Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate.

Area of Science:

• Genetics
• Human Disease Genetics

Background:

• Nonsyndromic cleft lip and palate (NSCLP) is a common birth defect with a polygenic inheritance pattern.
• Identifying causal genetic variants for NSCLP is challenging due to variable penetrance and complex genetics.
• Amerindian populations exhibit a high prevalence of NSCLP, yet lack comprehensive genetic studies.

Purpose of the Study:

• To identify candidate genes harboring rare genetic variants associated with NSCLP in a Honduran population.
• To leverage whole exome sequencing (WES) to uncover novel genetic factors contributing to NSCLP.
• To investigate genetic variants exhibiting dominant inheritance with incomplete penetrance.

Main Methods:

• Whole exome sequencing (WES) was conducted on members of 27 multiplex Honduran families affected by NSCLP.
• Rare heterozygous variants with predicted functional consequences were prioritized after filtering common variants (MAF > 1%).
• Segregation analysis and Sanger sequencing were employed for variant validation and confirmation.

Main Results:

• Over 3,700 rare heterozygous variants were identified, with 1,282 predicted to be functionally consequential.
• Twenty-three genes showed variants in at least three families, leading to 50 candidate variants.
• After validation, variants in ACSS2 and PHYH genes consistently segregated with NSCLP across multiple families.

Conclusions:

• Rare variants in ACSS2 and PHYH are strong candidates for causing NSCLP in this Honduran population.
• The findings highlight the role of dominant variants with incomplete penetrance in NSCLP etiology.
• This study provides crucial genetic insights into NSCLP in an underrepresented Amerindian population.