Abstract: Purpose: Achromatopsia (ACHM) is a genetically heterogenous relatively stationary congenital autosomal recessive cone disorder characterized typically by photophobia, low vision, nystagmus, hyperopia, grossly normal retinal appearance, and absent photopic responses by full-field electroretinography. Incomplete forms occur as well. This study investigates the genetic basis of clinically suspected ACHM in the United Arab Emirates.
Methods: Retrospective case series (January 2016-December 2023) of patients with (1) clinically suspected ACHM or (2) mutations in ACHM-associated genes ( CNGA3 , CNGB3 , GNAT2 , PDE6C , PDE6H , AT6 ).
Results: Twenty-two clinically suspected patients (19 probands) were identified. Biallelic disease genes and the number of probands were CNGA3 (9), CNGB3 (6), PDE6C (1), GNAT2 (1), RGS9BP (1), and CNNM4 (1). Some mutant alleles were recurrent across different families. Two probands had their diagnoses revised after genetic testing and phenotypic reassessment to RGS9BP -related bradyopsia and CNNM4 -related Jalili syndrome. Three additional cases (making 22 total probands) were identified from ACHM gene mutation review-one each related to PDE6C , to AT6 , and to CNGB3 in concert with CNGA3 (triallelic disease). All three presented with macular discoloration, an atypical finding for classic ACHM.
Conclusion: CNGA3 was the single most frequent implicated gene. Bradyopsia and Jalili syndrome can resemble incomplete ACHM. Recurrent mutant alleles may represent founder effects. Macular discoloration on presentation can occur in PDE6C -related disease, AT6 -related disease, and triallelic CNGB3 / CNGA3 -related disease. The possibility for triallelic disease exists and requires genetic counseling beyond that of simple autosomal recessive inheritance.
References: Aboshiha J, Dubis AM, Carroll J, et al. The cone dysfunction syndromes. Br J Ophthalmol 2016;100:115–121.
Michalakis S, Gerhardt M, Rudolph G, et al. Achromatopsia: genetics and gene therapy. Mol Diagn Ther 2022;26:51–59.
Burkard M, Kohl S, Krätzig T, et al. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. J Clin Invest 2018;128:5663–5675.
Liang X, Dong F, Li H, et al. Novel CNGA3 mutations in Chinese patients with achromatopsia. Br J Ophthalmol 2015;99:571–576.
Sun W, Li S, Xiao X, et al. Genotypes and phenotypes of genes associated with achromatopsia: a reference for clinical genetic testing. Mol Vis 2020;26:588–602.
Kohl S, Varsanyi B, Antunes GA, et al. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet 2005;13:302–308.
Mayer AK, Van Cauwenbergh C, Rother C, et al. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat 2017;38:1579–1591.
Zelinger L, Cideciyan AV, Kohl S, et al. Genetics and disease expression in the CNGA3 form of achromatopsia: steps on the path to gene therapy. Ophthalmology 2015;122:997–1007.
Aweidah H, Salameh M, Yahalom C, et al. A deep intronic substitution in CNGB3 is one of the major causes of achromatopsia among Jewish patients. Mol Vis 2021;27:588–600.
Abdelkader E, Brandau O, Bergmann C, et al. Novel causative variants in patients with achromatopsia. Ophthalmic Genet 2018;39:678–683.
Danish E, Alhashem A, Aljehani R, et al. Phenotype and genotype of 15 Saudi patients with achromatopsia: a case series. Saudi J Ophthalmol 2023;37:301–306.
Ahuja Y, Kohl S, Traboulsi EI. CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis 2008;14:1293–1297.
Khan AO. Phenotype-guided genetic testing of pediatric inherited retinal disease in the United Arab Emirates. Retina 2020;40:1829–1837.
Gerhardt MJ, Priglinger SG, Biel M, Michalakis S. Biology, pathobiology and gene therapy of CNG channel-related retinopathies. Biomedicines 2023;11:269.
Khan AO. Ocular genetic disease in the Middle East. Curr Opin Ophthalmol 2013;24:369–378.
Wiszniewski W, Lewis RA, Lupski JR. Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14. Hum Genet 2007;121:433–439.
Khan AO. The clinical presentation of bradyopsia in children. J AAPOS 2017;21:507–509.e1.
Nishiguchi KM, Sandberg MA, Kooijman AC, et al. Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation. Nature 2004;427:75–78.
Parry DA, Mighell AJ, El-Sayed W, et al. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum Genet 2009;84:266–273.
Khan AO, Bifari IN, Bolz HJ. Ophthalmic features of children not yet diagnosed with Alstrom syndrome. Ophthalmology 2015;122:1726–1727.e2.
Khan AO, Alrashed M, Alkuraya FS. Clinical characterisation of the CABP4-related retinal phenotype. Br J Ophthalmol 2013;97:262–265.
Vincent A, Robson AG, Holder GE. Pathognomonic (diagnostic) ERGs. A review and update. Retina 2013;33:5–12.
Mastey RR, Georgiou M, Langlo CS, et al. Characterization of retinal structure in ATF6-associated achromatopsia. Invest Ophthalmol Vis Sci 2019;60:2631–2640.
Ritter M, Arno G, Ba-Abbad R, et al. Macular maldevelopment in ATF6-mediated retinal dysfunction. Ophthalmic Genet 2019;40:564–569.
Thiadens AAHJ, Roosing S, Collin RWJ, et al. Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy. Ophthalmology 2010;117:825–830.e1.
Nishiguchi KM, Sandberg MA, Gorji N, et al. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat 2005;25:248–258.
Processing Request
No Comments.