José German Casas Martin, Belgium

KU Leuven Laboratory of Inborn Errors of Immunity, department of Microbiology and Immunology

Presenter Of 1 Presentation

Poster Display DNA repair disorders

LATE-ONSET AGAMMAGLOBULINEMIA REVEALING DNA LIGASE IV DEFICIENCY IN A PATIENT WITHOUT NEUROLOGIC IMPAIRMENT

Lecture Time
10:02 - 10:03
Room
Poster Area
Date
19.09.2019, Thursday
Session Time
10:00 - 17:00
Board Number
66
Presentation Topic
DNA repair disorders

Abstract

Background and Aims

Hypomorphic homozygous mutations of LIG4, encoding DNA ligase IV, cause a wide spectrum of developmental and immune defects, from SCID presentations to a phenotype resembling other chromosomal instability syndromes. Most patients present growth failure, microcephaly, facial dysmorphism, mental retardation, diverse skin and bone manifestations, and immunodeficiency ranging from SCID to humoral deficiency. Isolated bone marrow failure and hematological malignancies have also been reported.

Methods

Whole exome sequencing (WES) was performed in a 24-year-old man who was healthy until the age of 16 years-old, when he manifested hidradenitis suppurativa. At 18, he was hospitalized for pneumonia, which resolved uneventfully. At the age of 21 he had a complicated Haemophilus influenzae pneumonia. At that time he was found to have absent IgG, IgA and IgM, no responses to recall antigens, no B cells yet normal T-cell subset. He is a tall, overweight patient with no dysmorphic features and no bone abnormalities, but presenting vitiligo. The patient has been on SCIg replacement and is asymptomatic since diagnosis.

Results

WES identified a homozygous mutation in LIG4 (p.R278H), previously reported as pathogenic, resulting in radiosensitivity and in a subtle VDJ recombination defect. Two other homozygous patients have been described, with very different phenotypes: one with normal development and radiosensitivity manifested as detrimental response to acute leukemia therapy, and one with developmental delay, dysmorphic features and pancytopenia.

Conclusions

We report the first DNA Ligase IV deficient patient with isolated late-onset agammaglobulinemia as unveiled by an unbiased sequencing approach.

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