Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study

Irène Gottlob ,Jing Jin ,Karen Grønskov ,Vasily Smirnov ,Abdullah Aamir ,Zhanhan Tu ,Rebecca J Mclean ,Frank A Proudlock ,Benoit Arvelier ,Girish Varma ,Lluı́s Montoliu ,Viral Sheth Bmedsci ,Michael Hisaund ,Prateek Pani ,Brian P Brooks ,Sasha Strul ,Laura May ,Fred K Chen ,Ravi Purohit ,Maria M Van Genderen ,Mervyn G Thomas ,Elizabeth C Engle ,Ayesha Girach ,Jae‐Hwan Choi ,Gail Maconachie ,Rachael C Heath Jeffery ,Ronaldo Yuiti Sano ,Garima Nishad ,Basu Dawar ,Helen J Kuht ,Susanne Kohl ,Dayong Bai ,Jinu Han ,Aihua Wei ,Line Kessel ,Martin D Tobin ,Richard W Hertle ,Wei Li ,Yonghong Jiao

doi:10.1016/j.ophtha.2022.02.010

Abstract

To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). Multicenter, observational study. A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n= 523) or extracted from publicly available datasets from previously reported literature (n= 384). Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square= 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P= 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square= 31.4, P < 0.0001) and VA (P= 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems todemonstrate more variability. Our findings provide mechanistic insight into disorders associated with FHand have significant prognostic and diagnostic value.

Highlights

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record
Atypical foveal hypoplasia (FH) is associated with much worse prognosis compared to all other forms of FH
In typical FH, our data suggests that arrested retinal development occurs earlier in SLC38A8, ocular albinism (OA), Hermansky-Pudlak syndrome (HPS) and AHR

Summary

Introduction

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article.

Results

Discussion

Conclusion