Format

Send to

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

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

Author information

1
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
2
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
3
BGI-Shenzhen, Shenzhen, 518083, China.
4
China National GeneBank, BGI-Shenzhen, Shenzhen, 518120, China.
5
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. lennart.hammarstrom@ki.se.
6
BGI-Shenzhen, Shenzhen, 518083, China. lennart.hammarstrom@ki.se.
7
China National GeneBank, BGI-Shenzhen, Shenzhen, 518120, China. lennart.hammarstrom@ki.se.

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.

KEYWORDS:

Dysgammaglobulinemia; Exome sequencing; Genetic diagnosis; Primary antibody deficiency

PMID:
29921932
DOI:
10.1038/s41436-018-0012-x
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center