Homozygous duplication identified by whole genome sequencing causes LRBA deficiency
Abstract In more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diag...
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Nature Portfolio
2021
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oai:doaj.org-article:28825eb4a8ee44ae8a4339e8b884b5772021-11-21T12:42:50ZHomozygous duplication identified by whole genome sequencing causes LRBA deficiency10.1038/s41525-021-00263-z2056-7944https://doaj.org/article/28825eb4a8ee44ae8a4339e8b884b5772021-11-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00263-zhttps://doaj.org/toc/2056-7944Abstract In more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration.Daniele MericoYehonatan PasternakMehdi ZarreiEdward J. HigginbothamBhooma ThiruvahindrapuramOri ScottJessica Willett-PachulEyal GrunebaumJulia UptonAdelle AtkinsonVy H. D. KimElbay AliyevKhalid FakhroStephen W. SchererChaim M. RoifmanNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-6 (2021) |
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Medicine R Genetics QH426-470 |
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Medicine R Genetics QH426-470 Daniele Merico Yehonatan Pasternak Mehdi Zarrei Edward J. Higginbotham Bhooma Thiruvahindrapuram Ori Scott Jessica Willett-Pachul Eyal Grunebaum Julia Upton Adelle Atkinson Vy H. D. Kim Elbay Aliyev Khalid Fakhro Stephen W. Scherer Chaim M. Roifman Homozygous duplication identified by whole genome sequencing causes LRBA deficiency |
| description |
Abstract In more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration. |
| format |
article |
| author |
Daniele Merico Yehonatan Pasternak Mehdi Zarrei Edward J. Higginbotham Bhooma Thiruvahindrapuram Ori Scott Jessica Willett-Pachul Eyal Grunebaum Julia Upton Adelle Atkinson Vy H. D. Kim Elbay Aliyev Khalid Fakhro Stephen W. Scherer Chaim M. Roifman |
| author_facet |
Daniele Merico Yehonatan Pasternak Mehdi Zarrei Edward J. Higginbotham Bhooma Thiruvahindrapuram Ori Scott Jessica Willett-Pachul Eyal Grunebaum Julia Upton Adelle Atkinson Vy H. D. Kim Elbay Aliyev Khalid Fakhro Stephen W. Scherer Chaim M. Roifman |
| author_sort |
Daniele Merico |
| title |
Homozygous duplication identified by whole genome sequencing causes LRBA deficiency |
| title_short |
Homozygous duplication identified by whole genome sequencing causes LRBA deficiency |
| title_full |
Homozygous duplication identified by whole genome sequencing causes LRBA deficiency |
| title_fullStr |
Homozygous duplication identified by whole genome sequencing causes LRBA deficiency |
| title_full_unstemmed |
Homozygous duplication identified by whole genome sequencing causes LRBA deficiency |
| title_sort |
homozygous duplication identified by whole genome sequencing causes lrba deficiency |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/28825eb4a8ee44ae8a4339e8b884b577 |
| work_keys_str_mv |
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