Initial diagnoses of patients found to be homozygous for a KCNV2 founder mutation on the Arabian Peninsula (c.427G>T; p.Glu143*)

To The Editor: KCNV2 (potassium channel voltage-gated subfamily V member 2) encodes a voltage-gated potassium channel modulatory subunit (Kv8.2) that is highly expressed in cone and rod photoreceptors (1). Biallelic pathogenic variants in the gene result in cone dystrophy with supranormal rod response, an ocular-only phenotype that is one of the few retinal dystrophies for which standard full-field electroretinography (ERG) is pathognomonic (2–6). Photopic tracings show generalized cone dysfunction. The dim flash scotopic response shows rod dysfunction. The combined response to bright flash has a characteristic waveform shape, typically with an unusually large b-wave. Rather than indicating increased function, the large b-wave is an artifact from the gene mutation. Patients with KCNV2-related retinopathy show variable onset of visual signs and symptoms, usually in infancy or early childhood (5–7). Subnormal visual acuity is universal. Color vision defects, impaired light adaptation, mild photophobia, and nyctalopia are common. Young children can sometimes have nystagmus and head shaking, both of which typically improve with time. The macula appearance can seem normal, mildly abnormal, or grossly dystrophic. Retinal function is relatively stable over time. Refractive errors can be hyperopic, myopic, or unremarkable. This clinical profile is based on reports of patients with numerous different biallelic KCNV2 pathogenic variants. Over 100 pathogenic variants in KCNV2 have been reported (5,6). On the Arabian Peninsula, a founder KCNV2 pathogenic variant (c.427G>T; p.Glu143*) is recurrent (7,8). This founder mutation is responsible for all reported cases in the United Arab Emirates. An Emirati cohort of KCNV2-retinopathy patients thus provides an opportunity to review clinical presenting features of a group of patients with an identical KCNV2 genotype and highlight the associated clinical profile. We reviewed the charts of patients confirmed to be homozygous for KCNV2: c.427G>T; p.Glu143* seen in the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi (2016–2021) with attention to initial symptoms and diagnoses. This genotype was found in all of our molecularly confirmed KCNV2-retinopathy patients. There were 14 patients (9 families). Most (11 patients) presented with blurred vision as children or young adults and half (7 patients) complained of nyctalopia. Some noted photophobia (4 patients). Those with early-childhood nystagmus (3 patients) noted improvement in the nystagmus with time. Fundus examination often revealed central macula abnormalities, but for some, it was grossly normal. Refractive errors were hyperopic, myopic, or unremarkable. Most patients were referred with suspicion of a retinal dystrophy diagnosis (10 patients) such as Stargardt disease, rod-cone dystrophy, or cone dystrophy. However, others had referral diagnoses of amblyopia, congenital nystagmus, and high myopia. Definitive diagnosis of KCNV2-related retinopathy was made after ERG, and directed genetic testing confirmed homozygosity for the KCNV2 founder mutation. Table 1 summarizes the clinical features of the 14 patients. Our review of patients homozygous for the Arabian Peninsula KCNV2 founder mutation (c.427G>T; p. Glu143*) revealed a range of clinical presentations. This single KCNV2 genotype was not associated with a uniform presenting phenotype; rather, homozygosity for the founder mutation was associated with variable expressivity to an extent similar to what has been described for multiple different biallelic KCNV2 pathogenic variants (5,6,9,10). In our cohort (and in others), subnormal vision was universal, and some patients had nyctalopia with photophobia or nystagmus that improved with time. Also, macular findings ranged from grossly normal to frankly dystrophic. In general, patients with subnormal vision that is related to maculopathy or that has no apparent cause should be investigated by ERG. This is particularly true on the Arabian Peninsula. ERG is sufficient to diagnose KCNV2-related retinopathy. Molecular genetic confirmation enables family genetic counselling.