Submission Details

SPATA7 was first reported in relation to autosomal recessive retinal dystrophy in 2009 (Wang et al., PMID: 19268277). Affected individuals with SPATA7-related retinopathy show a wide range of age at onset, with a subset of cases presenting in infancy and others developing symptoms later in life. Common clinical features include nystagmus and severe visual loss, but significant inter- and inta-familial phenotypic variability has been described, including diagnoses of Leber congenital amaurosis and retinitis pigmentosa with variable age at onset. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic SPATA7 disruption) were found to be consistent among patients diagnosed with Leber congenital amaurosis 3 (MIM# 604232) or retinitis pigmentosa 94, variable age at onset, autosomal recessive (MIM# 604232). The phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic SPATA7 variants have been lumped into a single disease entity, referred to as SPATA7-related retinopathy.

Nine variants (two nonsense, four frameshift, two missense and one in-frame indel) that have been reported in ten probands in six publications (PMIDs: 19268277, 22136677, 26854980, 29411205, 28481129, 21310915) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be biallelic loss-of-function.

This gene-disease association is also supported by expression studies showing that SPATA7 is expressed in multiple layers of the mouse retina (PMID: 19268277). More specifically, Eblimit et. al. show that SPATA7 is localized to the connecting cilium of hTERT RPE-1 cells and mouse photoreceptors. This same group also provides evidence that SPATA7 interacts with RPGRIP1, a protein that has previously been implicated in an X-linked form of retinal dystrophy. Finally, the relevant publication also discusses the findings in a Spata7-null mouse model. Mutant mice had severely reduced outer nuclear layer thickness, defective light response as measured by electroretinogram (ERG), as well as a reduction in expression and mislocalization of the RPGRIP1 and RHO proteins (PMID: 25398945). Another Spata7 knockout mouse model supports these results (PMID: 35368022).

In summary, SPATA7 is definitively associated with autosomal recessive SPATA7-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on August 1, 2024 (SOP Version 10).