Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study

Helen J. Kuht, Gail D.E. 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, 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 Arveiler, 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

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)708-718
Number of pages11
Issue number6
StatePublished - Jun 2022

Bibliographical note

Publisher Copyright:
© 2022 American Academy of Ophthalmology


  • AHR
  • Albinism
  • Aniridia
  • FRMD7
  • Foveal hypoplasia
  • GPR143
  • Genetics
  • Genotype-phenotype correlation
  • Hermansky–Pudlak syndrome
  • OCT
  • PAX6
  • Retinal development
  • SLC38A8
  • Cytoskeletal Proteins
  • Albinism, Ocular/diagnosis
  • Humans
  • Fovea Centralis/abnormalities
  • Membrane Proteins
  • Color Vision Defects/diagnosis
  • Vision Disorders/diagnosis
  • Albinism, Oculocutaneous/diagnosis

PubMed: MeSH publication types

  • Observational Study
  • Multicenter Study
  • Journal Article
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't


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