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 (α) of 0.32, supporting the existence of a disease-causing gene for autosomal-dominant CVID/IgAD on chromosome 4q.
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Acknowledgements
We would like to acknowledge the help of Dr Tom Nijenhuis, Dr Corrie MR Weemaes, Dr Ina Klasen, and Dr Anna Simon in conducting the clinical sample collection and the support of Dr Ulrich Salzer in the laboratory. We thank an anonymous reviewer for very helpful suggestions that improved the manuscript. We thank the families and their physicians for their participation in this research study supported by Grant SFB620/C2 to BG from the Deutsche Forschungsgemeinschaft, by a grant from the Swedish research council to LH, by the Intramural Program of the National Institutes of Health, by the Fondazione Camillo Golgi, Brescia, Italy, and by EU-Projects QLRT-2001-01536 (IMPAD) and SP23-CT-2005-006411 (EURO-Policy-PID).
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Finck, A., Van der Meer, J., Schäffer, A. et al. Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. Eur J Hum Genet 14, 867–875 (2006). https://doi.org/10.1038/sj.ejhg.5201634
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DOI: https://doi.org/10.1038/sj.ejhg.5201634
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