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Markus N Preising, Anna-Maria Zuliani, Birgit Lorenz; Investigations for the underlying genetic cause in a consanguineous family with complete achromatopsia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3167.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To Identify the underlying genetic cause in a multiple consanguineous German family with achromatopsia (ACHM).
Methods: DNA was obtained from 14 individuals of an eight generation German family with two branches and three patients (mother, son, cousin) affected with ACHM. The patients were examined by best corrected visual acuity (BCVA), Ganzfeld ERG (ffERG), Goldmann visual field (GVF), Lanthony panel D15 color test, and fundus photography. Linkage to CNGA3, CNGB3, and GNAT2 was excluded by locus specific markers prior to this study. The three patients were genotyped for SNPs by an Affymetrix Gene Chip® Human Mapping 10K Array. The array data were analyzed by dCHIP for association. The three patients and 11 further relatives were genotyped with microsatellite markers (SSR) for linkage analysis on Chromosome 2q23.3-33.3 and 14q22.1-31.3.Finally, next-generation sequencing was applied to identify point mutations and small indels of the whole exom (WES).
Results: An affected cousin was the latest descendant of the first branch with suspected distant consanguinity of the parents. The second branch was highly consanguineous and the latest affected descendant of this branch was the consanguineous son of an affected female. The clinical data of the three patients indicated complete ACHM (BCVA: 0,1 - 0,2; cone responses in ffERG below threshold, rod responses within the normal range; unremarkable fundus appearance even up to the age of 37 y).Non-parametric linkage mapping using SNP-data in dCHIP revealed two candidate loci on chromosome 2q23.3-33.3 and 14q22.1-31.3. Both were excluded by SSR linkage analysis. Subsequently WES was performed in the son and revealed the common c.1148delC sequence change in CNGB3 in the homozygous state. Homozygosity of this mutation was confirmed in the cousin. All other 12 family members typed including the mother were heterozygous for this sequence change. Subsequent WES in the mother excluded pathogenic sequences changes in previously reported ACHM genes. Further analysis of the available data in the mother is ongoing.
Conclusion: We identified the common c.1148delC sequence change in CNGB3 as the genetic cause of ACHM in two patients in distant branches of a highly consanguineous family. In the third patient all known ACHM genes were excluded pointing towards a novel genetic cause of complete ACHM.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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