Spectrum of BTK gene mutations in a single-centre cohort of

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Spectrum of BTK gene mutations in a single-centre cohort of X-linked agammaglobulinemia from North India Surjit Singh1, Amit Rawat1, Deepti Suri1, Anju Gupta1, Ravinder Garg1, Biman Saikia2, Ranjana Walker Minz2, Shobha Sehgal2, Koon-Wing Chan3, Yu Lung Lau3, Chikako Kamae4, Kenichi Honma4, Noriko Nakagawa4, Kohsuke Imai4, Shigeaki Nonoyama4, Koichi Oshima5, Noriko Mitsuiki5, Osamu Ohara5 1Pediatric Allergy and Immunology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 2Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 3 Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 4Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan 5 Kazusa DNA Research Institute, Kisarazu, Chiba, Japan Introduction Topology of BTK gene mutations at PGIMER, Chandigarh X-linked agammaglobulinemia (XLA) is the prototypic humoral immunodeficiency resulting BTK gene mutations BTK gene (Chromosome X; Xq22.1-Xq22) spans 19 exons & 37.5 kilobases BTKbase; version BTK:160802 shows 1374 public variants with 713 unique variants We follow a large cohort of 56 children with XLA and BTK gene mutations in 34 at Advanced Pediatrics Centre, PGIMER, Chandigarh, India Materials and Methods Comprehensive analysis of 34 BTK gene mutations in our cohort of XLA patients BTK gene sequencing was performed at Kazusa DNA Research, Chiba, Japan and Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong Effect of missense mutations was assessed using in-silico prediction tools Table 1. BTK gene mutations in XLA cohort at Chandigarh Patient Exon/Intro n Domain Nucleotide change Codon Change Type of mutation 1 Exon 10 SH2 8842G>A W281X Point mutation (Nonsense mutation) 2 Intron 5 PH IVS5-1G>C Point mutation (Intronic/splice site) 3 Exon 16 TK 1771C>A N526K Point mutation (Missense mutation) 4 Intron 8~9 SH3 Deletion 5 Intron 17 c.1750+2,T>C Point mutation (Intronic/splice site ) 6 Exon 1-3 7 Exon 2 83G>A R28H Point mutation (Missense) 8 Intron 18 IVS18-8 G>A p.53GlyfsX5 9 10 Exon 15 1514 T>A V505D Point mutation (Missense mutation) 11 Exon 12 1064 T>A I355N 12 Exon 19 1921C>T R641C 13 126 T>A Y42X Point mutation (Nonsense) 14 Exon 3 158-159 insG G53fsX5 Frameshift mutation (Insertion 15 Frameshift mutation (Insertion) 16 Exon 2-3 17 1594 C>T Gln532>X Point mutation (Nonsense ) 18 1002T>G Tyr(Y)334X 19 Intron 1 IVS1+1 G>A Point mutation (Splice site) 20 1589 T>C L486P 21 Exon 17 1828C>T P566S Point mutation (Missense ) 22 169C>T R13X 23 Exon 18 2013_2014delTA Y627fsX635 Frameshift mutation (Deletion) 24 Exon8 895C>T R255X 25 Exon 6 TH c.461G>A C154Y 26 1863delA C577fsX586 27 1713_1716delTTTG C527fsX528 28 29 Exon 8-9 30 c.1696C>T 31 c. 1732C>T S578P 32 c. 1573C>G R525G 33 Exon 9 803_804delAT Y268fsX270 34 Exon 14 c.1325dupT p.F442fsX44 4 Results Single nucleotide substitutions (missense, nonsense and splice-site mutations) most common (65%; 22/34) Frame-shift mutations resulting from small deletions and insertions accouted for 23% of mutations (8/34) Large deletions accounted for 12% of all mutations Of single nucleotide substitutions, missense 50%, nonsense 27% and splice-site 23% Fifty (50%) of mutations in exons encoding for the SH1 or TYK3 domain, followed by those in PH domain (34%) Distribution of mutations across different domains similar to previously reported cohorts Five novel mutations were identified in our cohort Figure 1. BTK mutation spectrum Figure 2. Types of misense mutations Table 2. Prediction of effect of missesnse mutations S. No. Nucleotide Change Codon Prediction by various in-silico bioinformatic tools SIFT PMut PolpPhen Condel 1. 83G>A R28H Damaging Pathological Probably Deleterious 2. 1771C>A N526K 3. 1828C>T P566S Neutral 4. 1514T>A V505D 5. 1064T>A I355N 6. 1921C>T R641C 7. 1589 T>C L486P 8. 461G>A C154Y 9. c. 1732C>T S578P 10. c. 1573C>G R525G References Buckley CR. Agammaglobulinemia, by Col. Ogden C. Bruton, MC, USA, Pediatrics, 1952;9:722-728. Pediatrics. 1998;102:213e215. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361:226e233. Suri D, Rawat A, Singh S. X-linked Agammaglobulinemia. Indian J Pediatr. 2016;83:331-7. Bhattad S, Vignesh P, Rawat A, et al. Spondylodiscitis in a Boy with X-linked Agammaglobulinemia: an Unusual Occurrence. J Clin Immunol. 2016;36:360-2 Contact: Dr Amit Rawat, Additional Professor of Pediatric Allergy and Immunology, Advanced Pediatrics Centre, PGIMER, Chandigarh, INDIA. Email: rawatamit@yahoo.com