HYCC1 was first reported in association with autosomal hypomyelinating leukodystrophy 5 (OMIM:610532) in 2006 (Zara et al., PMID: 16951682). HYCC1 codes for the Hyccin protein, which is involved in the PI4KA lipid kinase complex and is used for synthesis of phosphatidylinositol 4-phosphate (PI4P). Hyccin is essential for myelin development and growth. Hypomyelinating leukodystrophy 5 is characterized by bilateral congenital cataracts, developmental delay, mild-to-moderate intellectual disability, pyramidal signs and spasticity, cerebellar signs/ataxia, seizures, and scoliosis. MRI findings include hypomyelination and abnormalities of the brainstem pyramidal tract. (PMID: 21911699).
Eight variants (2 splice-site, 2 missense, 1 intragenic deletion, 3 frameshift) from 4 publications (PMID: 16951682, 17928815, 23998934, 21911699) have been included in this curation. Segregation data from four families was also scored as genetic evidence in this curation (PMID: 16951682, 17928815). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, the c.51+1G>A variant and c.414+1G>T variant have been reported in multiple unrelated families as potential founder variants in Mediterranean populations (PMID: 16951682, 21911699, 34192786). The mechanism of pathogenicity for HYCC1 is loss of function.
This gene-disease relationship is also supported by experimental evidence. Gazzerro et al. showed that the Hyccin protein is expressed in relevant disease tissues in mice (PMID: 22461884). Zhang et al. demonstrated that Hyccin knockdown Drosophila demonstrated overlapping phenotype with human disease, which was rescued by the expression of the human HYCC1 gene (PMID: 34894559).
In summary, there is definitive evidence supporting the relationship between HYCC1 and hypomyelinating leukodystrophy 5 (MONDO: 0012514), also known as HYCC1-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy GCEP on February 12, 2025 (SOP version 11).
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