Evaluating rare coding variants as contributing causes to non-syndromic cleft lip and palate

Area of Science:

• Genetics
• Developmental Biology
• Public Health

Background:

• Non-syndromic cleft lip and palate (NSCL/P) is a common birth defect.
• Previous studies identified numerous rare coding variants associated with NSCL/P.
• Advances in exome sequencing provide new resources for genetic analysis.

Purpose of the Study:

• To evaluate the etiological significance of previously reported rare coding variants in NSCL/P.
• To compare NSCL/P-associated variants with large control exome databases.
• To determine if reported variants are truly associated with NSCL/P or are benign common variants.

Main Methods:

• Collation of rare coding variants reported in NSCL/P candidate genes.
• Comparison of these variants against large exome databases from control populations.
• Statistical analysis to assess the frequency and significance of variants.

Main Results:

• 71% of variants previously described as etiologic for NSCL/P were absent in control exome data.
• This supports the role of many reported rare variants in NSCL/P.
• Support for variants in some candidate genes was diminished, while support for others was strengthened.

Conclusions:

• The findings provide strong evidence for the contribution of many previously identified rare variants to NSCL/P.
• The study highlights the utility of large control exome datasets for variant interpretation.
• The complex nature of NSCL/P means definitive conclusions about individual variant risk remain challenging.