1. ¹Department of Medicine, Division of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany
2. ²Department of Medicine and Nijmegen University, Center for Infectious Diseases, Nijmegen, The Netherlands
3. ³National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
4. ⁴Hôpital Saint-Louis, Center Hayem, Paris, France
5. ⁵Department of Pediatrics and Institute of Medicine 'Angelo Novicelli', University of Brescia, Brescia, Italy
6. ⁶Department of Clinical Immunology, Royal Free Hospital, London, UK
7. ⁷Department of Medicine, Division of Clinical Immunology, Karolinska Institute at Huddinge, Stockholm, Sweden

Correspondence: Dr B Grimbacher, Division of Rheumatology and Clinical Immunology, University Hospital Freiburg, Hugstetterstr. 55, Freiburg 79106, Germany. Tel: +49 761 270 3696; Fax: 49 761 270 3531; E-mail: grimbacher@medizin.ukl.uni-freiburg.de

Received 5 December 2005; Revised 2 March 2006; Accepted 16 March 2006; Published online 26 April 2006.

Abstract

The phenotype of common variable immunodeficiency (CVID) is characterized by recurrent infections owing to hypogammaglobulinemia, with deficiency in immunoglobulin (Ig)G and at least one of IgA or IgM. Family studies have shown a genetic association between CVID and selective IgA deficiency (IgAD), the latter being a milder disorder compatible with normal health. Approximately 20–25% of CVID cases are familial, if one includes families with at least one case of CVID and one of IgAD. Nijenhuis et al described a five-generation family with six cases of CVID, five cases of IgAD, and three cases of dysgammaglobulinemia. We conducted a genome-wide scan on this family seeking genetic linkage. One interval on chromosome 4q gives a peak multipoint LOD score of 2.70 using a strict model that treats only the CVID patients and one obligate carrier with dysgammaglobulinemia as affected. Extending the definition of likely affected to include IgAD boosts the peak multipoint LOD score to 3.38. The linkage interval spans at least from D4S2361 to D4S1572. We extended our study to a collection of 32 families with at least one CVID case and a second case of either CVID or IgAD. We used the same dominant penetrance model and genotyped and analyzed nine markers on 4q. The 32 families have a peak multipoint LOD score under heterogeneity of 0.96 between markers D4S423 and D4S1572 within the suggested linkage interval of the first family, and an estimated proportion of linked families () of 0.32, supporting the existence of a disease-causing gene for autosomal-dominant CVID/IgAD on chromosome 4q.