TY - JOUR

T1 - Genotypic and Phenotypic Spectrum of Foveal Hypoplasia

T2 - A Multicenter Study

AU - Kuht, Helen J.

AU - Maconachie, Gail D.E.

AU - Han, Jinu

AU - Kessel, Line

AU - van Genderen, Maria M.

AU - McLean, Rebecca J.

AU - Hisaund, Michael

AU - Tu, Zhanhan

AU - Hertle, Richard W.

AU - Grønskov, Karen

AU - Bai, Dayong

AU - Wei, Aihua

AU - Li, Wei

AU - Jiao, Yonghong

AU - Smirnov, Vasily

AU - Choi, Jae Hwan

AU - Tobin, Martin D.

AU - Sheth, Viral

AU - Purohit, Ravi

AU - Dawar, Basu

AU - Girach, Ayesha

AU - Strul, Sasha

AU - May, Laura

AU - Chen, Fred K.

AU - Heath Jeffery, Rachael C.

AU - Aamir, Abdullah

AU - Sano, Ronaldo

AU - Jin, Jing

AU - Brooks, Brian P.

AU - Kohl, Susanne

AU - Arveiler, Benoit

AU - Montoliu, Lluis

AU - Engle, Elizabeth C.

AU - Proudlock, Frank A.

AU - Nishad, Garima

AU - Pani, Prateek

AU - Varma, Girish

AU - Gottlob, Irene

AU - Thomas, Mervyn G.

N1 - Publisher Copyright: © 2022 American Academy of Ophthalmology

PY - 2022

Y1 - 2022

N2 - Purpose: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). Design: Multicenter, observational study. Participants: 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). Methods: 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. Main Outcome Measures: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS–), molecular diagnosis, and visual acuity (VA). Results: 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. Conclusions: 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 to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

AB - Purpose: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). Design: Multicenter, observational study. Participants: 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). Methods: 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. Main Outcome Measures: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS–), molecular diagnosis, and visual acuity (VA). Results: 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. Conclusions: 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 to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

KW - AHR

KW - Albinism

KW - Aniridia

KW - FHONDA

KW - Foveal hypoplasia

KW - FRMD7

KW - Genetics

KW - Genotype-phenotype correlation

KW - GPR143

KW - Hermansky–Pudlak syndrome

KW - OCT

KW - PAX6

KW - Retinal development

KW - SLC38A8

U2 - 10.1016/j.ophtha.2022.02.010

DO - 10.1016/j.ophtha.2022.02.010

M3 - Journal article

C2 - 35157951

AN - SCOPUS:85127772996

VL - 129

SP - 708

EP - 718

JO - Ophthalmology

JF - Ophthalmology

SN - 0161-6420

IS - 6

ER -