Mutations that are a common cause of Leber congenital amaurosis in northern America are rare in southern India

Abstract

Purpose: To test patients from southern India for the presence of mutations that most commonly cause Leber congenital amaurosis (LCA) in northern America.

Methods: A review of the literature identified 177 unique LCA causing mutations in eight different genes: aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), crumbs homolog 1 (CRB1), cone-rod homeobox (CRX), guanylate cyclase 2D (GUCY2D), nephronophthisis 6 (NPHP6), retinol dehydrogenase 12 (RDH12), retinal pigment epithelium-specific protein 65 kDa (RPE65), and retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1). Allele-specific ligation assay and bidirectional sequencing were used to test 38 unrelated LCA patients from southern India for 104 of these mutations, which contribute to more than 30% of the LCA cases in a northern American population.

Results: Only one participant was found to harbor one of the 104 mutations in the allele-specific assay (homozygous RPE65 Tyr368His). A mutation that was not part of the assay (homozygous RPE65 Tyr143Asp) was incidentally detected in a second patient when an equivocal signal from one allele on the assay was followed up with automated DNA sequencing.

Conclusions: Mutations that contribute to 30% of the LCA cases in northern America were detected in only 2.6% of LCA cases in our cohort from southern India. There were no instances of IVS26 c.2991+1655 A>G in NPHP6, the most commonly detected mutation in LCA. These data suggest that LCA in India is caused primarily by a different set of mutations in the same genes associated with disease in northern America, or by mutations in other genes that have not yet been discovered. Therefore, mutation-specific assays developed for European and northern American cohorts may not be suited for testing LCA patients from India or other ethnically distinct populations.

Figure 1

Clinical and molecular data for patient ILCA-65–1 and family. The proband first presented for ophthalmic examination at 3 years of age. A: There were no recordable responses to light in the electroretinogram. Examples shown are from the left eye for a dark-adapted combined response and a light-adapted photopic response. Arrowhead points to the timing of the 10-ms bright light pulse. B: The family tree shows the proband (filled circle with arrow) and a sibling as clinically affected and both parents as unaffected. C: Bidirectional sequencing showed that the RPE65 Tyr368His TAT>CAT mutation was homozygous in the affected proband (S1) and affected sibling (S3), and was heterozygous in the mother (M) and father (F). Reverse strand sequence around RPE65 Tyr368 (caNatct) is shown against an ethnic unrelated and unaffected control normal (NL).

Figure 2

Clinical and molecular data for patient ILCA-100–1 and family. The proband first presented for ophthalmic examination at 4 months of age. When the proband was 3 years old (A), there were no recordable responses to light in the electroretinogram. Examples shown are from the left eye for a dark-adapted combined response and a light-adapted photopic response. Arrowhead marks the timing of the 10-ms bright light pulse. B: The family tree shows the proband (filled circle with arrow) as clinically affected, and both parents are unaffected. C: Bidirectional sequencing showed that the RPE65 Tyr143Asp TAC>GAC mutation was homozygous in the affected proband (P) and was heterozygous in the mother (M) and father (F). Reverse strand sequence around RPE65 Tyr143 (atNacta) is shown against an ethnic unrelated and unaffected control normal (NL).