Supplementary Data
Family Studies and Gene Analysis. DNA was obtained from all family members (her parents and two brothers).
In light of the clinical and biochemical findings, initial studies focused on sequencing the gene for STAT5b, which
proved to be wild type. Whole exome sequencing was then performed at the Broad Institute (Cambridge, MA
USA) in the patient and one sibling as previously described (1). Given the consanguinity, the hypothesis was that
the patient had a homozygous recessive disorder due to an extremely rare genetic variant. Therefore, novel
homozygous variants present in the proband but not homozygous in the unaffected sibling were screened. Novel
variants
were
defined
as
not
being
present
in
either
the
1000
Genomes
Database
(http://browser.1000genomes.org/index.html), the National Heart Lung and Blood Institute Exome Variant Server
(http://evs.gs.washington.edu/EVS/) or dbSNP. Twenty-three variants met these criteria of which 11 were nonsynonymous (9 missense, 1 frameshift, and 1 splice site variant). Upon reviewing these variants, a novel
homozygous frameshift mutation in the LRBA-gene c.5505delT (p.Ile1836*) was highlighted as the causal variant
(Fig1). Sanger sequencing confirmed this variant to be homozygous in the patient and absent in the unaffected
brother.
1
Table1.Immunological features of the patient
Patient
Age references(2)
ALC, /mm3
1600
>1500
AGC, /mm3
2100
>1500
IgG, mg/dl
1140
835-2094
IgA, mg/dl
327
67-433
IgM, mg/dl
34.46
47-484
IgE, kU/L
3.8
Isohemagglutinin titer
Blood type
O Rh +
Anti A titer
1/16
Anti B titer
1/8
CD3+ CD16-CD56-
67
58-82
+
CD3 CD4
+
43
26-48
+
+
24
16-32
CD3-CD16+CD56+
18
8-30
CD19+
13
10-30
+
13
9-28
CD4+CD45RA+
3
8-26
CD4+CD45RO+
11
10-30
TCRγδ,
1.3
CD4+CD45RA+CD31+
18.1
CD3 CD8
CD20
T cell activation response to PHA
CD3+CD25+, %
+
+
CD3 CD69 , %
DHR test
83
46-89
41
50-76
Normal
2
Table2. B cell subsets of the patient
+
+
CD 19 IgM-27 IgD
-
%
Normal levels in healthy Turkish children(3)
EUROCLASS(4)
12
12.9-45
6.5-29.2
9.8
5.1-11.8
7.2-30.8
86.3
62.2-76.2
2.6
3.2-5.9
1.1-6.9
6.1
2.8-10.2
0.6-3.5
(Switched memory B)
CD19+IgM+27+IgD+
(Marginal Zone B)
CD 19+IgM+27-IgD+
(Naive B)
CD19+CD38
Low
CD21
Low
(Activated B)
CD19+CD39
High
IgM
High
(Transitional B)
3
Table 3. The identified mutations in LRBA deficiency.
Chromosome
Position
Gene
cDNA change
Protein change
1
243336145
CEP170
c.T1276G
p.F426V
4
8229354
SH3TC1
c.G1933T
p.G645W
4
24801685
SOD3
c.A542T
p.H181L
4
151727435
LRBA
c.5505delT
p.Ile1836*
5
132083419
CCNI2
c.C232T
p.P78S
10
99342096
ANKRD2
c.G1018A
p.A340T
11
64410191
NRXN2
c.C85T
p.P29S
19
16265269
HSH2D
c.G271C
p.E91Q
19
36049477
ATP4A
c.1365+2T>A
NA
22
30775605
RNF215
c.G1118A
p.R373H
X
57618621
ZXDB
c.140T>C
p.L47P
All genomic positions are based on human genome build 19.
4
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5