The relationship between the NEU1 gene and sialidosis, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 1, 2022. NEU1 encodes neuraminidase 1 (PMID: 8985184), an enzyme that is involved in degradation of sialated glyconguates via hydrolyzing terminal N-acetylated neuraminic acids (sialic acids) in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates (as reviewed in PMID: 26949572). Patients with sialidosis show deficient neuraminidase I activity (PMID: 836321, PMID: 610423), leading to accumulation of sialylated oligosaccharides and glycoproteins and urinary excretion of sialylated oligosaccharides and glycoproteins and resulting in characteristic clinical disease manifestations including skeletal anomalies, coarse facies, hepatosplenomegaly, and neurologic impairment (as reviewed in PMID: 26949572).
The disease mechanism of sialidosis is loss of function. Sialidosis was first reported in 1968 by Spranger et al. (PMID: 4235073) and the first report of biallelic variants in NEU1 among sialidosis cases was in 1996 by Bonten et al. (PMID: 8985184). Both case-level (genetic) and experimental evidence support the relationship between NEU1 and sialidosis. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 8985184, PMID: 10767332, PMID: 9054950, PMID: 11702224, PMID: 11470272, PMID: 14695530, PMID: 18343720). In total, fourteen variants from ten probands in seven 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 for the relationship between NEU1 and sialidosis includes: the biochemical function of the gene product (neuraminidase 1) being consistent with the clinical and biochemical findings identified individuals with sialidosis (PMID: 8985184, PMID: 836321, PMID: 610423, PMID: 26949572); the biochemical and clinical features of NEU1 knockout mice (PMID: 12023988); and rescue of enzyme function via chaperone-mediated gene therapy in NEU1 transgenic mice (PMID: 23770387). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, NEU1 is definitively associated with sialidosis. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).
Data provided by the ClinGen Prenatal GCEP on January 28, 2025: Features of sialidosis that can be identified prenatally by fetal imaging include hydrops, ascites, pleural effusion, cardiomegaly, pericardial effusion, and hepatosplenomegaly (PMID: 11063730, 1119501). Neonates may also have hypotonia, dysostosis multiplex, and coarse facial features (PMID: 23433491, 25223955). Stillbirth or early death in individuals with congenital sialidosis is common (PMID: 11063730, 11195014). Note: This addition of the data from the ClinGen Prenatal GCEP does not change the scoring or classification of the gene-disease relationship that was approved by the ClinGen Lysosomal Diseases GCEP.
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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