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Susanne Kohl, Britta Baumann, Anja-Kathrin Mayer, Bernd Wissinger; Uniparental isodisomy of chromosome 2 in CNGA3-associated achromatopsia. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2782.
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© ARVO (1962-2015); The Authors (2016-present)
Achromatopsia (ACHM) is a rare autosomal recessive disorder characterized by color blindness, photophobia, nystagmus, and low visual acuity. It is genetically heterogeneous and caused by mutations in 6 different genes: CNGA3, CNGB3, GNAT2, PDE6C, PDE6H and ATF6. From our cohort of >1,000 independent ACHM patients that underwent genetic research testing, we here report a unique ACHM case caused by a chromosomal segregation defect.
Mutation detection in the index patient and segregation analysis in both parents was done by Sanger-sequencing of PCR fragments amplified from genomic DNA obtained from venous blood. Screening for heterozygous deletions was done via long-distance PCR and a SYBR Green-based qPCR assay for a segment of CNGA3 exon 7. For human Chr. 2 segregation analysis, ten microsatellite markers (D2S2211, D2S165, D2S2368, D2S160, D2S112, D2S2330, D2S364, D2S126, D2S396, D2S338) covering the entire Chr. 2 were genotyped by PCR amplification and fragment sizing on an ABI3130 capillary sequencer (Applied Biosystems) in Gene Scan mode.
A single female patient with a clinical diagnosis of ACHM was referred to our laboratory for genetic research testing. Sanger sequencing revealed an apparent homozygous missense mutation c.778G>C p.D260H in CNGA3, affecting a highly conserved amino acid residue in transmembrane domain S3 of the CNGA3 polypeptide. Segregation analysis showed that the father was a heterozygous mutation carrier, while the mutation was absent in the mother. A heterozygous deletion in the mother explaining the apparent homozygosity of the mutation in the patient was ruled out by long-distance and qPCR-based copy number analysis of exon 7. Genotyping of microsatellite markers revealed homozygosity for all tested markers on Chr. 2 in the patient for the paternal haplotype, providing evidence for paternal uniparental isodisomy (UPD) of Chr. 2.
UPD is a rare phenomenon involving the inheritance of both chromatids of a single chromosome from one parent, here the paternal chromosome carrying the missense mutation c.778G>C p.D260H in CNGA3, while the maternal chromosome is lost. It is one of very few examples for this mechanism observed and described in inherited retinal dystrophy, and the first for ACHM. The detection of UPD highlights the importance of segregation analysis and has important implications for proper counseling and recurrency risk assessment in the family.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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