Digenic triallelic inheritance in cone photoreceptor cyclic nucleotide gated channel associated retinopathies

Abstract

Purpose : Mutations in CNGA3 and CNGB3 together encode for the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel crucial for cone phototransduction, and are the most common cause of achromatopsia (ACHM). Patients carrying the CNGB3 mutation c.1208G>A;p.R403Q have been reported with a variable retinal phenotype ranging from complete and incomplete ACHM to moderate cone dysfunction or progressive cone and macular dystrophy.

Methods : Genetic screening of CNGA3 and CNGB3 in our cohort of >1000 ACHM patients, as well as literature research, was performed. In addition, patients with a clinical diagnosis of cone (n=316), cone-rod (n=450) and macular (n=408) dystrophy were specifically screened for CNGB3/R403Q. All patients carrying the CNGB3/R403Q mutation were sequenced for additional mutations in CNGA3. A Cngb3^R403Q/R403Q mouse model was generated and crossbred with Cnga3-deficient mice (Cnga3^-/-). Homozygous Cngb3^R403Q/R403Q mice were evaluated and characterized for their retinal phenotype in comparison to triallelic digenic mice (Cngb3^R403Q/R403Q;Cnga3^+/-) and wildtype littermates.

Results : In our cohort, we identified 13 independent individuals who were homozygous for CNGB3/R403Q or (compound) heterozygous for CNGB3/R403Q and another pathogenic CNGB3 mutation, respectively, as well as 4 single heterozygous cases. Literature research provided evidence for 3 additional such cases. Genetic analysis revealed the co-occurrence of an additional heterozygous mutant CNGA3 allele in 62.5% (10/16) of the cases with biallelic CNGB3 mutations, thus most likely constituting a digenic triallelic cause of the disease phenotype. The analysis of digenic triallelic Cngb3^R403Q/R403Q;Cnga3^+/- mutant mice showed that - similar to human patients - the presence of one heterozygous Cnga3 null allele aggravates the cone dystrophy phenotype in homozygous Cngb3^R403Q/R403Q mice.

Conclusions : Our investigations strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with ACHM and related diseases, linked to the CNGB3/R403Q mutation with important implications for diagnosis, prognosis and genetic counseling.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.