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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Autores principales:	Adiratna Mat Ripen, Mei Yee Chiow, Prakash Rao Rama Rao, Saharuddin Bin Mohamad
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	whole exome sequencing (WES) chronic granulomatous disease (CGD) Williams-Beuren syndrome (WBS) copy number variation (CNV) blended phenotypes dual molecular diagnosis Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/9acd6a90a7a041688017b2bd1e7aaed6
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spelling	oai:doaj.org-article:9acd6a90a7a041688017b2bd1e7aaed62021-11-04T05:30:23ZRevealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing1664-322410.3389/fimmu.2021.778133https://doaj.org/article/9acd6a90a7a041688017b2bd1e7aaed62021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.778133/fullhttps://doaj.org/toc/1664-3224Blended 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.Adiratna Mat RipenMei Yee ChiowPrakash Rao Rama RaoSaharuddin Bin MohamadSaharuddin Bin MohamadFrontiers Media S.A.articlewhole exome sequencing (WES)chronic granulomatous disease (CGD)Williams-Beuren syndrome (WBS)copy number variation (CNV)blended phenotypesdual molecular diagnosisImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	whole exome sequencing (WES) chronic granulomatous disease (CGD) Williams-Beuren syndrome (WBS) copy number variation (CNV) blended phenotypes dual molecular diagnosis Immunologic diseases. Allergy RC581-607
spellingShingle	whole exome sequencing (WES) chronic granulomatous disease (CGD) Williams-Beuren syndrome (WBS) copy number variation (CNV) blended phenotypes dual molecular diagnosis Immunologic diseases. Allergy RC581-607 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
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.
format	article
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
title	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_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_sort	revealing chronic granulomatous disease in a patient with williams-beuren syndrome using whole exome sequencing
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/9acd6a90a7a041688017b2bd1e7aaed6
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Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing

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