Submission Details

The relationship between the GALC gene and Krabbe disease, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 18, 2022. GALC encodes galactocerebrosidase (GALC), a lysosomal enzyme involved that removes galactose from galactosylceramide, a glycosphingolipid (PMID: 8281145, PMID: 1164212, PMID: 5271165). When GALC is deficient, as is the case among individuals with Krabbe disease, the enzyme acid ceramidase removes the fatty acyl chain from galactosylceramide to generate psychosine (PMID: 31527255). Psychosine is a cytotoxic glycolipid that results in loss of oligodendrocytes and Schwann cells, leading to CNS and PNS demyelination and the neurologic anomalies seen in Krabbe disease (PMID: 34449528, PMID: 31527255).

The disease mechanism of Krabbe disease is loss of function. Krabbe disease was first reported in 1916 (PMID: 24137751) and the first report of biallelic variants in GALC among patients with Krabbe was published in 1994 (PMID: 8297359). Since then, at least 260 unique variants have been identified (PMID: 34449528). Both case-level (genetic) and experimental evidence support the relationship between Krabbe disease and GALC. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger deletions, including a recurrent 30kb deletion encompassing exons 11-17 (as reviewed in PMID: 34449528). In total, nine variants from five probands in three publications were curated (PMID: 23462331, PMID: 8786069, PMID: 20886637); 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 GALC and Krabbe disease includes the biochemical function of the gene product (the GALC enzyme) being consistent with the clinical and biochemical findings identified individuals with Krabbe disease (PMID: 8281145, PMID: 1164212, PMID: 5271165, PMID: 34449528, PMID: 31527255), the biochemical and clinical features of a mouse animal model (‘twitcher’ mouse model) homozygous for the p.W339* variant (PMID: 7417782, PMID: 8769874), and the impact of hematopoietic stem cell transplant therapy among human Krabbe patients (PMID: 15901860, PMID: 28855403). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, GALC is definitively associated with Krabbe disease. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time.