Mutation screening of SPTLC1andSPTLC2in amyotrophic lateral sclerosis

Background: Recently, several rare variants of SPTLC1were identified as disease cause for juvenile amyotrophic lateral sclerosis (ALS) by disrupting the normal homeostatic regulation of serine palmitoyltransferase (SPT). However, further exploration of the rare variants in large cohorts was still necessary. Meanwhile, SPTLC2plays a similar role as SPTLC1in the SPT function. Methods: To explore the genetic role of SPTLC1and SPTLC2in ALS, we analyzed the rare protein-coding variants in 2011 patients with ALS and 3298 controls from the Chinese population with whole exome sequencing. Fisher’s exact test was performed between each variant and disease risk, while at gene level over-representation of rare variants in patients was examined with optimized sequence kernel association test (SKAT-O). Results: Totally 33 rare variants with minor allele frequency < 0.01 were identified, including 17 in SPTLC1and 16 in SPTLC2. One adult-onset patient carried the variant p.E406K (SPTLC1) which was reported in previous study. Additionally, three adult-onset patients carried variants in the same amino acids as the variants identified in previous studies (p.Y509C, p.S331T, and p.R239Q in SPTLC1). At gene level, rare variants of SPTLC1and STPLC2were not enriched in patients. Conclusion: These results broadened the variant spectrum of SPTLC1and SPTLC2in ALS, and paved the way for future research. Further replication was still needed to explore the genetic role of SPTLC1in ALS.