Heterozygous variants in POLR1A resulting in a reduced protein function underlie a more variable phenotype than previously known. A study published in the American Journal of Human Genetics reports a cohort of 17 patients with heterozygous pathogenic POLR1A variants who showed neurodevelopmental anomalies and structural heart defects in addition to craniofacial and limb malformations.

The researchers performed cell and animal model studies to explore how specific functional effects of individual variants may result in variable phenotypes. The protein encoded by POLR1A forms the largest subunit of RNA polymerase I, which is responsible for synthesis of ribosomal RNA (rRNA). As the basic unit of ribosomes, rRNA is essential for protein biosynthesis required for proper cell growth and function. The researchers showed that specific POLR1A variants had different effects on rRNA transcription and nucleolar morphology. Their investigations in mice demonstrated that the protein is required for normal embryonic development including cardiac and neural development.