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Susanne Kohl, Anja K. Mayer, caroline Van Cauwenbergh, Christine Rother, Britta Baumann, Peggy Reuter, Elfride De Baere, Bernd Wissinger; Copy number variations in CNGB3-linked autosomal recessive achromatopsia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6044.
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© ARVO (1962-2015); The Authors (2016-present)
Achromatopsia (ACHM) is a rare autosomal recessive retinal disorder characterized by color vision defects, photophobia, nystagmus, and severely reduced visual acuity. The disease is caused by mutations in genes encoding crucial components of the cone phototransduction cascade (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) or in ATF6, involved in the unfolded protein response. CNGB3 encodes the beta subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is the major ACHM gene in Europe and the US. Yet a considerable number of cases remain genetically unsolved, in some cases because only a single heterozygous mutation was identified in one of the known ACHM genes. We show here that copy number variations (CNVs) contribute to these missing alleles in CNGB3-linked ACHM.
We searched for CNVs applying quantitative realtime PCR (qPCR) for all coding exons of CNGB3 in 43 single heterozygotes, followed by high-resolution microarray-based comparative genomic hybridization (CGH) to confirm and confine the CNVs, and defined the extent of the CNVs by breakpoint mapping.
The qPCR data implied 6 subjects with deletions and 10 with duplications spanning 1-10 consecutive exons of CNGB3. In addition, a homozygous deletion spanning 15 consecutive CNGB3 exons was discovered by diagnostic genetic testing. All CNVs were successfully validated by CGH arrays. While the deletions were unique to each patient or family, a duplication encompassing exons 4−7 was observed in 3 independent families and a duplication of exon 7 in 6 independent families. Precise breakpoint mapping was achieved for all intragenic CNVs. The sizes of the duplications/insertions ranged from 10,599 - 98,770bp, while the sizes of the mapped deletions ranged from 5,026 - 63,252bp. All duplicative events were consistently found to be in tandem.
About 10% of patients with CNGB3 mutations only harbored a single heterozygous point mutation after standard genetic analysis. In this study we identified 9 different heterozygous CNVs in 16 unrelated patients accounting for the missing second CNGB3-allele in these patients. Moreover, one patient with a homozygous CNGB3 deletion encompassing exons 4−18 was identified, highlighting the importance of CNV analysis for this gene.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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