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 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 Arvelier; 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 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

Centre for Ophthalmology and Visual Science (affiliated with the Lions Eye Institute)

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

36 Citations (Scopus)

Abstract

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

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10.1016/j.ophtha.2022.02.010Licence: CC BY

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Accelerating the identification and treatment of splice-altering mutations underlying inherited retinal diseases
Chen, F. (Investigator 01), Fletcher, S. (Investigator 02), McLenachan, S. (Investigator 03) & Cunningham, P. (Investigator 04)
NHMRC National Health and Medical Research Council
1/01/20 → 31/12/24
Project: Research
MRFF - Developing Personalised Treatment for Retinal Degeneration
Chen, F. (Investigator 01)
NHMRC National Health and Medical Research Council
1/01/18 → 31/12/21
Project: Research
From discovery to therapy in genetic eye diseases
Mackey, D. (Investigator 01), Craig, J. (Investigator 02), Hewitt, A. (Investigator 03), Burdon, K. (Investigator 04), Jamieson, R. (Investigator 05), Grigg, J. (Investigator 06), MacGregor, S. (Investigator 07), Chen, F. (Investigator 08), Otlowski, M. (Investigator 09) & Schofield, D. (Investigator 10)
NHMRC National Health and Medical Research Council
1/01/16 → 31/12/20
Project: Research

Cite this

Kuht, H. J., Maconachie, G. DE., 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 BMedSci, V., Purohit, R., ... Thomas, M. G. (2022). Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multi-centre Study. Ophthalmology, 129(6), 708-718. https://doi.org/10.1016/j.ophtha.2022.02.010

@article{726003a107be4e3998784d140c6d6804,

title = "Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multi-centre Study",

abstract = "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.",

author = "Kuht, {Helen J} and Maconachie, {Gail DE} 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 Jae-Hwan Choi and Tobin, {Martin D} and {Sheth BMedSci}, Viral 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 Arvelier 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}",

year = "2022",

month = jun,

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

language = "English",

volume = "129",

pages = "708--718",

journal = "Ophthalmology",

issn = "0161-6420",

publisher = "Elsevier",

number = "6",

}

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, J-H, Tobin, MD, Sheth BMedSci, 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, Arvelier, 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 Multi-centre Study', Ophthalmology, vol. 129, no. 6, pp. 708-718. https://doi.org/10.1016/j.ophtha.2022.02.010

TY - JOUR

T1 - Genotypic and Phenotypic Spectrum of Foveal Hypoplasia

T2 - A Multi-centre Study

AU - Kuht, Helen J

AU - Maconachie, Gail DE

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 BMedSci, 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 - Arvelier, 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

PY - 2022/6

Y1 - 2022/6

N2 - 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.

AB - 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.

U2 - 10.1016/j.ophtha.2022.02.010

DO - 10.1016/j.ophtha.2022.02.010

M3 - Article

C2 - 35157951

SN - 0161-6420

VL - 129

SP - 708

EP - 718

JO - Ophthalmology

JF - Ophthalmology

IS - 6

ER -

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

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Accelerating the identification and treatment of splice-altering mutations underlying inherited retinal diseases

MRFF - Developing Personalised Treatment for Retinal Degeneration

From discovery to therapy in genetic eye diseases

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