Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing
Blended phenotypes exhibited by a patient may present a challenge to the establishment of diagnosis. In this study, we report a seven-year-old Murut girl with unusual features of Williams-Beuren syndrome (WBS), including recurrent infections and skin abscesses. Considering the possibility of a secon...
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| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.778133/full |
| _version_ | 1818731513715359744 |
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| author | Adiratna Mat Ripen Mei Yee Chiow Prakash Rao Rama Rao Saharuddin Bin Mohamad Saharuddin Bin Mohamad |
| author_facet | Adiratna Mat Ripen Mei Yee Chiow Prakash Rao Rama Rao Saharuddin Bin Mohamad Saharuddin Bin Mohamad |
| author_sort | Adiratna Mat Ripen |
| collection | DOAJ |
| description | Blended phenotypes exhibited by a patient may present a challenge to the establishment of diagnosis. In this study, we report a seven-year-old Murut girl with unusual features of Williams-Beuren syndrome (WBS), including recurrent infections and skin abscesses. Considering the possibility of a second genetic disorder, a mutation screening for genes associated with inborn errors of immunity (IEI) was conducted using whole exome sequencing (WES). Analysis of copy number variations (CNVs) from the exome data revealed a 1.53Mb heterozygous deletion on chromosome 7q11.23, corresponding to the known WBS. We also identified a biallelic loss of NCF1, which indicated autosomal recessive chronic granulomatous disease (CGD). Dihydrorhodamine (DHR) flow cytometric assay demonstrated abnormally low neutrophil oxidative burst activity. Coamplification of NCF1 and its pseudogenes identified a GT-deletion (ΔGT) at the start of exon 2 in NCF1 (NM_000265.7: c.75_76delGT: p.Tyr26Hisfs*26). Estimation of NCF1-to-NCF1 pseudogenes ratio using ΔGT and 20-bp gene scans affirmed nil copies of NCF1 in the patient. While the father had a normal ratio of 2:4, the mother had a ratio of 1:5, implicating the carrier of ΔGT-containing NCF1. Discovery of a 7q11.23 deletion involving one NCF1 allele and a ΔGT in the second NCF1 allele explained the coexistence of WBS and CGD in our patient. This study highlights the capability of WES to establish a molecular diagnosis for a case with blended phenotypes, enabling the provision of appropriate prophylactic treatment. |
| first_indexed | 2024-12-17T23:18:53Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T23:18:53Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9acd6a90a7a041688017b2bd1e7aaed62022-12-21T21:28:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-11-011210.3389/fimmu.2021.778133778133Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome SequencingAdiratna Mat Ripen0Mei Yee Chiow1Prakash Rao Rama Rao2Saharuddin Bin Mohamad3Saharuddin Bin Mohamad4Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Selangor, MalaysiaInstitute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, MalaysiaPediatrics Department, Keningau Hospital, Ministry of Health Malaysia, Sabah, MalaysiaInstitute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, MalaysiaCentre of Research in Systems Biology, Structural Bioinformatics and Human Digital Imaging (CRYSTAL), University of Malaya, Kuala Lumpur, MalaysiaBlended phenotypes exhibited by a patient may present a challenge to the establishment of diagnosis. In this study, we report a seven-year-old Murut girl with unusual features of Williams-Beuren syndrome (WBS), including recurrent infections and skin abscesses. Considering the possibility of a second genetic disorder, a mutation screening for genes associated with inborn errors of immunity (IEI) was conducted using whole exome sequencing (WES). Analysis of copy number variations (CNVs) from the exome data revealed a 1.53Mb heterozygous deletion on chromosome 7q11.23, corresponding to the known WBS. We also identified a biallelic loss of NCF1, which indicated autosomal recessive chronic granulomatous disease (CGD). Dihydrorhodamine (DHR) flow cytometric assay demonstrated abnormally low neutrophil oxidative burst activity. Coamplification of NCF1 and its pseudogenes identified a GT-deletion (ΔGT) at the start of exon 2 in NCF1 (NM_000265.7: c.75_76delGT: p.Tyr26Hisfs*26). Estimation of NCF1-to-NCF1 pseudogenes ratio using ΔGT and 20-bp gene scans affirmed nil copies of NCF1 in the patient. While the father had a normal ratio of 2:4, the mother had a ratio of 1:5, implicating the carrier of ΔGT-containing NCF1. Discovery of a 7q11.23 deletion involving one NCF1 allele and a ΔGT in the second NCF1 allele explained the coexistence of WBS and CGD in our patient. This study highlights the capability of WES to establish a molecular diagnosis for a case with blended phenotypes, enabling the provision of appropriate prophylactic treatment.https://www.frontiersin.org/articles/10.3389/fimmu.2021.778133/fullwhole exome sequencing (WES)chronic granulomatous disease (CGD)Williams-Beuren syndrome (WBS)copy number variation (CNV)blended phenotypesdual molecular diagnosis |
| spellingShingle | Adiratna Mat Ripen Mei Yee Chiow Prakash Rao Rama Rao Saharuddin Bin Mohamad Saharuddin Bin Mohamad Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing Frontiers in Immunology whole exome sequencing (WES) chronic granulomatous disease (CGD) Williams-Beuren syndrome (WBS) copy number variation (CNV) blended phenotypes dual molecular diagnosis |
| title | Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing |
| title_full | Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing |
| title_fullStr | Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing |
| title_full_unstemmed | Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing |
| title_short | Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing |
| title_sort | revealing chronic granulomatous disease in a patient with williams beuren syndrome using whole exome sequencing |
| topic | whole exome sequencing (WES) chronic granulomatous disease (CGD) Williams-Beuren syndrome (WBS) copy number variation (CNV) blended phenotypes dual molecular diagnosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.778133/full |
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