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 Dawar; Ayesha 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

doi:10.1016/j.ophtha.2022.02.010

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

Ophthalmology & Visual Neurosciences

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	708-718
Number of pages	11
Journal	Ophthalmology
Volume	129
Issue number	6
DOIs	https://doi.org/10.1016/j.ophtha.2022.02.010
State	Published - Jun 2022

Bibliographical note

Funding Information:
This study was supported by the Medical Research Council (MRC), London, UK (grant number: MR/J004189/1, MRC/N004566/1 and MC_PC_17171), Fight for Sight (Grant ref: 5009/5010 and 24NN181), Ulverscroft Foundation, Korea Centers for Disease Control and Prevention (2018-ER6902-02), the National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. 2020R1C1C1007965), The Rebecca D. Considine Research Institute, Akron Children's Hospital. F.K.C.: supported by the National Health and Medical Research Council Fellowship (MRF1142962) and the National Health and Medical Research Council Project Grant (GNT1188694, GNT1116360). E.C.E.: is an HHMI Investigator. R.C.H.J.: supported by the Miocevich Retina Fellowship. B.P.B.: supported by the Intramural Program at the National Eye Institute, National Institutes of Health. B.D.: supported by the National Institute for Health Research. H.J.K.: supported by a Wellcome Trust Fellowship. M.G.T.: supported by the National Institute for Health Research (CL-2017-11-003). The sponsor or funding organization had no role in the design or conduct of this research. F.K.C.: Board membership – Novartis, Roche; Consultant – Apellis, Janssen; Investigator grant – Australian NH&MRC; Payments for lectures, speakers bureau – Novartis. J.H.: Grants – Korea Centers for Disease Control and Prevention (grant no. 2018-ER6902-02), National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant no. 2020R1C1C1007965). Obtained funding: Thomas, Gottlob; Study was performed as part of the authors' regular employment duties. No additional funding was provided.

Funding Information:
J.H.: Grants – Korea Centers for Disease Control and Prevention (grant no. 2018-ER6902-02), National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant no. 2020R1C1C1007965).

Funding Information:
This study was supported by the Medical Research Council (MRC), London, UK (grant number: MR/J004189/1 , MRC/N004566/1 and MC_PC_17171 ), Fight for Sight (Grant ref: 5009/5010 and 24NN181 ), Ulverscroft Foundation , Korea Centers for Disease Control and Prevention ( 2018-ER6902-02 ), the National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. 2020R1C1C1007965 ), The Rebecca D. Considine Research Institute, Akron Children’s Hospital. F.K.C.: supported by the National Health and Medical Research Council Fellowship ( MRF1142962 ) and the National Health and Medical Research Council Project Grant ( GNT1188694 , GNT1116360 ). E.C.E.: is an HHMI Investigator. R.C.H.J.: supported by the Miocevich Retina Fellowship. B.P.B.: supported by the Intramural Program at the National Eye Institute, National Institutes of Health. B.D.: supported by the National Institute for Health Research . H.J.K.: supported by a Wellcome Trust Fellowship. M.G.T.: supported by the National Institute for Health Research ( CL-2017-11-003 ). The sponsor or funding organization had no role in the design or conduct of this research.

Publisher Copyright:
© 2022 American Academy of Ophthalmology

Keywords

AHR
Albinism
Aniridia
FHONDA
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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10.1016/j.ophtha.2022.02.010

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Kuht, H. J., Maconachie, G. D. E., Han, J., Kessel, L., van Genderen, M. M., McLean, R. J., Hisaund, M., Tu, Z., Hertle, R. W., Gronskov, K., Bai, D., Wei, A., Li, W., Jiao, Y., Smirnov, V., Choi, J. H., Tobin, M. D., Sheth, V., Purohit, R., ... Thomas, M. G. (2022). Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study. Ophthalmology, 129(6), 708-718. https://doi.org/10.1016/j.ophtha.2022.02.010

Kuht, HJ, Maconachie, GDE, Han, J, Kessel, L, van Genderen, MM, McLean, RJ, Hisaund, M, Tu, Z, Hertle, RW, Gronskov, K, Bai, D, Wei, A, Li, W, Jiao, Y, Smirnov, V, Choi, JH, Tobin, MD, Sheth, V, Purohit, R, Dawar, B, Girach, A, Strul, S, May, L, Chen, FK, Heath Jeffery, RC, Aamir, A, Sano, R, Jin, J, Brooks, BP, Kohl, S, Arveiler, B, Montoliu, L, Engle, EC, Proudlock, FA, Nishad, G, Pani, P, Varma, G, Gottlob, I & Thomas, MG 2022, 'Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study', Ophthalmology, vol. 129, no. 6, pp. 708-718. https://doi.org/10.1016/j.ophtha.2022.02.010

@article{739adf23b9104e2ca9b66e16a44443bc,

title = "Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study",

abstract = "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.",

keywords = "AHR, Albinism, Aniridia, FHONDA, 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",

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

note = "Funding Information: This study was supported by the Medical Research Council (MRC), London, UK (grant number: MR/J004189/1, MRC/N004566/1 and MC_PC_17171), Fight for Sight (Grant ref: 5009/5010 and 24NN181), Ulverscroft Foundation, Korea Centers for Disease Control and Prevention (2018-ER6902-02), the National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. 2020R1C1C1007965), The Rebecca D. Considine Research Institute, Akron Children's Hospital. F.K.C.: supported by the National Health and Medical Research Council Fellowship (MRF1142962) and the National Health and Medical Research Council Project Grant (GNT1188694, GNT1116360). E.C.E.: is an HHMI Investigator. R.C.H.J.: supported by the Miocevich Retina Fellowship. B.P.B.: supported by the Intramural Program at the National Eye Institute, National Institutes of Health. B.D.: supported by the National Institute for Health Research. H.J.K.: supported by a Wellcome Trust Fellowship. M.G.T.: supported by the National Institute for Health Research (CL-2017-11-003). The sponsor or funding organization had no role in the design or conduct of this research. F.K.C.: Board membership – Novartis, Roche; Consultant – Apellis, Janssen; Investigator grant – Australian NH&MRC; Payments for lectures, speakers bureau – Novartis. J.H.: Grants – Korea Centers for Disease Control and Prevention (grant no. 2018-ER6902-02), National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant no. 2020R1C1C1007965). Obtained funding: Thomas, Gottlob; Study was performed as part of the authors' regular employment duties. No additional funding was provided. Funding Information: J.H.: Grants – Korea Centers for Disease Control and Prevention (grant no. 2018-ER6902-02), National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant no. 2020R1C1C1007965). Funding Information: This study was supported by the Medical Research Council (MRC), London, UK (grant number: MR/J004189/1 , MRC/N004566/1 and MC_PC_17171 ), Fight for Sight (Grant ref: 5009/5010 and 24NN181 ), Ulverscroft Foundation , Korea Centers for Disease Control and Prevention ( 2018-ER6902-02 ), the National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. 2020R1C1C1007965 ), The Rebecca D. Considine Research Institute, Akron Children{\textquoteright}s Hospital. F.K.C.: supported by the National Health and Medical Research Council Fellowship ( MRF1142962 ) and the National Health and Medical Research Council Project Grant ( GNT1188694 , GNT1116360 ). E.C.E.: is an HHMI Investigator. R.C.H.J.: supported by the Miocevich Retina Fellowship. B.P.B.: supported by the Intramural Program at the National Eye Institute, National Institutes of Health. B.D.: supported by the National Institute for Health Research . H.J.K.: supported by a Wellcome Trust Fellowship. M.G.T.: supported by the National Institute for Health Research ( CL-2017-11-003 ). The sponsor or funding organization had no role in the design or conduct of this research. Publisher Copyright: {\textcopyright} 2022 American Academy of Ophthalmology",

year = "2022",

month = jun,

doi = "10.1016/j.ophtha.2022.02.010",

language = "English (US)",

volume = "129",

pages = "708--718",

journal = "Ophthalmology",

issn = "0161-6420",

publisher = "Elsevier Inc.",

number = "6",

}

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 - Gronskov, 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 - Funding Information: This study was supported by the Medical Research Council (MRC), London, UK (grant number: MR/J004189/1, MRC/N004566/1 and MC_PC_17171), Fight for Sight (Grant ref: 5009/5010 and 24NN181), Ulverscroft Foundation, Korea Centers for Disease Control and Prevention (2018-ER6902-02), the National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. 2020R1C1C1007965), The Rebecca D. Considine Research Institute, Akron Children's Hospital. F.K.C.: supported by the National Health and Medical Research Council Fellowship (MRF1142962) and the National Health and Medical Research Council Project Grant (GNT1188694, GNT1116360). E.C.E.: is an HHMI Investigator. R.C.H.J.: supported by the Miocevich Retina Fellowship. B.P.B.: supported by the Intramural Program at the National Eye Institute, National Institutes of Health. B.D.: supported by the National Institute for Health Research. H.J.K.: supported by a Wellcome Trust Fellowship. M.G.T.: supported by the National Institute for Health Research (CL-2017-11-003). The sponsor or funding organization had no role in the design or conduct of this research. F.K.C.: Board membership – Novartis, Roche; Consultant – Apellis, Janssen; Investigator grant – Australian NH&MRC; Payments for lectures, speakers bureau – Novartis. J.H.: Grants – Korea Centers for Disease Control and Prevention (grant no. 2018-ER6902-02), National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant no. 2020R1C1C1007965). Obtained funding: Thomas, Gottlob; Study was performed as part of the authors' regular employment duties. No additional funding was provided. Funding Information: J.H.: Grants – Korea Centers for Disease Control and Prevention (grant no. 2018-ER6902-02), National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant no. 2020R1C1C1007965). Funding Information: This study was supported by the Medical Research Council (MRC), London, UK (grant number: MR/J004189/1 , MRC/N004566/1 and MC_PC_17171 ), Fight for Sight (Grant ref: 5009/5010 and 24NN181 ), Ulverscroft Foundation , Korea Centers for Disease Control and Prevention ( 2018-ER6902-02 ), the National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. 2020R1C1C1007965 ), The Rebecca D. Considine Research Institute, Akron Children’s Hospital. F.K.C.: supported by the National Health and Medical Research Council Fellowship ( MRF1142962 ) and the National Health and Medical Research Council Project Grant ( GNT1188694 , GNT1116360 ). E.C.E.: is an HHMI Investigator. R.C.H.J.: supported by the Miocevich Retina Fellowship. B.P.B.: supported by the Intramural Program at the National Eye Institute, National Institutes of Health. B.D.: supported by the National Institute for Health Research . H.J.K.: supported by a Wellcome Trust Fellowship. M.G.T.: supported by the National Institute for Health Research ( CL-2017-11-003 ). The sponsor or funding organization had no role in the design or conduct of this research. Publisher Copyright: © 2022 American Academy of Ophthalmology

PY - 2022/6

Y1 - 2022/6

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 - FRMD7

KW - Foveal hypoplasia

KW - GPR143

KW - Genetics

KW - Genotype-phenotype correlation

KW - Hermansky–Pudlak syndrome

KW - OCT

KW - PAX6

KW - Retinal development

KW - SLC38A8

KW - Cytoskeletal Proteins

KW - Albinism, Ocular/diagnosis

KW - Humans

KW - Fovea Centralis/abnormalities

KW - Membrane Proteins

KW - Color Vision Defects/diagnosis

KW - Vision Disorders/diagnosis

KW - Albinism, Oculocutaneous/diagnosis

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UR - http://www.scopus.com/inward/citedby.url?scp=85127772996&partnerID=8YFLogxK

U2 - 10.1016/j.ophtha.2022.02.010

DO - 10.1016/j.ophtha.2022.02.010

M3 - Article

C2 - 35157951

AN - SCOPUS:85127772996

SN - 0161-6420

VL - 129

SP - 708

EP - 718

JO - Ophthalmology

JF - Ophthalmology

IS - 6

ER -

Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study

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