A number sign (#) is used with this entry because Leber congenital amaurosis-3 (LCA3) and a form of retinitis pigmentosa with variable age at onset (RP94) are caused by homozygous or compound heterozygous mutation in the SPATA7 gene (609868) on chromosome 14q31.

Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered retinitis pigmentosa (Gu et al., 1997). SPATA7-associated retinopathy shows a variable age at onset, ranging from infancy to adulthood, as well as phenotypic variability, including intrafamilial differences (Wang et al., 2009; Avila-Fernandez et al., 2011; Feldhaus et al., 2018; Sengillo et al., 2018).

Mackay et al. (2011) concluded that SPATA7 retinopathy is an infantile-onset severe cone-rod dystrophy with early extensive peripheral retinal atrophy but with variable foveal involvement.

For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000.

Reviews

Kannabiran (2020) reviewed reported SPATA7 mutations and the associated phenotypes. The author noted that there were no clear-cut correlations between genotype and phenotype, and that phenotypic heterogeneity had been observed among patients with the same mutation. Clinical variability was also often seen in patients with SPATA7 mutations, with some phenotypes resembling cone-rod dystrophy or choroideremia.

Stockton et al. (1998) reported a large consanguineous Saudi Arabian kindred (KKESH-019) segregating Leber congenital amaurosis. In addition to poor visual acuity (typically less than 5/200), affected individuals manifested moderate midfacial hypoplasia with enophthalmos, complex vertical, horizontal, and rotatory nystagmus present from early life, moderate hypermetropic refractive errors with astigmatism, and various presentations of esotropia and exotropia. At least 4 individuals had hospital-based electroretinograms (ERGs) which were nonrecordable in both photopic and scotopic components in the first 2 years of life.

Li et al. (2009) reported a Saudi Arabian family (KKESH-060) segregating LCA. The 3 affected sibs had poor vision, nonrecordable ERGs, hypermetropic astigmatism, and infantile nystagmus. Two also showed neuroretinal atrophy and markedly attenuated vessels of the fundi.

Mackay et al. (2011) reported affected members of 5 unrelated families with LCA3. The retina had widespread retinal pigment epithelial atrophy, with minimal pigment migration into the neurosensory retina. Fundus autofluorescence (FAF) imaging showed a parafoveal annulus of increased autofluorescence. High-definition optical coherence tomography (OCT) showed preservation of the inner/outer segment junction at the fovea.

Retinitis Pigmentosa 94, with Variable Age at Onset

Wang et al. (2009) reported 2 unrelated patients with juvenile-onset retinitis pigmentosa (RP) and mutation in the SPATA7 gene. The first was a 7-year-old Portuguese girl (patient 28608) who had excellent (20/20) visual acuity without nystagmus. She developed nyctalopia before age 2 and had 5-degree visual fields on Goldmann perimetry with nondetectable ERGs. The second patient was a French-Canadian man (patient 1348) who was found to have hand-motion vision at age 55 years. He reported initially normal vision in childhood that declined, with the development of night blindness and nystagmus. Examination revealed advanced retinal pigmentary degeneration, with narrow arterioles, optic disc pallor, and mild maculopathy. ERGs were nondetectable and visual fields were reduced to 5 degrees with the V4e target.

Avila-Fernandez et al. (2011) reported 2 Spanish sibs from a consanguineous family with late-onset RP and mutation in the SPATA7 gene. The proband developed night blindness at age 25 years, at which time visual fields were normal. At age 29, she experienced loss of peripheral visual fields, and reexamination showed narrowed retinal vessels and bone-spicule pigmentation in the peripheral retina, with subnormal rod responses on ERG. At age 31, her visual field was limited to 10 degrees, and the ERG showed severely decreased a- and b-wave responses with both scotopic and photopic stimulation. Her affected sib was asymptomatic, but mixed ERG at age 26 showed a moderate reduction in the amplitude of the a-wave and delay in both a- and b-wave latency bilaterally.

Clinical Variability

Matsui et al. (2016) studied a Hispanic boy who presented with a cone-rod dystrophy phenotype that developed into late-stage RP, and who had mutation in the SPATA7 gene. The proband was diagnosed with RP at age 7 years, with retinal pigmentary changes on funduscopy and an abnormal ERG. At age 9, best-corrected visual acuity (BCVA) was 20/25 and 20/32, funduscopy showed a waxy optic disc, minimal vessel attenuation, bull's eye-like change in the macula, and a tigroid appearance of the peripheral retina. Full-field ERG showed reduced rod-mediated responses with nondetectable cone-mediated responses. Visual fields were severely limited to a small central island and midperipheral island of vision. The ERG and visual field findings were consistent with a cone-rod dystrophy. Follow-up over 12 years showed progressive loss of peripheral vision, and by age 17 years, only central vision was detectable. ERG at ages 17 and 21 years showed nondetectable rod function, whereas cone function remained measurable at fixation. OCT showed progressive thinning of the outer nuclear layer (ONL) and rod outer segments (ROS), with the ONL eventually barely detectable and the ROS unmeasurable.

Sengillo et al. (2018) reported a 63-year-old man who had RP with a choroideremia-like phenotype and mutation in the SPATA7 gene. The proband, who had a long history of progressive nyctalopia, visual field constriction, and reduction in visual acuity, and was diagnosed with RP at 31 years of age, presented with a recent subacute decrease in visual acuity of the left eye accompanied by a halo effect around objects. Upon examination, he had BCVAs of 20/30 and 20/60 in the right and left eyes, respectively, and funduscopy showed extensive chorioretinal degeneration of the peripheral retina, progressing toward the macula which contained islands of spared RPE. FAF imaging revealed widespread continuous loss of RPE encroaching on the central macula in both eyes. Spectral domain OCT confirmed those findings, and showed extensive degeneration and sclerosis of the choroid in areas of RPE loss, with focal areas of RPE thickening that were more prominent in the left eye. Full-field ERG revealed completely extinguished scotopic and photopic responses. On follow-up 2 years later, the proband reported no changes in vision, and examination showed BCVAs of 20/25 and 20/60, but progression of disease was evident on SD-OCT and FAF, with FAF confirming a reduction in the area of centrally spared RPE compared to baseline.

Feldhaus et al. (2018) reported a German brother and sister with retinal degeneration and mutation in the SPATA7 gene. Upon examination, the 52-year-old brother was more severely affected than his 48-year-old sister. BCVA in the brother was 20/100 and 20/175, with concentric narrowing to 2 degrees. His sister had BCVAs of 20/160 bilaterally, with visual field narrowing to 40 degrees. ERG responses in the brother were nondetectable, with significantly elevated thresholds for dark adaptation, whereas ERG in the sister showed reduced cone and rod responses, with better-preserved rod function and moderately elevated thresholds for dark adaptation. Color vision testing showed color confusion without assignment to a specific axis in the brother, and a tritanomalous defect in the sister. Both had bone spicule-like pigmentation, more prominent in the brother, and both had attenuated arterioles and optic disc pallor. Central retinal thickness was normal in the brother and reduced in the sister. The clinical diagnosis in the brother was rod-cone dystrophy, whereas in the sister it was cone-rod dystrophy. Age at onset was not reported.

Stockton et al. (1998) used a DNA pooling strategy comparing the genotypes of affected to unaffected control pools in a genomewide search for identity by descent in a consanguineous Saudi Arabian LCA family (KKESH-019). A shift to homozygosity was observed in the affected DNA pool compared with the control pool at linked markers D14S606 and D14S610. Testing of markers closely linked to and flanking these loci confirmed linkage with a maximum lod score of 13.29 at theta = 0.0. From these data, the LCA locus, designated LCA3, was assigned to 14q24. This locus and the previously identified loci for LCA were excluded in other Saudi Arabian pedigrees, indicating yet further genetic heterogeneity in LCA.

Using short tandem repeat markers in a Saudi Arabian family (KKESH-060) segregating LCA, Li et al. (2009) found linkage of the disorder to the LCA3 locus at 14q24 (lod score of 3.0). All 3 affected members were homozygous between markers D14S61 and D14S1066, a 13.4-Mb interval, whereas unaffected family members were heterozygous or wildtype. Li et al. (2009) noted that the haplotype in their family was different from that in the family reported by Stockton et al. (1998).

By whole-genome SNP analysis and fine mapping of the distal boundary of the LCA3 locus in 1 affected subject from each of the 2 families with LCA previously studied by Stockton et al. (1998) and Li et al. (2009), Wang et al. (2009) refined the critical region of homozygosity to 3.8 Mb between markers D14S1022 and D14S1005 on chromosome 14q31.3. The critical region contained 9 candidate genes.

In 2 Spanish sibs from a consanguineous family with typical late-onset RP, Avila-Fernandez et al. (2011) performed genomewide linkage analysis followed by homozygosity mapping and identified a 3.7-Mb region on chromosome 14 with a lod score of 2.8 that encompassed the SPATA7 gene.

Leber Congenital Amaurosis 3

In 2 unrelated Saudi Arabian families (KKESH-019 and KKESH-060) with Leber congenital amaurosis (LCA3; 604232) previously reported by Stockton et al. (1998) and Li et al. (2009), respectively, Wang et al. (2009) sequenced 9 candidate genes and identified a homozygous mutation in the SPATA7 gene (R108X; 609868.0001) in family KKESH-060 that segregated with the disease and was not found in 50 Saudi Arabian and 100 European samples. Mutation analysis in additional patients revealed homozygosity for the same R108X mutation in a Dutch LCA patient as well as a frameshift mutation in another LCA patient of Middle Eastern origin (609868.0002). Wang et al. (2009) also identified homozygous SPATA7 mutations in 2 patients with juvenile-onset retinitis pigmentosa (see later).

Mackay et al. (2011) screened all coding exons in the SPATA7 gene in 141 patients diagnosed with LCA or early childhood-onset severe retinal dystrophy and identified 4 disease-causing mutations in 5 families. They concluded that mutations in SPATA7 are a rare cause of childhood retinal dystrophy, accounting for 1.7% of disease in their cohort. Four consanguineous families with LCA, 3 of Pakistani and 1 of Bangladeshi origin, had a homozygous mutation in exon 5 (609868.0007) or exon 8 (609868.0002). In a nonconsanguineous British Caucasian family, 2 brothers had compound heterozygous mutations, one in exon 5 (609868.0005) and the other in exon 12 (609868.0006). One of the brothers had clinical features consistent with LCA, having severe visual loss from early infancy, pendular nystagmus, and sluggish pupillary responses. His brother had a milder phenotype with onset of nystagmus at 8 weeks of age. He was able to fix and follow at this age. When older, he was noted to have severe nyctalopia and constricted visual fields. These symptoms deteriorated significantly from 14 years of age.

Retinitis Pigmentosa 94, Variable Age at Onset

In 2 patients with juvenile-onset retinitis pigmentosa (RP94; see 604232), Wang et al. (2009) identified homozygosity for 2 different different nonsense and frameshift mutations in the SPATA7 gene (609868.0003 and 609868.0004, respectively). Wang et al. (2009) noted that, consistent with the observation that LCA has a more severe clinical phenotype than juvenile RP, the nonsense mutations associated with LCA are located in the middle of the SPATA7 coding region, whereas those associated with juvenile RP are located in the last 2 exons of SPATA7.

In 2 Spanish sibs from a consanguineous family with typical late-onset RP mapping to the SPATA7 locus on chromosome 14, Avila-Fernandez et al. (2011) identified homozygosity for the R85X mutation in the SPATA7 gene (609868.0007), previously reported in affected individuals from 3 families with LCA (Mackay et al., 2011). Avila-Fernandez et al. (2011) suggested that the phenotypic variability might be explained by modifier alleles contributing to penetrance and expressivity, or intronic variants influencing severity.

In a 21-year-old Hispanic man with retinal degeneration that had progressed over 12 years from a cone-rod dystrophy phenotype to a late-stage RP phenotype, Matsui et al. (2016) screened 163 retinal disease-associated genes and identified homozygosity for a 1-bp deletion in the SPATA7 gene (609868.0008).

In a 63-year-old man who had severe RP associated with prominent RPE atrophy and choroidal sclerosis, Sengillo et al. (2018) performed whole-exome sequencing and identified compound heterozygosity for mutations in the SPATA7 gene: a missense mutation (Y367C; 609868.0009) and a 2-bp deletion (609868.0010). An unaffected family member was heterozygous for 1 of the variants, both of which were present at very low minor allele frequency (less than 0.00003) in the gnomAD database. The authors stated that future studies were needed to discern whether unidentified genetic modifiers were involved or whether this represented a phenotypic subset of SPATA7-associated retinal degeneration.

In a German brother and sister with retinal degeneration, diagnosed as rod-cone and cone-rod dystrophy, respectively, Feldhaus et al. (2018) analyzed genomic DNA using a panel of 286 retinal disease-associated genes and identified homozygosity for a missense mutation in the SPATA7 gene (I371T; 609868.0011). The variant, which was found at low minor allele frequency (0.0003249) in the ExAC database, was present in heterozygosity in their 85-year-old mother, who had normal age-related findings on all tests; DNA was unavailable from the father. The authors noted that although the sibs were homozygous for the same mutation, they exhibited phenotypic variability, and thus genotype/phenotype correlation remained difficult.

Leber congenital amaurosis-13 (612712), which is caused by mutation in the RDH12 gene (608830) on chromosome 14q23.3, was originally thought to be the same as LCA3. However, affected members of the Saudi Arabian family reported by Stockton et al. (1998) do not have mutations in the RDH12 gene.

Eblimit et al. (2015) generated Spata7-knockout mice and observed severe early-onset retinal defects, with a marked reduction in the thickness of the outer nuclear layer compared to wildtype mice. The loss in thickness was progressive, suggesting that photoreceptor cells degenerate in the absence of Spata7 function; other cell types in the mutant retinas were unaffected. Quantification of cone and rod cells per unit area indicated that cone photoreceptor degeneration proceeds at a substantially lower rate compared to rods in Spata7-mutant retinas. Transmission electron microscopy revealed shortened outer segments and disorganization of the disc membranes in mutant retinas compared to wildtype retinas, where the discs were well-organized into stacks. Analysis of rod and cone electroretinography (ERG) responses in the Spata7-null mice showed a decline in rod responses by postnatal day (P) 15 that became more pronounced with age, whereas cone-mediated responses showed only a slight age-dependent decline. Rod function was almost undetectable by age 12 months.

Eblimit et al. (2018) generated a conditional SPATA7-knockout allele to determine which cell type requires Spata7 function for photoreceptor survival. In Spata7 photoreceptor-specific conditional knockout mice, both rod and cone photoreceptor dysfunction and degeneration was observed, characterized by progressive thinning of the outer nuclear layer and reduced response to light. However, RPE-specific deletion of Spata7 did not impair retinal function or cell survival. The authors noted that the alteration in both rod and cone function resulting from loss of Spata7 in photoreceptors was consistent with the clinical phenotypes of LCA and RP observed in patients with SPATA7 mutations.