NTF4

Inheritance Pattern: AD

Disease ID:MONDO:0013134

Submitter: ClinGen

The *NTF4* locus was first reported in relation to open-angle glaucoma in 2009 (Pasutto et al., PMID: 20463313), following an earlier genome-wide linkage study identifying markers within the relevant genomic region on chromosome 19q13.33 associated with adult onset primary open angle glaucoma (PMID: 10767336). The first study with genotyping of *NTF4* in affected patients reported 7 cases harboring heterozygous missense variants. All of these cases exhibited optic disc atrophy and glaucomatous visual field defects, however, only 6 out of 7 patients exhibited ocular hypertension. As a result, six cases received a diagnosis of primary open angle glaucoma, while one was diagnosed with normal tension glaucoma. Patients’ ages of diagnoses formed a broad range of ages (36 years to 80 years) and included one case diagnosed as juvenile primary open-angle glaucoma. Subsequent reports of patients harboring heterozygous variants in *NTF4* have increased the variability of phenotypes and ages of diagnosis, with additional cases of both normal tension and high tension primary open angle glaucoma (PMID: 22815630, PMID: 20806036) and at least one case of primary congenital glaucoma with onset before the age of 1 year and additional phenotypes such as photophobia, corneal opacity, and buphthalmos (PMID: 31367175). Some subsequent studies of *NTF4* genotypes in the glaucoma population have reached other conclusions, with some failing to find *NTF4* variants in large cohorts (PMID: 20215012, PMID: 20463313, PMID: 29540704) and/or raising questions about the pathogenicity of some of the previously identified variants (PMID: 20215012). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance was found to be consistent across all 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, O (MONDO:0013134). Twelve potentially deleterious variants were scored as part of this curation (eleven missense and one nonsense), which have been collectively reported in twelve probands in five publications (PMID: 20463313, PMID: 22815630, PMID: 20806036, PMID: 31367175, PMID: 20215012). All probands scored in this curation harbored one variant allele within the *NTF4* locus, and genotyping of other potential causative loci in most cases was limited to *MYOC*, *OPTN*, *WDR36*, and/or *CYP1B1*. The mechanism of pathogenicity in some cases may be monoallelic loss of *NTF4* function, as at least one missense variant was found to be severely reduced or absent at the protein level (PMID: 22815630). On the other hand, an unaffected patient harboring a nonsense variant was identified in the control group of one case-control study (PMID: 20215012), and was intentionally included but not scored in this curation. This finding highlights the absence of evidence in the current patient population for loss of function in *NTF4* as a definitive cause of disease. Some of the candidate alleles are quite common in control populations, suggesting that while they may contribute to the glaucoma susceptibility through a multifactorial mechanism, they are likely insufficient to cause glaucoma on their own. Co-segregation of the variant with affected status has not yet been reported in a family with more than two affected members, so this form of evidence did not play a role in the scoring of this gene-disease relationship. This gene-disease association is supported by biochemical studies of the NTF4 gene product, a neurotrophic signaling factor known as neurotrophin 4 that acts as a ligand for the TRKB receptor tyrosine kinase. Treatment of rat neurons with NTF4 protein stimulates their survival and prevents apoptosis when cultured *in vitro* (PMID: 8145295) as well as *in vivo* (PMID: 8159743). NTF4 stimulation of retinal ganglion cells in particular can promote their axonal branching under atrophy-inducing conditions (PMID: 8656282) and can rescue these neuronal cells from injury-induced apoptosis (PMID: 8613749). This neuroprotective effect may be relevant to glaucoma in that neuronal cell death (specifically retinal ganglion cell apoptosis) is a recognized mechanism by which intraocular pressure causes eye injury (PMID: 9920498). On the other hand, the survival benefit of NTF4 treatment on retinal ganglion cells may be short term only (PMID: 9667016). While expression profiling across various human tissues indicates that *NTF4* is highly expressed in a variety of tissue types (PMID: 30239781), its expression within the retina is specific to the ganglion cell layer (PMID: 19765683). Mice with homozygous disruption of the *NTF4* ortholog have been primarily characterized as showing learning and long-term memory defects (PMID: 7746324), while their intraocular pressure may not have been evaluated. However, these animals exhibit reduced neuronal cell content in one of their sensory ganglia (PMID: 8757249) and enhanced loss of retinal ganglion cells in particular after an ischemic injury (PMID: 15671298), indicating that the neuroprotective function of NTF4 may be present in mice. Overall, experimental evidence on *NTF4* is consistent with but not highly supportive of a role in open-angle glaucoma. In summary, contradictory evidence has been found to dispute the asserted association between *NTF4* and glaucoma 1, open angle, O. 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 Disputed classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on December 16th, 2022 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0013134

Submitter: PanelApp Australia