Ciliopathy Variant Burden and Developmental Delay in Children with Hypoplastic Left Heart Syndrome

Gabrielle C. Geddes, Medical College of Wisconsin
Karl Stamm, Marquette University
Michael Mitchell, Medical College of Wisconsin
Kathleen Mussatto, Children's Hospital of Wisconsin
Aoy Tomita-Mitchell, Medical College of Wisconsin

Genetics in Medicine (2016). DOI.



To test the hypothesis that patients with hypoplastic left heart syndrome (HLHS) and developmental delay will have a higher average summative C-score in ciliopathy genes than patients with HLHS without developmental delay.


Ciliopathy gene variant burden was determined utilizing a summative C-score for 14 ciliopathy genes in children with HLHS (n = 24). Mean summative C-scores were compared between children with and without developmental delay. Genome-wide randomizing gene sets were evaluated as a scoring control.


Children with developmental delay had a mean summative C-score of 4.05 in ciliopathy genes as compared to a mean summative C-score of 2.02 for children without developmental delay. This difference in means was higher than 99.1% (empirical P value <0.01) of 2 million random lists of 14 genes.


Genetically complex disorders such as ciliopathies can be assessed to determine phenotypic risk with summative C-score in appropriately chosen gene sets. If these results are replicated in subsequent cohorts, a diagnostic gene panel could identify risk for developmental delay and other ciliopathy-related comorbidities in infants with congenital heart disease.