Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts

Giuliana Giannuzzi (1) , Nicolas Chatron (2, 1) , Katrin Mannik (1) , Chiara Auwerx (1) , Sylvain Pradervand (1) , Gilles Willemin (1) , Kendra Hoekzema , Xander Nuttle , Jacqueline Chrast (1) , Marie Sadler , Eleonora Porcu (1) , Nicolas Chatron (1) , Katrin Männik (1) , Damien Sanlaville , Caroline Schluth-Bolard , Cédric Le Caignec , Mathilde Nizon , Sandra Martin (3) , Sébastien Jacquemont , Armand Bottani , Marion Gérard , Sacha Weber , Aurélia Jacquette , Catherine Vincent-Delorme , Aurora Currò , Francesca Mari , Alessandra Renieri , Alfredo Brusco , Giovanni Battista Ferrero , Yann Herault (3) , Bertrand Isidor , Brigitte Gilbert-Dussardier , Evan Eichler , Zoltan Kutalik , Alexandre Reymond (1)

1 UNIL - Université de Lausanne = University of Lausanne
2 INMG-AR - Institut NeuroMyoGène - Appui à la recherche
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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 ( P adj = 0.04) and increased neutrophil ( P adj = 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.

Domaines: Génétique humaine; Hématologie

Giuliana Giannuzzi, Nicolas Chatron, Katrin Mannik, Chiara Auwerx, Sylvain Pradervand, et al.. Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts. npj Genomic Medicine, 2022, 7 (1), pp.38. ⟨10.1038/s41525-022-00308-x⟩. ⟨hal-03862012⟩