The relationship between the FUCA1 gene and fucosidosis, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 27, 2022. FUCA1 encodes alpha-L-fucosidase, a lysosomal enzyme involved in the degradation of fucose-containing glycoproteins and glycolipids via cleaving via hydrolyzing alpha-fucose moieties at the non-reducing terminus of oligosaccharides (PMID: 2803312). Among patients with fucosidosis, alpha-fucosidase deficiency results in the accumulation of fucose-containing glycoproteins and glycolipids in multiple tissues (PMID: 4172303, PMID: 4241464).
The disease mechanism of fucosidosis is loss of function. Fucosidosis was first reported in 1968 by Van Hoof and Hers (PMID: 4172303) and the first report of biallelic variants in FUCA1 among patients with fucosidosis in 1989 by Kretz (PMID: 2642067). Both case-level (genetic) and experimental evidence support the relationship between FUCA1 and fucosidosis. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 33266441, PMID: 2642067, PMID: 1281988, PMID: 8097260, PMID: 8401503, PMID: 8401503, PMID: 9039984, PMID: 8081399). In total, eight variants from seven probands in six 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 FUCA1 and fucosidosis includes: the biochemical function of the gene product (alpha-fucosidase) being consistent with the clinical and biochemical findings identified individuals with fucosidosis (PMID: 4172303, PMID: 4241464); the biochemical and clinical features of FUCA1 knockout mice (PMID: 27491075); and rescue of alpha-fucosidase enzyme function via hematopoietic cell transplantation in a patient with fucosidosis (PMID: 11360116). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, FUCA1 is definitively associated with fucosidosis. 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 August 2, 2022 (SOP v9).
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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