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Sep 16, 2020

Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations

Avigail Beryozkin, Samer Khateb, Carlos Alberto Idrobo-Robalino, Muhammad Imran Khan, Frans P. M. Cremers, Alexey Obolensky,Mor Hanany, Eedy Mezer, Itay Chowers, Hadas Newman, Tamar Ben-Yosef, Dror Sharon, Eyal Banin | Scientific Reports | 10 | 16 September 2020 | https://doi.org/10.1038/s41598-020-72028-0


Abstract

FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th–5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.


Introduction

Retinitis pigmentosa [RP (MIM #268000)] is the most prevalent hereditary degeneration of the retina in humans, with a prevalence of 1:4,500 (in Europe and USA)1,2,3,4, and 1:2,100 in the vicinity of Jerusalem5. RP is genetically and clinically heterogeneous, and is characterized by night blindness, progressive degeneration of photoreceptors leading to gradual loss of peripheral and then central vision, and eventually often leads to blindness6. On fundus examination patients typically show waxy pallor of the optic discs, attenuation of retinal vessels, and bone spicule-like pigmentary (BSP) changes, and on functional full field electroretinographic (ERG) testing responses are severely diminished and may be non-detectable6,7. Genetically, RP can be inherited in all Mendelian modes including autosomal recessive (AR, ~ 30% of patients), autosomal dominant (AD, ~ 20%), X-linked (~ 10%), and the remaining 40% are isolate cases8.


Currently, mutations in 41 genes were reported to cause non-syndromic ARRP (RetNet, https://sph.uth.edu/retnet/), including FAM161A, which has been identified in 2010 simultaneously by others and by us9,10. FAM161A was found to be localized to the base of the connecting cilium, the basal body region, and the adjacent centriole in photoreceptor cells11,12,13, and is part of the cytoskeleton fraction of the cilia and a component of the human centrosome14,15. It was also found to be a member of the Golgi-centrosomal interactome, a network of proteins interconnecting Golgi maintenance, intracellular transport and centrosome organization16.


Since the identification of FAM161A as a cause for ARRP in 2010, 13 pathogenic mutations have been reported (Supplementary Fig. S1 and Supplementary Table S1)9,10,17,18,19,20,21,22,23,24,25,26,27. Two of these mutations (frameshift c.1355_6del and nonsense c.1567C > T) were originally identified to be relatively common among the Jewish population in Israel9 and two were reported in Palestinian families9,20. Mutations in this gene are the most common cause of ARRP in Israel (18.2%, Fig. 1a) while the frequency elsewhere is relatively low (ranging from 0.003 to 2%17,19,21,22,28).


To date, a total of 82 patients with ARRP caused by FAM161A mutations have been reported in various publications (42 residing in Israel and 53 worldwide), with a phenotype that largely falls within the spectrum described in other genes causing ARRP9,10,17,18,19,20,21,22,28. In the current study we further explore the clinical phenotype in a large cohort of 100 Israeli patients harboring FAM161A mutations for whom clinical data was available. This aims to provide information on the clinical spectrum and course of disease associated with this gene, including identification of characteristic features. The findings can assist in the evaluation and diagnosis of these patients, provide data on prognosis, and may be relevant for future application of novel therapies such as gene augmentation, including windows for intervention and possible outcome measures.


Results

Identification of FAM161A mutations

We analyzed more than 1,500 index cases from our cohort, who suffer from AR or isolate RP, or other IRD types. Using a number of molecular genetic methods, as detailed above, biallelic FAM161A mutations were identified in 81 index cases, with a total of 114 patients in these 81 families-42 of whom were previously reported9, with emphasis on the genetic findings (Supplementary Table S2).



 

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