For autosomal recessively inherited Achromatopsia (Rod monochromatism), a subject of intense research for many years, we have been able to identify all disease-associated genes - CNGA3, CNGB3, GNAT2, PDE6C, PDE6H - and more recently the now sixth disease gene ATF6. This is very interesting, as all other achromatopsia genes are exclusively expressed in the cone photoreceptor, and there encode for proteins of the phototransduction. In contrast, ATF6 is expressed in every cell of the body and is known for its function in ER (endoplasmatic reticulum) stress regulation and the unfolded protein response (UPR). Why and how a defect in ATF6 exclusively causes a cone photoreceptor defect is to date subject of our research.

• Kohl et al. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet. 2015;47:757ff.

In this context, we have collected - also through international collaboration - the world's largest patient DNA collection for this rare disorder with >1000 patients and families. We had provided comprehensive mutation spectrum papers for PDE6C-, CNGB3- and GNAT2-associated Achromatopsia allowing to assess the prevalence of these genes in this rare disorder as well as the prevalence of certain common recurrent mutations. This has now been extended by further “Mutation Update” in the journal “Human Mutation” for the CNGA3 gene including pathogenicity scoring, which is highly relevant, as CNGA3 is one of the prime targets in current gene therapy trials.

• Mayer et al. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017;38:1579ff.
• Weisschuh et al. Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Hum Mutat. 2018;39:1366ff.
• Felden et al. Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene. Hum Mutat. 2019;40:1145ff.
• Solaki et al. Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia. Hum Mutat. 2022 Mar 25. Online ahead of print.

Deep genetic characterization projects identified yet hidden variations in CNGB3 including copy number variations and deep intronic mutations as an important disease cause in this rare disorder solving a considerable portion of yet unexplained cases.

• Mayer et al. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017;38:1579ff.
• Weisschuh et al. Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation. Hum Mutat. 2020;41:255ff.

A recent publication describes - for the first time - digenic triallelic inheritance in autosomal recessive achromatopsia.

• Burkard et al. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. J Clin Invest. 2018;128:5663ff.

Culminating out of all this research, we were able to coordinate and participate in the first-in-man phase I/II clinical safety study for gene supplementation therapy of CNGA3-associated achromatopsia (http://www.rd-cure.de/). In the preceding natural history study we assessed and described the phenotype of 32 CNGA3-associated Achromatopsia patients, of which 9 were finally treated in the clinical trial by subretinal injection.

• Kahle, RD-Cure Consortium, et al. Development of Methodology and Study Protocol: Safety and Efficacy of a Single Subretinal Injection of rAAV.hCNGA3 in Patients with CNGA3-Linked Achromatopsia Investigated in an Exploratory Dose-Escalation Trial. Hum Gene Ther Clin Dev. 2018;29:121ff.
• Zobor, RD-Cure Consortium, et al. The Clinical Phenotype of CNGA3-Related Achromatopsia: Pretreatment Characterization in Preparation of a Gene Replacement Therapy Trial. Invest Ophthalmol Vis Sci. 2017;58:821ff.
• Fischer, RD-Cure Consortium, et al.. Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol. 2020;138:643ff.
• Reichel, RD-Cure Consortium, et al.. Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non randomised controlled trial. Br J Ophthalmol. 2021 May 18. Online ahead of print.

Recently we have identified and described the first autosomal recessive gene for foveal hypoplasia and infantile nystagmus in an Palastine family of three affecteds. Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus.

• Mayer et al. Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus. Brain. 2019 Apr 22.

We have shown the correction of a deep intronic mutation in the OPA1 gene found in patients with autosomal dominant optic atrophy by antisense oligonucleotide mediated splice correction.

• Bonifert et al. Antisense Oligonucleotide Mediated Splice Correction of a Deep Intronic Mutation in OPA1. Mol Ther Nucleic Acids. 2016;5:e390.

A considerable number of cases with a clinical diagnosis of Leber hereditary optic neuropathy (LHON) remained genetically undefined. Only recently it has been shown that autosomal recessive mutations in DNAJC30 account for a large proportion of these cases. We were able to replicate this in a large cohort of genetically unsolved LHON and optic atrophy cases, and provide evidence that the missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in this autosomal recessively inherited LHON cohort, and we confirmed a strong founder effect for this missense variant in the European population. In addition, clinical investigation of these patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA.

• Kieninger et al. DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy. J Med Genet. 2022 Jan 28. Online ahead of print.

Three different mutation types contribute to X-linked Blue cone monochromatism (BCM). Point mutations, most commonly the C203R inactivating missense mutation, exon 3 interchange haplotype mutations resulting in missplicing, and large deletions. In a recent study, we were able to characterized the extent of these deletions in >70 families and identified 42 distinct structural variants ranging from 142 bp to 207 kb. By the deletion mapping we also were able to refine the upstream locus control region to an essential enhancer element of 358 bp.

• Wissinger et al. The Landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying Blue Cone Monochromacy: Evidence for the instability of gene clusters with increased copy number. PNAS June 27, 2022; 119 (27) e2115538119; https://doi.org/10.1073/pnas.2115538119