ASB10

Inheritance Pattern: AD

Disease ID:MONDO:0011311

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011311

Submitter: ClinGen

The *ASB10* locus was first reported in relation to open-angle glaucoma in 2012 (Pasutto et al., PMID: 22156576), following an earlier linkage study that mapped primary open angle glaucoma within a large, multi-generation family to the relevant genomic region on chromosome 7q35-q36 (PMID: 10037570). Other case-control studies found significant enrichment of *ASB10* missense variants among glaucoma cases relative to controls, with some cohorts of patients exhibiting normal tension (PMID: 20309402) and others high ocular tension (PMID: 22156576, PMID: 26713451). However, this enrichment did not prove to be reproducible in other cohorts (PMID: 22798626, PMID: 31522561). A follow-up study with targeted genotyping of *ASB10* in one family reported 9 affected individuals harboring a synonymous variant in the coding region confirmed to be absent from 3 unaffected individuals (PMID: 22156576). Affected individuals were found to express a smaller *ASB10* transcript with skipping of exon 3, resulting in a frameshift and premature stop codon (PMID: 22156576). Affected family members were diagnosed at a broad range of ages (25 years to 70 years and exhibited elevated intraocular pressure, optic disc cupping with optic cup-disc ratios >0.6 in at least one eye, gonioscopy showing an iridocorneal angle >40 degrees, and in some cases visual field defects characteristic of glaucomatous damage (PMID: 10037570). While this reported family introduced the possibility of variants in *ASB10* as a cause of monogenic disease, case-control studies performing *ASB10* genotyping in glaucoma patient cohorts have not identified other disease-associated variants with high penetrance or demonstrated impact on the gene product. Genotyping in most cases was limited to the *ASB10* locus, and other loci were not investigated for potential modifiers. In one family with multiple affected and some unaffected members harboring a missense variant in *ASB10*, a homozygous individual was observed to be more severely affected than the heterozygous siblings (PMID: 26713451). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance was found to be consistent across most of the asserted cases, despite the phenotypic heterogeneity of their clinical presentation. These factors provided a rationale for this curation to lump the diverse cases under a single disease entity, referred to as glaucoma 1, open angle, F (MONDO:0011311). This curation scored seven potentially deleterious variants (five missense, one nonsense, and one synonymous), which have been collectively reported in eight probands in two publications (PMID: 22156576, PMID: 26713451). Genotyping of potential causative loci was limited to *ASB10* in most cases. In one case, co-segregation of the synonymous variant with disease in a family with genotyping of all genes within the linkage region was scored as part of this gene-disease relationship (PMID: 22156576). Seven out of eight probands harbored one variant allele while one harbored a homozygous variant within the *ASB10* locus. The mechanism of pathogenicity in some cases may be monoallelic loss of *ASB10* function, as the synonymous variant was associated exon skipping and premature termination, while the nonsense variant was predicted to trigger nonsense-mediated decay (PMID: 22156576). On the other hand, many of the candidate variants have been down-scored due to relatively high frequencies in control databases or detection among both cases and unaffected controls. These findings indicate that while some variants may contribute to the glaucoma susceptibility through a multifactorial mechanism, they are likely insufficient to cause glaucoma on their own. Some scoring was assigned to case-control studies based on the reproducible enrichment of *ASB10* variants among cases relative to controls (PMID: 22156576, PMID: 20309402, PMID: 26713451, PMID: 22798626, PMID: 31522561). Additional experiments will be required to evaluate the potential impact of missense variants on *ASB10* function and/or the development of glaucoma. Additional case reports with more comprehensive genotyping of glaucoma-associated loci will be required to confirm that *ASB10*-related disease occurs in the absence of variants in other genes. Evaluation of this gene-disease association considered biochemical studies of the ASB10 gene product, a component of a ubiquitin ligase complex that also includes CUL5, RBX2, and UBC (PMID: 24337577). ASB10 also co-localizes with HSP70 and components of the proteasome (PMID: 23901248). These findings are consistent with a role of ASB10 in the ubiquitin- and proteasome-mediated degradation pathway. *ASB10* mRNA and protein were found to be normally expressed in the iris, trabecular meshwork, Schlemm's canal, and other ocular tissues (PMID: 30239781), however, its levels are higher in skeletal muscle and cardiac tissues (PMID: 11509662). Transient *ASB10* silencing in cultured anterior segment exhibited ~50% reduction in flow rate / outflow relative to a non-targeting shRNA control. This tissue defect may be a match to the increased intraocular pressure observed in some of the human patients (PMID: 22156576). Interestingly, the same effect can be triggered by proteasome inhibition (PMID: 23901248). Overall, experimental evidence on *ASB10* is consistent with but not highly supportive of a role in open-angle glaucoma. In summary, both supportive and contradictory evidence have been found relevant to the asserted association between *ASB10* and glaucoma 1, open angle, F. The absence of more complete genotyping of the asserted cases to exclude variants in other potential causative loci and the limited availability of experimental evidence at this time to functionally characterize candidate variants have led to a Limited classification. While *ASB10* variants may be enriched in glaucoma cases relative to controls, additional case reports with more comprehensive genotyping of glaucoma-associated loci will be required to determine whether these variants can act as a monogenic cause of disease or contribute to glaucoma through a polygenic mechanism. Murine or other animal models of *Asb10* disruption will also inform the future re-classification of this gene-disease relationship. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on March 16th, 2023 (SOP Version 9).

Inheritance Pattern: Unknown

Disease ID:MONDO:0011311

Submitter: Labcorp Genetics (formerly Invitae)