Authors :
Presenting Author: Tanya Brown, PhD – TESS Research Foundation
Kim Nye, AB – TESS Research Foundation; Brenda Porter, MD, PhD – Stanford University; Emily Spelbrink, MD, PhD – Stanford University
Rationale: Loss of function variants in the SLC13A5 gene cause SLC13A5 Citrate Transporter Disorder, a debilitating disease, initially identified by seizures starting within the first days of life. In addition to frequent seizures, patients affected by SLC13A5 Citrate Transporter Disorder have a severe movement disorder, limited verbal communication skills, low-tone, as well as hypodontia and amelogenesis imperfecta. This disorder is caused by loss-of-function variants in SLC13A5 that encodes for a sodium-dependent citrate transporter, NaCT. This disorder was initially described in 2014 and is an ultra rare disorder. To better understand the genetics of this disorder, we assessed SLC13A5 patient variants.
Methods: Using the TESS Research Foundation patient registry, we assessed known SLC13A5 patient variants. This is the largest registry to date for SLC13A5 Citrate Transporter Disorder. We determined the total number of unique patient variants and classified variants by variant type.
Results: The TESS patient registry includes 130 patients. Of these patients, we identified 56 unique genetic SLC13A5 variants. Of these unique variants, at the amino acid level, 52% were classified as missense variants. Additionally, 3.6% were partial or whole gene deletion and 16.1% were frameshift variants. Interestingly, 10.7% of the variants were predicted to alter splicing. Additionally, the most common variant found was c.655G >A (p.G219R), present in at least 24% of the known patient population. We also found that 39% of known patients had compound heterozygous SLC13A5 variants and 61% of patients had homozygous SLC13A5 variants.
Conclusions: In conclusion, we have identified the most common SLC13A5 variant found in a quarter of patients with SLC13A5 Citrate Transporter Disorder. We have also determined that a majority of patients are homozygous for SLC13A5 variants and that half of all identified SLC13A5 variants are classified as missense variants. These findings, demonstrating that the majority of SLC13A5 variants, are classified as missense variants, may influence the type of therapeutics developed to treat SLC13A5 Citrate Transporter Disorder.
Funding:
Funding was provided by the Chan Zuckerberg Initiative Rare As One Grant and TESS Research Foundation.