relatives from nsCPO pedigrees to identify shared rare variants.
• Candidate genes were selected based on their association with facial development, variant frequency, and expression patterns.
• Selected candidate genes were resequenced in a larger cohort of nsCPO cases and controls using molecular inversion probes.

Main Results:

• No rare loss-of-function mutations were found, but deleterious missense variants were identified in ACACB, PTPRS, and MIB1 in independent nsCPO families.
• A novel variant in GRHL3 and a variant in CREBBP were identified in patients with nsCPO, genes known to cause syndromic cleft palate.
• These findings suggest that nsCPO in some individuals may represent milder forms of known genetic syndromes.

Conclusions:

• Rare variants in genes such as ACACB, PTPRS, and MIB1 may contribute to nsCPO risk.
• The study identifies novel candidate genes for nsCPO, warranting further investigation into their roles in palate development.
• The findings suggest a potential overlap between nonsyndromic and syndromic forms of cleft palate due to specific genetic variants.