Carrier frequency estimation of Zellweger spectrum disorder using ExAC database and bioinformatics tools

We aimed to estimate the carrier frequency of Zellweger spectrum disorder (ZSD), a rare autosomal recessive disease, and the associated disease incidence based on data from the Exome Aggregation Consortium (ExAC) of approximately 60,000 individuals.

We obtained variants from ExAC in 13 PEX genes associated with ZSD. Potentially pathogenic missense variants were identified with computational variant analysis tools according to three stringency levels. Using variants classified as potentially pathogenic, we estimated the carrier frequency and the associated incidence for the entire ExAC population and its subpopulations. We also evaluated variants based on pathogenicity criteria for sequence variant interpretation outlined by the American College of Medical Genetics and Genomics (ACMG) and calculated the carrier frequency and incidence based on those variants.

The bioinformatically estimated incidence rate of ZSD in the ExAC population is 1 in 83,841 using our least stringent pathogenicity cutoff. Under clinical guidelines outlined by ACMG, the estimated incidence is 1 in 3,275,751 births.

We outlined a process for estimating the ZSD disease carrier frequency and incidence in a large consortium using bioinformatics tools. Our results are close to current newborn screening estimates in New York of 1 in 90,000 births, estimated from 1.08 million screenings.