Lack of phenotypic effect of triallelic variation in SPATA7 in a family with Leber congenital amaurosis resulting from CRB1 mutations

PURPOSE: To identify the causative gene for autosomal recessive Leber congenital amaurosis (LCA) in a Chinese family. METHODS: One Chinese LCA family was identified and an ophthalmologic examination was performed. The genetic defects were analyzed simultaneously by a genome-wide linkage scan with 382 polymorphic microsatellite markers, as well as by comprehensive mutational screening of 15 genes known to associate with LCA on the genomic DNA of this family. RESULTS: Suggestive linkages were found in 13 chromosomal regions, of which only one harbored a known causative gene, crumbs homolog 1 (CRB1), on chromosome 1. Sanger sequencing of CRB1 identified two novel heterozygous mutations, c.3221T>C (p.L1074S) and c.2677–2A>C. In addition, a novel missense heterozygous mutation, c.938C>A (p.A313D), in spermatogenesis associated 7 (SPATA7), was detected in the proband after screening of the other 14 LCA causative genes. All three affected individuals of the family had compound heterozygous CRB1 mutations, and one of the three (the proband) had an additional mutation in SPATA7. The unaffected mother had the heterozygous c.3221T>C mutation in CRB1 and the heterozygous c.938C>A mutation in SPATA7. The unaffected father could not be tested, but presumably had the heterozygous c.2677–2A>C mutation in CRB1. The proband, with triallelic mutations in CRB1 and SPATA7, had a phenotype similar to other two affected brothers, suggesting the additional mutant allele in SPATA7 might not contribute to the disease. Similarly, the mother, with digenic mutations in CRB1 and SPATA7, had normal vision and fundi, suggesting the digenic mutations in these two genes might not cause disease. CONCLUSIONS: Digenic and triallelic mutations of CRB1 and SPATA7 were detected in a family with LCA. Our results imply that CRB1 and SPATA7 may not interact with each other directly. This emphasizes that care should be taken in invoking a mutation–disease association for digenic and triallelic mutations.