The relationship between the SLC17A5 gene and free sialic acid storage disease (free SASD) an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 11, 2022. SLC17A5 encodes solute carrier family 17 member 5 (also known as sialin), a lysosomal membrane transporter protein that exports sialic acid (the majority of which is N-acetylneuraminic acid, Neu5Ac) and other acidic hexoses from lysosomes (PMID: 2010546). Among patients with free sialic acid storage disease, deficient SLC17A5 function results in impaired sialic acid export from lysosomes and lysosomal accumulation of sialic acid (PMID: 15557321), leading to a spectrum of clinical manifestations including urinary excretion of free sialic acid, neurological and developmental symptoms with severity ranging from the milder phenotype, Salla disease (SD), to the most severe phenotype, infantile free sialic acid storage disease (ISSD) (as reviewed in PMID: 20301643, 33862140).
Lumping and splitting: Variants in SLC17A5 have been reported in individuals with Salla disease (MIM# 604369) and Sialic acid storage disorder, infantile (MIM# 269920). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern for these conditions. Salla disease and Sialic acis storage disorder, infantile represent a clinical continuum (PMIDs: 20301643, 33862140). Therefore, the two entities have been lumped as free sialic acid storage disease.
The disease mechanism for free SASD is loss of function. ISSD was first reported by Tondeur et al. in 1982 (PMID: 7151835); first report of biallelic variants in SLC17A5 among ISSD patients by Verheijen in 1999 (PMID: 10581036). Both case-level (genetic) and experimental evidence support the relationship between SLC17A5 and ISSD. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 15172005, PMID: 23900835, PMID: 15805149, PMID: 10581036). In total, ten variants from seven probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.
Experimental evidence (4 points total) for the relationship between SLC17A5 and free SASD includes: the biochemical function of the gene product (solute carrier family 17 member 5) being consistent with the clinical and biochemical findings identified in individuals with ISSD (PMID: 2010546, PMID: 15557321, PMID: 33862140; PMID: 10581036) and the biochemical and clinical features of SLC17A5 knockout mice (PMID: 28189729).
In sum, SLC17A5 is definitively associated with free SASD. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. Classification approved by the ClinGen Lysosomal Diseases Gene Curation Expert Panel, October 30, 2023 (SOP v9).
The relationship between the SLC17A5 gene and free sialic acid storage disease (free SASD) an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 11, 2022. SLC17A5 encodes solute carrier family 17 member 5 (also known as sialin), a lysosomal membrane transporter protein that exports sialic acid (the majority of which is N-acetylneuraminic acid, Neu5Ac) and other acidic hexoses from lysosomes (PMID: 2010546). Among patients with free sialic acid storage disease, deficient SLC17A5 function results in impaired sialic acid export from lysosomes and lysosomal accumulation of sialic acid (PMID: 15557321), leading to a spectrum of clinical manifestations including urinary excretion of free sialic acid, neurological and developmental symptoms with severity ranging from the milder phenotype, Salla disease (SD), to the most severe phenotype, infantile free sialic acid storage disease (ISSD) (as reviewed in PMID: 20301643, 33862140).
Lumping and splitting: Variants in SLC17A5 have been reported in individuals with Salla disease (MIM# 604369) and Sialic acid storage disorder, infantile (MIM# 269920). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern for these conditions. Salla disease and Sialic acis storage disorder, infantile represent a clinical continuum (PMIDs: 20301643, 33862140). Therefore, the two entities have been lumped as free sialic acid storage disease.
The disease mechanism for free SASD is loss of function. ISSD was first reported by Tondeur et al. in 1982 (PMID: 7151835); first report of biallelic variants in SLC17A5 among ISSD patients by Verheijen in 1999 (PMID: 10581036). Both case-level (genetic) and experimental evidence support the relationship between SLC17A5 and ISSD. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 15172005, PMID: 23900835, PMID: 15805149, PMID: 10581036). In total, ten variants from seven probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.
Experimental evidence (4 points total) for the relationship between SLC17A5 and free SASD includes: the biochemical function of the gene product (solute carrier family 17 member 5) being consistent with the clinical and biochemical findings identified in individuals with ISSD (PMID: 2010546, PMID: 15557321, PMID: 33862140; PMID: 10581036) and the biochemical and clinical features of SLC17A5 knockout mice (PMID: 28189729).
In sum, SLC17A5 is definitively associated with free SASD. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. Classification approved by the ClinGen Lysosomal Diseases Gene Curation Expert Panel, October 30, 2023 (SOP v9).
Data provided by the ClinGen Prenatal GCEP from November 5, 2024 secondary analysis:
There is a clear prenatal/neonatal phenotype associated with SLC17A5 and free sialic acid storage disease, evident in many probands demonstrating the gene-disease association, biochemical function, and animal models. Common prenatal findings include ascites, hydrops fetalis, pericardial/pleural effusions, edema, ventriculomegaly, and hepatomegaly (PMIDs: 15805149, 29654786, 34906519).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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