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 ( the National Heart Lung and Blood Institute Exome Variant Server ( or dbSNP. Twenty-three variants met these criteria of which 11 were non-synonymous (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.

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
CD3+CD8+ / 24 / 16-32
CD3-CD16+CD56+ / 18 / 8-30
CD19+ / 13 / 10-30
CD20+ / 13 / 9-28
CD4+CD45RA+ / 3 / 8-26
CD4+CD45RO+ / 11 / 10-30
TCRγδ, / 1.3
CD4+CD45RA+CD31+ / 18.1
T cell activation response to PHA
CD3+CD25+, % / 83 / 46-89
CD3+CD69+, % / 41 / 50-76
DHR test / Normal

Table2. B cell subsets of the patient

% / Normal levels in healthy Turkish children(3) / EUROCLASS(4)
CD 19+ IgM-27+IgD-
(Switched memory B) / 12 / 12.9-45 / 6.5-29.2
CD19+IgM+27+IgD+
(Marginal Zone B) / 9.8 / 5.1-11.8 / 7.2-30.8
CD 19+IgM+27-IgD+
(Naive B) / 86.3 / 62.2-76.2
CD19+CD38LowCD21Low
(Activated B) / 2.6 / 3.2-5.9 / 1.1-6.9
CD19+CD39HighIgMHigh
(Transitional B) / 6.1 / 2.8-10.2 / 0.6-3.5

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.

REFERENCES

1.Dauber A, Stoler J, Hechter E, Safer J, Hirschhorn JN. Whole exome sequencing reveals a novel mutation in CUL7 in a patient with an undiagnosed growth disorder. J Pediatr. 2013;162(1):202-4 e1.

2.Ikinciogullari A, Kendirli T, Dogu F, Egin Y, Reisli I, Cin S, et al. Peripheral blood lymphocyte subsets in healthy Turkish children. Turk J Pediatr. 2004;46(2):125-30.

3.Cipe FE, Dogu F, Guloglu D, Aytekin C, Polat M, Biyikli Z, et al. B-cell subsets in patients with transient hypogammaglobulinemia of infancy, partial IgA deficiency, and selective IgM deficiency. J Investig Allergol Clin Immunol. 2013;23(2):94-100.

4.Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111(1):77-85.

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