Expanding the Genetic Landscape of Craniofacial Anomalies Through Transcriptome-Wide Association Studies

Area of Science:

• Genetics
• Developmental Biology
• Medical Informatics

Background:

• Craniofacial anomalies are common congenital conditions with significant mortality and morbidity.
• Current genetic testing for Mendelian causes has a low diagnostic yield (~25%).
• Oligogenic and polygenic inheritance may explain the low diagnostic rate.

Purpose of the Study:

• To identify genetic associations with craniofacial anomalies using large electronic health record systems.
• To investigate patterns of genetic associations with known craniofacial anomaly genes.
• To explore the role of gene expression in craniofacial anomaly development.

Main Methods:

• Performed transcriptome-wide association studies (TWAS) in two large cohorts (BioVU and eMERGE).
• Evaluated associations between genetically predicted gene expression and craniofacial anomalies.
• Utilized a list of 391 previously identified craniofacial anomaly-associated genes.

Main Results:

• Found significant associations between predicted gene expression and craniofacial anomalies in 3.1% (BioVU) and 4.6% (eMERGE) of known genes.
• Identified 53 novel genes associated with craniofacial anomalies.
• Observed that known craniofacial genes are frequently associated with other congenital anomalies (heart, nervous system, urinary system).

Conclusions:

• Supports the contribution of both rare and common genetic variations in Mendelian disease-associated genes to craniofacial anomalies.
• Suggests these genes play a broad role in the development of various congenital anomalies.
• Highlights potential for improved genetic diagnostics by considering broader genetic architectures.