Spectrum, frequency, and genotype-phenotype of mutations in SPATA7

Abstract

Purpose: To describe the mutation spectrum of SPATA7 and associated ocular phenotypes.

Methods: As part of a continuing examination of the genetic basis of inherited ophthalmic diseases, sequencing variations in SPATA7 were identified in sequencing data from 5,090 probands. Mutations in SPATA7 were identified in 12 Chinese patients from ten families. Family history and clinical data were examined in detail in these patients. To evaluate possible gene-specific fundus changes, the results were combined with data from 66 patients from 50 families previously reported in the literature.

Results: Seven homozygous or compound heterozygous mutations, including two novel mutations (c.367C>T, p.Q123* and c.1083-2A>G) and five known mutations in SPATA7, were identified in ten families, including six families with Leber congenital amaurosis (LCA), three families with juvenile retinitis pigmentosa, and one family with early-onset high myopia. These families accounted for approximately 2.2% (6/269) of LCA and 0.4% (10/2,252) of inherited retinal dystrophies in this case series. A combined analysis of data from the present study and data from 60 families reported in the literature showed that 93.3% (112/120) of mutant alleles were truncation mutations, whereas only about 5.0% were missense mutations, and 1.7% were non-frameshift indels. Common SPATA7-associated fundus changes, including narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottled hypopigmentation in the midperipheral retina, were identified in this cohort and in patients in the literature. Missense mutations were not associated with specific phenotypic features or severity.

Conclusions: Narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottling hypopigmentation in the midperipheral retina may be considered early and common fundus changes specific to SPATA7-associated retinopathy. The fact that similar mutations result in varied phenotypes points to the existence of other potential modifiers of the disease. Uncovering the identity of these modifiers might aid the development of novel treatments.

Figure 1

Pedigrees of ten families with biallelic mutations in SPATA7. The arrow indicates the proband in each family. The affected individuals are shown as filled squares (male) or circles (female). Mutations are listed under each family, and their segregation in families is shown in the pedigrees.

Figure 2

Fundus images from patients with biallelic mutations in SPATA7. Representative fundus images show yellowish-white frosted degeneration in the midperiphery in patient F01-II:1 (A and B) and yellowish-white sand-like deposits in the midperiphery sparing the inferior area close to the optic fissure (C–F), in addition to yellowish-white mottled degeneration in the midperiphery (G–I). The homozygous novel mutation c.367C>T was identified in the F05-II:1, which is highlighted in red in G and H.

Figure 3

Fundus images showing age-dependent changes in a patient (F07-II:1). The fundus appeared nearly normal in the posterior area, with a few minor grayish-white spots in the midperiphery at the age of 3 years and 5 months (A), and progressed to significant yellowish-white spots in the midperiphery at the age of 7 years and 5 months (B, C). By the age of 8 years and 7 months, diffuse mottling hypopigmentation, with a few small intraretinal pigments, was visible (D–I). Mild salt-and-pepper-like changes were observed (E, H).

Figure 4

A schematic diagram of the mutation spectrum frequency in SPATA7. The two horizontal bars represent the coding regions based on two alternative splicing isoforms. Most loss-of-function mutations are listed on the top of the upper bar. A gross deletion involving the first five exons, four missense mutations, and two in-frame deletions are listed under the upper bar. The line height indicates the number of mutated alleles in 60 families.