Poster 136

by in  Poster Session 2

Leber Congenital Amaurosis in Chuuk, Federated States of Micronesia

Amani S. Albakri, MD; Jenina Capasso, LCGC; Sarina Kopinsky, LCGC; Tom Glaser, MD, PhD; Anamaria Yomai, MD; John Chiang, PhD, FACMG; Adele Schneider, MD; Alex V. Levin, MD
Wills Eye Hospital
Philadelphia,  PA

 

Introduction: Leber Congenital Amaurosis (LCA) is an early severe form of retinal dystrophy. Mutations in at least 18 genes cause LCA, including crumbs homolog 1 (CRB1), which may account for 10% of LCA [1].

Methods: Our team visited Chuuk, Micronesia to investigate ocular genetic disease in this geographically confined population. We tested genes associated with LCA for causative mutations by PCR target enrichment and Next Generation Sequencing. Novel pathogenic variants were confirmed by Sanger sequencing and restriction analysis.

Results: Five children from three consanguineous kindreds on Tonoas Island were diagnosed as having LCA based on clinical history and ophthalmological exams. All were born with poor vision. They had hand-motion or light perception vision, nystagmus and a fundus appearance of diffuse gray gliosis, marked midperipheral pigment clumping for 360° and retinal vascular attenuation. All affected children were homozygous for a novel c.3134delT frameshift mutation in CRB1 exon 10, and their parents were heterozygous. CRB1 genotypes of 47 other DNA samples, representing 7 islands in Chuuk state, were wild-type.

Discussion: Pathogenic loss-of-function mutations in CRB1 (LCA8, OMIM #613835) are known to cause severe retinal dystrophy, with autosomal recessive inheritance. Previously reported mutations include a downstream frameshift allele, c.3345delT in exon 12, and support the pathogenicity of the novel change in our patients [2].

Conclusion: Homozygosity in this small island community reflects a history of population bottlenecks, with identity by descent, and suggest a new founder mutation for LCA disease in Chuuk, Micronesia.

References: 1- Den Hollander AI, Roepman R, Koenekoop RK, Cremers FPM. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 2008;27:391-419
2- Hanein, S., Perrault, I., Gerber, S., Tanguy, G., Barbet, F., Ducroq, D., Calvas, P., Dollfus, H., Hamel, C., Lopponen, T., Munier, F., Santos, L., Shalev, S., Zafeiriou, D., Dufier, J.-L., Munnich, A., Rozet, J.-M., Kaplan, J. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum. Mutat. 23: 306-317, 2004.

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