Clinical Implications of Systematic Phenotyping and Exome Sequencing in Patients With Primary Antibody Deficiency Publisher Pubmed



Abolhassani H^{1, 2} ; Aghamohammadi A² ; Fang M^{1, 3, 4} ; Rezaei N² ; Jiang C^{3, 4} ; Liu X^{3, 4} ; Panhammarstrom Q¹ ; Hammarstrom L^{1, 3, 4}
Source: Genetics in Medicine Published:2019

Abstract

Purpose: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown. Methods: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants. Results: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients. Conclusion: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members. © 2018, American College of Medical Genetics and Genomics.