Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
09
12
2020
accepted:
25
06
2021
entrez:
12
7
2021
pubmed:
13
7
2021
medline:
23
11
2021
Statut:
epublish
Résumé
X-linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals. We performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed. All patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. We could not identify any single nucleotide variants or small insertion/ deletions from the WES dataset that correlates with the clinical feature of the patient. Structural variant analysis through WGS data identifies a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed a South Asian ancestry. WGS led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling genetic counselling and prenatal diagnosis in the family.
Identifiants
pubmed: 34252140
doi: 10.1371/journal.pone.0254407
pii: PONE-D-20-38741
pmc: PMC8274882
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0254407Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Nature. 2020 Jul;583(7814):90-95
pubmed: 32499645
Hum Mol Genet. 2016 Sep 1;25(17):3754-3767
pubmed: 27436579
Curr Opin Allergy Clin Immunol. 2012 Dec;12(6):623-8
pubmed: 23095910
Cell. 1993 Jan 29;72(2):279-90
pubmed: 8425221
Immunol Invest. 2004 Feb;33(1):81-93
pubmed: 15015835
N Engl J Med. 2002 Oct 10;347(15):1162-8
pubmed: 12374877
Mol Genet Genomic Med. 2016 Sep 17;4(6):604-616
pubmed: 27896283
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Eur J Pediatr. 2010 Sep;169(9):1069-74
pubmed: 20414676
Immun Inflamm Dis. 2015 Sep;3(3):171-81
pubmed: 26417435
Hum Mutat. 2006 Dec;27(12):1209-17
pubmed: 16969761
Immunol Rev. 2009 Mar;228(1):58-73
pubmed: 19290921
Front Immunol. 2019 Oct 01;10:2325
pubmed: 31681265
J Clin Immunol. 2009 Jul;29(4):501-7
pubmed: 19089603
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Nucleic Acids Res. 1988 Feb 11;16(3):1215
pubmed: 3344216
J Hum Genet. 2003;48(6):322-326
pubmed: 12768435
Eur J Hum Genet. 2012 May;20(5):490-7
pubmed: 22258526
J Pediatr. 1977 Sep;91(3):408-12
pubmed: 197220
Genome Biol. 2014 Jun 26;15(6):R84
pubmed: 24970577
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Pediatrics. 2015 Dec;136(6):e1621-4
pubmed: 26527549
J Hematol Oncol. 2016 Feb 13;9:9
pubmed: 26873735
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Genet Med. 2007 Feb;9(2):117-22
pubmed: 17304053
Medicine (Baltimore). 2006 Jul;85(4):193-202
pubmed: 16862044
Genet Med. 2018 Dec;20(12):1663-1676
pubmed: 29907799
Immunol Rev. 2005 Feb;203:216-34
pubmed: 15661032
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Genome Biol. 2011 Sep 14;12(9):128
pubmed: 21920051
Hum Mutat. 2000 Apr;15(4):385
pubmed: 10737994
Eur J Hum Genet. 2005 Nov;13(11):1231-4
pubmed: 16030524
Dev Immunol. 2001;8(3-4):171-81
pubmed: 11785667
J Clin Immunol. 2020 Jan;40(1):66-81
pubmed: 32048120
J Med Genet. 2003 Jan;40(1):e3
pubmed: 12525551
Pediatr Allergy Immunol. 2001 Apr;12(2):107-11
pubmed: 11338284
PLoS Genet. 2012 Jan;8(1):e1002453
pubmed: 22291602
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
BMC Pediatr. 2013 Sep 27;13:150
pubmed: 24074005
Am J Hum Genet. 2008 Feb;82(2):320-32
pubmed: 18252213
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Pediatrics. 1952 Jun;9(6):722-8
pubmed: 14929630
Nat Methods. 2015 Oct;12(10):966-8
pubmed: 26258291
J Biol Chem. 1996 Nov 29;271(48):30303-6
pubmed: 8939985
World Allergy Organ J. 2019 Mar 22;12(3):100018
pubmed: 30937141
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5473-8
pubmed: 25827230
Pediatr Transplant. 2020 Feb;24(1):e13625
pubmed: 31821668
BMC Bioinformatics. 2008 Dec 16;9:540
pubmed: 19087329
BMC Neurol. 2019 Dec 12;19(1):320
pubmed: 31830942