Revealing hidden genetic diagnoses in the ocular anterior segment disorders
PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion.
METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases.
RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6.
CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Genetics in medicine : official journal of the American College of Medical Genetics - 22(2020), 10 vom: 04. Okt., Seite 1623-1632 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ma, Alan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.04.2021 Date Revised 10.02.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41436-020-0854-x |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM310791782 |
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| 100 | 1 | |a Ma, Alan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Revealing hidden genetic diagnoses in the ocular anterior segment disorders |
| 264 | 1 | |c 2020 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 27.04.2021 | ||
| 500 | |a Date Revised 10.02.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion | ||
| 520 | |a METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases | ||
| 520 | |a RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6 | ||
| 520 | |a CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a exome and genome sequencing | |
| 650 | 4 | |a eye | |
| 650 | 4 | |a genomic medicine | |
| 650 | 4 | |a ocular anterior segment dysgenesis | |
| 650 | 4 | |a ophthalmology | |
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| 700 | 1 | |a Minoche, Andre E |e verfasserin |4 aut | |
| 700 | 1 | |a Cowley, Mark J |e verfasserin |4 aut | |
| 700 | 1 | |a Nash, Benjamin M |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Gladys |e verfasserin |4 aut | |
| 700 | 1 | |a Gayagay, Thet |e verfasserin |4 aut | |
| 700 | 1 | |a Lai, Tiffany |e verfasserin |4 aut | |
| 700 | 1 | |a Farnsworth, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Hackett, Emma L |e verfasserin |4 aut | |
| 700 | 1 | |a Fisk, Katrina |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Karen |e verfasserin |4 aut | |
| 700 | 1 | |a Holman, Katherine J |e verfasserin |4 aut | |
| 700 | 1 | |a Jenkins, Gemma |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Anson |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Frank |e verfasserin |4 aut | |
| 700 | 1 | |a Karaconji, Tanya |e verfasserin |4 aut | |
| 700 | 1 | |a Elder, James E |e verfasserin |4 aut | |
| 700 | 1 | |a Enriquez, Annabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Meredith |e verfasserin |4 aut | |
| 700 | 1 | |a Amor, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Stutterd, Chloe A |e verfasserin |4 aut | |
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| 700 | 1 | |a Dinger, Marcel E |e verfasserin |4 aut | |
| 700 | 1 | |a Bennetts, Bruce |e verfasserin |4 aut | |
| 700 | 1 | |a Jamieson, Robyn V |e verfasserin |4 aut | |
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