Rapid Molecular Analysis of the STAT3 Gene in Job Syndrome of Hyper-IgE and Recurrent Infectious Diseases Attila Kumánovics, Carl T. Wittwer, Robert.

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Rapid Molecular Analysis of the STAT3 Gene in Job Syndrome of Hyper-IgE and Recurrent Infectious Diseases Attila Kumánovics, Carl T. Wittwer, Robert J. Pryor, Nancy H. Augustine, Mark F. Leppert, John C. Carey, Hans D. Ochs, Ralph J. Wedgwood, Ralph J. Faville, Paul G. Quie, Harry R. Hill The Journal of Molecular Diagnostics Volume 12, Issue 2, Pages 213-219 (March 2010) DOI: 10.2353/jmoldx.2010.090080 Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 1 Amplicon melting analysis. Five of the 10 amplicons showed very tight clustering (A), whereas four exons (11, 13, 14, and 16) showed more variation, as shown by exon 11 in B. The genotype of these outliers as determined by sequencing was the same as the main cluster (see the green and blue colored outliers in B as well). In the case of exon 15, however, the one clear outlier from the main cluster was sequenced as a heterozygous C to T polymorphism (c1361T>C, p.L454P; C), which is putatively benign because it was found in an asymptomatic blood donor. The Journal of Molecular Diagnostics 2010 12, 213-219DOI: (10.2353/jmoldx.2010.090080) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 2 Mutation in exon 13 changing the DNA-binding region. A: High resolution melting and sequencing of exon 13 revealed three HIES genotypes in addition to the wild-type (WT). All three exon 13 HIES genotypes change the codon encoding R382. These genotypes are detected as different from wild-type, but were not differentiated. B: An example of a de novo R382Q mutation that arose in the proband (II/4) and was inherited by two of the proband's four children (III/3 and III/4) is shown. IgE serum levels are shown in IU/ml if known. Family members were tested if available; family members not labeled as WT or HIES were not tested. The Journal of Molecular Diagnostics 2010 12, 213-219DOI: (10.2353/jmoldx.2010.090080) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 3 Mutation in exon 21 changing the SH2 region. A: This figure shows an example of a mutation changing the SH2 region of STAT3. Exon 21 encodes part of the SH2 region of STAT3 protein. B: E638G is a de novo mutation in the proband. Family members were tested if available; family members not labeled as WT (wild-type) or HIES were not tested. IgE serum levels are shown in IU/ml if known. The Journal of Molecular Diagnostics 2010 12, 213-219DOI: (10.2353/jmoldx.2010.090080) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 4 Deletion in the transactivation domain. A: A large, 32-bp deletion occurred in the proband (II/4) and was inherited by two of the proband's children (III/3 and III/4). B: This large heterozygous deletion was detected in all three patients. Family members were tested if available; family members not labeled as WT (wild-type) or HIES were not tested. IgE serum levels are shown in IU/ml if known. The Journal of Molecular Diagnostics 2010 12, 213-219DOI: (10.2353/jmoldx.2010.090080) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 5 Clinical diagnosis versus genetic testing. The proband of this family pedigree and her son were confirmed to have a missense mutation in exon 13 of STAT3. The proband's father (bold square) was suspected to have HIES because he had some signs and symptoms. Genetic testing showed a wild-type (WT) sequence. Family members were tested if a sample was available; family members not labeled as WT or HIES were not tested. IgE serum levels are shown in IU/ml if known. The Journal of Molecular Diagnostics 2010 12, 213-219DOI: (10.2353/jmoldx.2010.090080) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions