Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations.

Purpose: Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a rare, often fatal, metabolic disorder and monogenic form of steroid-resistant nephrotic syndrome. Other manifestations include primary adrenal insufficiency, ichthyosis, and neurological defects. SPLIS is caused by biallelic pathogenic variants in , encoding sphingosine-1-phosphate lyase, a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the final step of sphingolipid metabolism. Treatment is primarily supportive, but pyridoxine supplementation may be therapeutic in some cases, and gene therapy is being explored. We sought to determine the prevalence of SPLIS globally and among different populations to facilitate patient finding in anticipation of SPLIS clinical trials.

Methods: Using publicly available genomic data sets, including Genome Aggregation Database (gnomAD) v.2.1.1 and gnomAD v3.1.2, Iranome, IndiGen, and private genomic data sets from Israeli, Saudi, South Dakota Hutterite, and Turkish populations, we estimated SPLIS prevalence based on cumulative variant allele frequencies for high-confidence pathogenic variants. SPLIS prevalence estimates were adjusted by the level of inbreeding when the inbreeding coefficient was known. A Bayesian point estimate and 95% credible interval for worldwide SPLIS were calculated based on gnomAD v2.1.1 (GRCh37).

Results: The SPLIS prevalence estimate based on the total number of samples included from gnomAD v.2.1.1 ( = 141,430) was 0.015/100,000 (95% CI: 0.010 to 0.021). Using additional population data sets, we calculated SPLIS prevalence ranging from 0.046/100,000 to 0.078/100,000 in Turkish and Iranian populations, respectively.

Conclusion: The estimated worldwide number of SPLIS individuals is 11,707. Individuals with East Asian, Finnish, Turkish, and Iranian ancestries have an especially high estimated prevalence.