Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multi-centre Study

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

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


PURPOSE: To characterise the genotypic and phenotypic spectrum of foveal hypoplasia (FH) DESIGN: Multi-centre, observational study SUBJECTS: 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR or achromatopsia (ACHM) from twelve centres in nine 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 optical coherence tomography (OCT) scans were identified from twelve centres or from the literature, between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCTs.

MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialisation (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 ACHM cases. Atypical FH in ACHM had significantly worse VA compared to typical FH (p<0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (X2=60.4, p<0.0001). All SLC38A8 cases were PRS- (p=0.003), while all FRMD7 cases were PRS+ (p<0.0001). Analysis of albinism sub-types revealed a significant difference in the grade of FH (X2=31.4, p<0.0001) and VA (p=0.0003) between oculocutaneous albinism (OCA) compared to ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). OA 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 to other diagnoses associated with FH.

CONCLUSION: We characterised the phenotypic and genotypic spectrum of FH. Atypical 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, OA, HPS and AHR variants and much later in FRMD7 variants. The defined time-period of foveal developmental arrest for OCA and PAX6 variants appears to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and also have significant prognostic and diagnostic value.

Original languageEnglish
Pages (from-to)708-718
Number of pages11
Issue number6
Early online date11 Feb 2022
Publication statusPublished - Jun 2022


Dive into the research topics of 'Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multi-centre Study'. Together they form a unique fingerprint.

Cite this