Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma
Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) may be misdiagnosed as primary congenital glaucoma (PCG) due to similar clinical phenotypes during early infancy. In this study, we identified a family with CHED2, which was previously misdiagnosed as having PCG, and followed up...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-01-01
|
| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/14/2/310 |
| _version_ | 1797620817892212736 |
|---|---|
| author | Khazeema Yousaf Sadaf Naz Asma Mushtaq Elizabeth Wohler Nara Sobreira Bo-Man Ho Li-Jia Chen Wai-Kit Chu Rasheeda Bashir |
| author_facet | Khazeema Yousaf Sadaf Naz Asma Mushtaq Elizabeth Wohler Nara Sobreira Bo-Man Ho Li-Jia Chen Wai-Kit Chu Rasheeda Bashir |
| author_sort | Khazeema Yousaf |
| collection | DOAJ |
| description | Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) may be misdiagnosed as primary congenital glaucoma (PCG) due to similar clinical phenotypes during early infancy. In this study, we identified a family with CHED2, which was previously misdiagnosed as having PCG, and followed up for 9 years. Linkage analysis was first completed in eight PCG-affected families, followed by whole-exome sequencing (WES) in family PKGM3. The following in silico tools were used to predict the pathogenic effects of identified variants: I-Mutant 2.0, SIFT, Polyphen-2, PROVEAN, mutation taster and PhD-SNP. After detecting an <i>SLC4A11</i> variant in one family, detailed ophthalmic examinations were performed again to confirm the diagnosis. Six out of eight families had <i>CYP1B1</i> gene variants responsible for PCG. However, in family PKGM3, no variants in the known PCG genes were identified. WES identified a homozygous missense variant c.2024A>C, p.(Glu675Ala) in <i>SLC4A11</i>. Based on the WES findings, the affected individuals underwent detailed ophthalmic examinations and were re-diagnosed with CHED2 leading to secondary glaucoma. Our results expand the genetic spectrum of CHED2. This is the first report from Pakistan of a Glu675Ala variant with CHED2 leading to secondary glaucoma. The p.Glu675Ala variant is likely a founder mutation in the Pakistani population. Our findings suggest that genome-wide neonatal screening is worthwhile to avoid the misdiagnosis of phenotypically similar diseases such as CHED2 and PCG. |
| first_indexed | 2024-03-11T08:48:01Z |
| format | Article |
| id | doaj.art-872688e9284d45b28bd4396c8622a1a3 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T08:48:01Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-872688e9284d45b28bd4396c8622a1a32023-11-16T20:41:11ZengMDPI AGGenes2073-44252023-01-0114231010.3390/genes14020310Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital GlaucomaKhazeema Yousaf0Sadaf Naz1Asma Mushtaq2Elizabeth Wohler3Nara Sobreira4Bo-Man Ho5Li-Jia Chen6Wai-Kit Chu7Rasheeda Bashir8Department of Biotechnology, Lahore College for Women University, Lahore 54000, PakistanSchool of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, PakistanDepartment of Ophthalmology, Children’s Hospital & the Institute of Child Health, Lahore 54000, PakistanMcKusick-Nathans Department of Genetic Medicine, Baylor Hopkins Center for Mendelian Genomics, Baltimore, MD 21205, USAMcKusick-Nathans Department of Genetic Medicine, Baylor Hopkins Center for Mendelian Genomics, Baltimore, MD 21205, USAMcKusick-Nathans Department of Genetic Medicine, Baylor Hopkins Center for Mendelian Genomics, Baltimore, MD 21205, USAHong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong 999077, ChinaHong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong 999077, ChinaDepartment of Biotechnology, Lahore College for Women University, Lahore 54000, PakistanAutosomal recessive congenital hereditary endothelial dystrophy (CHED2) may be misdiagnosed as primary congenital glaucoma (PCG) due to similar clinical phenotypes during early infancy. In this study, we identified a family with CHED2, which was previously misdiagnosed as having PCG, and followed up for 9 years. Linkage analysis was first completed in eight PCG-affected families, followed by whole-exome sequencing (WES) in family PKGM3. The following in silico tools were used to predict the pathogenic effects of identified variants: I-Mutant 2.0, SIFT, Polyphen-2, PROVEAN, mutation taster and PhD-SNP. After detecting an <i>SLC4A11</i> variant in one family, detailed ophthalmic examinations were performed again to confirm the diagnosis. Six out of eight families had <i>CYP1B1</i> gene variants responsible for PCG. However, in family PKGM3, no variants in the known PCG genes were identified. WES identified a homozygous missense variant c.2024A>C, p.(Glu675Ala) in <i>SLC4A11</i>. Based on the WES findings, the affected individuals underwent detailed ophthalmic examinations and were re-diagnosed with CHED2 leading to secondary glaucoma. Our results expand the genetic spectrum of CHED2. This is the first report from Pakistan of a Glu675Ala variant with CHED2 leading to secondary glaucoma. The p.Glu675Ala variant is likely a founder mutation in the Pakistani population. Our findings suggest that genome-wide neonatal screening is worthwhile to avoid the misdiagnosis of phenotypically similar diseases such as CHED2 and PCG.https://www.mdpi.com/2073-4425/14/2/310congenital hereditary endothelial dystrophyprimary congenital glaucomaintraocular pressure |
| spellingShingle | Khazeema Yousaf Sadaf Naz Asma Mushtaq Elizabeth Wohler Nara Sobreira Bo-Man Ho Li-Jia Chen Wai-Kit Chu Rasheeda Bashir Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma Genes congenital hereditary endothelial dystrophy primary congenital glaucoma intraocular pressure |
| title | Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma |
| title_full | Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma |
| title_fullStr | Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma |
| title_full_unstemmed | Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma |
| title_short | Exome Sequencing Reveals <i>SLC4A11</i> Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma |
| title_sort | exome sequencing reveals i slc4a11 i variant underlying congenital hereditary endothelial dystrophy ched2 misdiagnosed as congenital glaucoma |
| topic | congenital hereditary endothelial dystrophy primary congenital glaucoma intraocular pressure |
| url | https://www.mdpi.com/2073-4425/14/2/310 |
| work_keys_str_mv | AT khazeemayousaf exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT sadafnaz exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT asmamushtaq exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT elizabethwohler exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT narasobreira exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT bomanho exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT lijiachen exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT waikitchu exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma AT rasheedabashir exomesequencingrevealsislc4a11ivariantunderlyingcongenitalhereditaryendothelialdystrophyched2misdiagnosedascongenitalglaucoma |