HEXB

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0010006

Submitter: ClinGen

HEXB was first reported in relation to Sandhoff disease, an autosomal recessive lysosomal storage disorder, in 1986 (O’Dowd et al., PMID: 3017984). HEXB encodes the beta subunit of the enzyme hexosaminidase which is involved in the breakdown of GM2-gangliosides. A deficiency of Hex B results in reduced hexosaminidase activity, and subsequent accumulation of GM2-gangliosides in neuronal cells. Accumulation of GM2-gangliosides in neuronal cells causes various symptoms including developmental regression, exaggerated startle response, and a cherry-red spot on the macula. Sandhoff disease has a phenotypic continuum and can be divided into three clinical phenotypes: acute infantile, subacute juvenile, and late-onset SD. The diagnosis of Sandhoff disease is established by abnormally low enzymatic activity of hexosaminidases A and B, and identification of biallelic pathogenic variants in HEXB by molecular genetic testing (Xiao et al., 2022, PMID: 35420740). Six variants (1 missense, 1 splice site, 2 nonsense, 2 frameshift) that have been reported in five probands in two publications (Zampieri S, et al., 2009, PMID: 18758829; Alonso-Pérez J et al., 2021, PMID: 34210542) are included in this curation. Individuals with two null variants typically have the acute infantile phenotype, whereas individuals with one null and one missense variant typically have the subacute juvenile phenotype, and individuals with two missense variants typically have the late-onset phenotype (Xiao et al., 2022, PMID: 35420740). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence including animal models systems, rescue in animal models, protein interaction, and biochemical function of the HexB enzyme. Individuals with Sandhoff disease show accumulation of GM2 gangliosides in the neurons due to reduced or undetectable levels of hexosaminidase activity (Mahuran DJ, 1999, PMID: 10571007). The gene product of HEXB interacts with HEXA and GM2A which have both been implicated in other forms of GM2 gangliosidosis and exhibit symptoms similar to Sandhoff disease (Lemieux MJ, et al., 2006, PMID: 16698036). Zebrafish show loss of enzyme activity, accumulation of oligosaccharides, lysosomal abnormalities in glia and reduced locomotor activity, similar to the molecular, cellular, neuropathological, and motility aspects of Sandhoff disease in humans. Hexb deficient zebrafish seem to recapitulate early disease stages, but lack extensive neurodegeneration (Kuil LE et al., 2019, PMID: 31140649). Knockout mouse models displayed biochemical and clinical features similar to those seen in humans with Sandhoff disease (Phaneuf D, et al., 1996, PMID: 8789434; Sango K, et al., 1995, PMID: 7550345) Gene therapy in mice partially restored hexb activity in the brain, which had the following effects: normalized lysosomal function, corrected lipid storage, prevented GM2 storage, prevented neuroinflammation, and restored a normal lifespan and locomotor function (Niemir N, et al., 2018, PMID: 29325092; Dogbevia G, et al., 2020, PMID: 31357902). In summary, HEXB is definitively associated with Sandhoff disease. 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 Lysosomal Diseases Gene Curation Expert Panel on the meeting date 9/15/2022 (SOP Version 9).