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Hum Immunol. 2018 Jul;79(7):571-577. doi: 10.1016/j.humimm.2018.04.014. Epub 2018 Apr 27.

Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management.

Author information

1
EA3963, Université Paris 7 Denis Diderot, Centre Hayem, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France; Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France. Electronic address: nicolas.vince@univ-nantes.fr.
2
Laboratoire Central d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié Salpêtrière et INSERM UMR-S945, Bâtiment CERVI, Paris, France.
3
EA3963, Université Paris 7 Denis Diderot, Centre Hayem, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France; Département d'Immunologie Clinique, Hôpital Saint-Louis, AP-HP, 1 Avenue Claude Vellefaux, 75010 Paris, France.
4
Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Ecole Centrale de Nantes, Nantes, France.
5
EA3963, Université Paris 7 Denis Diderot, Centre Hayem, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
6
Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
7
Département d'Immunologie Clinique, Hôpital Saint-Louis, AP-HP, 1 Avenue Claude Vellefaux, 75010 Paris, France.

Abstract

The precise diagnosis of an immunodeficiency is sometimes difficult to assess, especially due to the large spectrum of phenotypic variation reported among patients. Common variable immunodeficiency disorders (CVID) do not have, for a large part, an identified genetic cause. The identification of a causal genetic mutation is important to confirm, or in some cases correct, the diagnosis. We screened >150 male patients with hypogammaglobulinemia for mutations in three genes involved in pediatric X-linked primary immunoglobulin deficiency: CD40LG, SH2D1A and BTK. The SH2D1A screening allowed to reclassify two individuals with an initial CVID presentation as XLP after mutations identification. All these mutations were associated with a lack of protein expression. In addition, 4 patients with a primary diagnosis of CVID and one with a primary IgG subclass deficiency were requalified as XLA after identifying BTK mutations. Interestingly, two out of these 5 patients carried a damaging coding BTK mutation associated with a lower, but detectable, BTK expression in monocytes, suggesting that a dysfunctional protein explains the disease phenotype in these patients. In conclusion, our results advocate to include SH2D1A and BTK in newly developed targeted NGS genetic testing, to contribute to providing the most appropriate medical treatment and genetic counselling.

KEYWORDS:

BTK; CD40L; CVID; Immunodeficiency; SAP

PMID:
29709555
DOI:
10.1016/j.humimm.2018.04.014
[Indexed for MEDLINE]

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