DIAGNOSTIC ASSESSMENT
According to the episodes of recurrent infection, hypogammaglobulinemia
(low levels of IgG in combination with low levels of IgA and IgM
levels), poor response to immunizations, absence of profound T cell
immunodeficiency and any other defined immunodeficiency state, CVID was
suggested as the possible diagnosis. In order to find the gene
responsible, whole exome sequencing (WES) was done approximately 6
months after initiating the treatment with IVIG (Table 2).
Two novel mutations in two different gene loci (TCF3 andLRBA ) were reported as possible candidates responsible for the
patient’s condition. The missense variants reported in both of these
genes were absent in population databases (ExAC, 1000G, and our local
databases) and were not reported previously for pathogenicity.
Predictions of computational tools were conflicting for both genes.
Mutation Taster, CADD, and SIFT supported the deleterious effect of the
heterozygous missense variant in the TCF3 gene on the gene or
gene product(s), while PolyPhen predicted it as benign. For the
homozygous missense variant in the LRBA gene, Mutation Taster and
CADD supported the deleterious effect of this variant on the gene or
gene product(s), while SIFT and PolyPhen predicted it as tolerated or
benign. Based on ACMG guidelines, both of these variants can be
classified as Variant of Uncertain Significance (VUS) .
The timetable is depicted in Figure 1.