Atypical free sialic acid storage disorder associated with tissue specific mosaicism of SLC17A5

Free sialic acid storage disorder (FSASD) is a rare autosomal recessive lysosomal storage disease caused by pathogenic SLC17A5 variants with variable disease severity. We performed a multidisciplinary evaluation of an adolescent female with suspected lysosomal storage disease and conducted comprehensive studies to uncover the molecular etiology. The proband exhibited intellectual disability, a storage disease gestalt, and mildly elevated urine free sialic acid levels. Skin electron micrographs showed prominent cytoplasmic vacuolation. Clinical exome and genome sequencing identified a maternally-inherited SLC17A5 variant: c.533delC;p.Thr178Asnfs*34. RNASeq of proband skin fibroblasts revealed exon 3 skipping, which was not detected in RNA from proband blood or parental fibroblasts. Targeted deep sequencing of proband fibroblast DNA revealed a 184 bp deletion in ∼15 % of reads, encompassing the 3' end of exon 3. Illumina Complete Long Read sequencing confirmed the deletion was in the paternally-inherited allele and found in a mosaic state in proband fibroblasts and muscle but not in blood or buccal cells. Functional studies, including SLC17A5 knockout cells and transient transfections of mutated SLC17A5 demonstrated pathogenicity of the identified variants. We report an adolescent female with atypical FSASD with tissue-specific mosaicism for an intragenic deletion in SLC17A5, explaining the atypical clinical course, mild biochemical abnormalities, and long diagnostic process.