Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts
Abstract Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and i...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-022-00308-x |
| _version_ | 1797817833042739200 |
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| author | Giuliana Giannuzzi Nicolas Chatron Katrin Mannik Chiara Auwerx Sylvain Pradervand Gilles Willemin Kendra Hoekzema Xander Nuttle Jacqueline Chrast Marie C. Sadler Eleonora Porcu 16p11.2 Consortium Yann Herault Bertrand Isidor Brigitte Gilbert-Dussardier Evan E. Eichler Zoltan Kutalik Alexandre Reymond |
| author_facet | Giuliana Giannuzzi Nicolas Chatron Katrin Mannik Chiara Auwerx Sylvain Pradervand Gilles Willemin Kendra Hoekzema Xander Nuttle Jacqueline Chrast Marie C. Sadler Eleonora Porcu 16p11.2 Consortium Yann Herault Bertrand Isidor Brigitte Gilbert-Dussardier Evan E. Eichler Zoltan Kutalik Alexandre Reymond |
| author_sort | Giuliana Giannuzzi |
| collection | DOAJ |
| description | Abstract Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3–8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions. |
| first_indexed | 2024-03-13T08:59:15Z |
| format | Article |
| id | doaj.art-46886538723645c79e39a958f7052132 |
| institution | Directory Open Access Journal |
| issn | 2056-7944 |
| language | English |
| last_indexed | 2024-03-13T08:59:15Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj.art-46886538723645c79e39a958f70521322023-05-28T11:23:38ZengNature Portfolionpj Genomic Medicine2056-79442022-06-017111010.1038/s41525-022-00308-xPossible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil countsGiuliana Giannuzzi0Nicolas Chatron1Katrin Mannik2Chiara Auwerx3Sylvain Pradervand4Gilles Willemin5Kendra Hoekzema6Xander Nuttle7Jacqueline Chrast8Marie C. Sadler9Eleonora Porcu1016p11.2 ConsortiumYann Herault11Bertrand Isidor12Brigitte Gilbert-Dussardier13Evan E. Eichler14Zoltan Kutalik15Alexandre Reymond16Center for Integrative Genomics, University of LausanneCenter for Integrative Genomics, University of LausanneCenter for Integrative Genomics, University of LausanneCenter for Integrative Genomics, University of LausanneCenter for Integrative Genomics, University of LausanneCenter for Integrative Genomics, University of LausanneDepartment of Genome Sciences, University of WashingtonCenter for Genomic Medicine, Massachusetts General HospitalCenter for Integrative Genomics, University of LausanneDepartment of Computational Biology, University of LausanneCenter for Integrative Genomics, University of LausanneUniversity of Strasbourg, CNRS, INSERM, PHENOMIN-ICS, Institute of Genetics and Molecular and Cellular BiologyService de Génétique Médicale, CHU de NantesService de Génétique, CHU de PoitiersDepartment of Genome Sciences, University of WashingtonDepartment of Computational Biology, University of LausanneCenter for Integrative Genomics, University of LausanneAbstract Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3–8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.https://doi.org/10.1038/s41525-022-00308-x |
| spellingShingle | Giuliana Giannuzzi Nicolas Chatron Katrin Mannik Chiara Auwerx Sylvain Pradervand Gilles Willemin Kendra Hoekzema Xander Nuttle Jacqueline Chrast Marie C. Sadler Eleonora Porcu 16p11.2 Consortium Yann Herault Bertrand Isidor Brigitte Gilbert-Dussardier Evan E. Eichler Zoltan Kutalik Alexandre Reymond Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts npj Genomic Medicine |
| title | Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts |
| title_full | Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts |
| title_fullStr | Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts |
| title_full_unstemmed | Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts |
| title_short | Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts |
| title_sort | possible association of 16p11 2 copy number variation with altered lymphocyte and neutrophil counts |
| url | https://doi.org/10.1038/s41525-022-00308-x |
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