Abstract TP448: Genome-wide CNV Array Analysis Following Post-hoc Targeted Amplicon Sequencing Revealed Genetic Anticipation in Parent-offspring Pairs with Moyamoya Disease

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Introduction: Molecular mechanisms underlying clinical observation of progressively earlier age of onset of Moyamoya disease (MMD) as it is passed on to the next generation, as known as clinical anticipation, is still obscure. This study investigates copy number variation (CNV) in parent-offspring pairs with MMD with and without clinical anticipation using genome-wide CNV array following high-throughput DNA sequencing.Methods: Fifteen out of 25 consecutive Japanese parent-offspring pairs with MMD treated at our institute since 1980 were enrolled. Demographics, inheritance pattern, angiographical stage, disease type at onset were reviewed. Using genomic DNA from whole blood, rs112735431 in RNF213 gene was genotyped, then genome-wide CNV analysis was conducted using a 2.6 M oligonucleotide array to compare CNV profile in parent-offspring pairs with and without clinical anticipation. Amplicon Sequencing was further conducted using Miseq.Results: Clinical anticipation was observed in 10 pairs (67%) and was not in 5 pairs (33%). In clinical anticipation group, mean age at onset was significantly lower in the offsprings than in the parents (p<0.001). There were no significant differences in other clinical and genetic backgrounds, including the genotype in RNF213 between the generations and between the groups with and without clinical anticipation. Genome-wide CNV profiling revealed that 10 CNV in chr7q, 8p, 9q, 14q, 16p, 19p, 20q, and 22q were overlapped for more than 3 individuals in the whole studied population. Of these CNV, copy number was different only in chr16p13.3 between the generations in clinical anticipation group (P=0.06). Fourteen genes were observed in this locus, including GNPTG gene, whose mutation is known to be associated with mucolipidosis. Amplicon sequence targeting these 14 genes revealed significant copy number loss at GNPTG gene locus, in the offsprings compared to their parent (P = 0.02, copy number = 1.8 and 2.0, respectively).Conclusion: These data suggest clinical anticipation of MMD in Japanese population can be observed regardless of the RNF213 genotype. This is the first genome-wide CNV profiling, suggesting the CNV in chr16p13.3 might be underlying mechanism for anticipation in familial MMD by reducing gene dosage.

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