Abstract Introduction Primary ciliary dyskinesia (PCD) is a rare, typically recessive disorder caused by mutations in genes involved in motile cilia function. These genes are linked to cilia ultrastructure subclasses corresponding to the components of cilia impacted, such as outer dynein arm (ODA) loss, dynein assembly defects, and central apparatus abnormalities. Despite this progress, the frequency and distribution of these variants in the general population is not well understood.It is unclear whether individuals carrying only one copy of a potentially harmful variant (heterozygotes) may exhibit subtle clinical features. Large-scale genetic databases now allow us to examine population-level distribution of these variants, in people not known to have PCD. This study aims to assess the burden of PCD-related variants in a large, diverse cohort not enriched for PCD. Methods We identified protein-altering coding variants (including nonsynonymous, stop-gained/lost, start-lost, frameshift, and in-frame insertion/deletion) within 37 “definitive” PCD genes defined by The Clinical Genome Resource (ClinGen). We used the BRAVO browser of the NHLBI Trans-Omics Precision Medicine (TOPMed) Study (freeze 10, 150,899 individuals). Variants were retained if they passed quality control, had a high-confidence LOFTEE loss-of-function annotation (indicating likely gene disruption), and a CADD score ≥20 (suggesting high predicted biological impact). ClinVar classifications were assigned when available and grouped as (1) benign/likely benign, (2) uncertain significance, or (3) pathogenic/likely pathogenic. Genes were categorized by ultrastructural subclass using GeneReviews. For each subclass, we calculated total variants, heterozygous and homozygous counts, and ClinVar classification distributions. Results We identified 829 variants in 34 PCD genes meeting our search criteria. 3 definitive genes were not represented in TOPMed. Most homozygous observations were linked to benign classifications; only one homozygote (TTC12) remained across the entire cohort, underscoring the extreme rarity of potential disease-causing genotypes in the general population. We identified 1,233 copies of pathogenic or likely pathogenic variants (Table 1). Zygosity and variant burden patterns were broadly consistent across ultrastructural subclasses, with outer dynein arm, combined ODA/IDA, and normal ultrastructure genes contributing the most variants. Conclusions This population-scale analysis reveals that pathogenic variants in PCD genes with definitive evidence are largely confined to heterozygous cases, with homozygous loss-of-function genotypes being extremely rare. Variant distribution patterns were similar across ultrastructural subclasses, suggesting gene-specific and variant-specific effects, rather than trends in ultrastructure class. Future studies leveraging large diverse sequencing cohorts and detailed phenotyping are needed to understand clinical impact and to inform precision approaches to ciliopathy-related disease. This abstract is funded by: T32HL007427
Baumann et al. (Fri,) studied this question.