Shinawi Marwan, Wegner Daniel J, Paul Alexander J, Buchser William, Schmidt Robert, Sharma Jaiprakash, Sardiello Marco, Sisco Kathleen, Manwaring Linda, Reynolds Margaret, Fulton Robert, Fronick Catrina, Shaver Andrew, Huang Tina Y, Carroll Ashley, Roessler Kyria, Halpern Aaron L, Dickson Patricia I, Wambach Jennifer A
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States of America.
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States of America.
Mol Genet Metab. 2025 Jan;144(1):109004. doi: 10.1016/j.ymgme.2024.109004. Epub 2024 Dec 24.
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.
游离唾液酸贮积症（FSASD）是一种罕见的常染色体隐性溶酶体贮积病，由致病性SLC17A5变异引起，疾病严重程度各异。我们对一名疑似溶酶体贮积病的青春期女性进行了多学科评估，并开展了全面研究以揭示分子病因。先证者表现出智力残疾、贮积病的整体形态，且尿游离唾液酸水平轻度升高。皮肤电子显微镜图像显示出明显的细胞质空泡化。临床外显子组和基因组测序鉴定出一个母系遗传的SLC17A5变异：c.533delC;p.Thr178Asnfs*34。先证者皮肤成纤维细胞的RNA测序显示外显子3跳跃，这在先证者血液或父母成纤维细胞的RNA中未检测到。先证者成纤维细胞DNA的靶向深度测序显示约15%的reads中存在184bp缺失，涵盖外显子3的3'端。Illumina全基因组长读长测序证实该缺失存在于父系遗传的等位基因中，且在先证者成纤维细胞和肌肉中呈嵌合状态，但在血液或颊细胞中未发现。包括SLC17A5基因敲除细胞和突变型SLC17A5的瞬时转染在内的功能研究证实了所鉴定变异的致病性。我们报告了一名患有非典型FSASD的青春期女性，其SLC17A5基因内缺失存在组织特异性嵌合现象，这解释了其非典型的临床病程、轻度生化异常以及漫长的诊断过程。
