Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency

Genet Med. 2019 Jan;21(1):243-251. doi: 10.1038/s41436-018-0012-x. Epub 2018 Jun 19.


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.

Keywords: Dysgammaglobulinemia; Exome sequencing; Genetic diagnosis; Primary antibody deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Child
  • Child, Preschool
  • Exome / genetics
  • Exome / immunology
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing*
  • Genomics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immune System Diseases / genetics*
  • Immune System Diseases / immunology
  • Immune System Diseases / pathology
  • Male
  • Mutation
  • Phenotype
  • Sequence Analysis, DNA
  • Whole Exome Sequencing
  • Young Adult