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

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

A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.

Context: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). Objective: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. Design and Patients: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. Results: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. Conclusion: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations