Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study.
Primary immunodeficiency disorders are a recognized public health problem worldwide. The prototype of these conditions is X-linked agammaglobulinemia (XLA) or Bruton's disease. XLA is caused by mutations in Bruton's tyrosine kinase gene (BTK), preventing B cell development and resulting in the almost total absence of serum immunoglobulins. The genetic profile and prevalence of XLA have not previously been studied in Eastern and Central European (ECE) countries. We studied the genetic and demographic features of XLA in Belarus, Croatia Hungary, Poland, Republic of Macedonia, Romania, Russia, Serbia, Slovenia, and Ukraine. We collected clinical, immunological, and genetic information for 122 patients from 109 families. The BTK gene was sequenced from the genomic DNA of patients with a high susceptibility to infection, almost no CD19(+) peripheral blood B cells, and low or undetectable levels of serum immunoglobulins M, G, and A, compatible with a clinical and immunological diagnosis of XLA. BTK sequence analysis revealed 98 different mutations, 46 of which are reported for the first time here. The mutations included single nucleotide changes in the coding exons (35 missense and 17 nonsense), 23 splicing defects, 13 small deletions, 7 large deletions, and 3 insertions. The mutations were scattered throughout the BTK gene and most frequently concerned the SH1 domain; no missense mutation was detected in the SH3 domain. The prevalence of XLA in ECE countries (total population 145,530,870) was found to be 1 per 1,399,000 individuals. This report provides the first comprehensive overview of the molecular genetic and demographic features of XLA in Eastern and Central Europe.
Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
Beáta
B
Tóth
Alla
A
Volokha
Alexander
A
Mihas
Malgorzata
M
Pac
Ewa
E
Bernatowska
Irina
I
Kondratenko
Alexander
A
Polyakov
Melinda
M
Erdos
Srdjan
S
Pasic
Michaela
M
Bataneant
Anna
A
Szaflarska
Kristina
K
Mironska
Darko
D
Richter
Katarina
K
Stavrik
Tadej
T
Avcin
Gabriella
G
Márton
Kálmán
K
Nagy
Beáta
B
Dérfalvi
Miklós
M
Szolnoky
Agnes
A
Kalmár
Michael
M
Belevtsev
Marina
M
Guseva
Aurica
A
Rugina
Gergely
G
Kriván
László
L
Timár
Zoltán
Z
Nyul
Bernadett
B
Mosdósi
Lidija
L
Kareva
Sonja
S
Peova
Liudmyla
L
Chernyshova
Ioan
I
Gherghina
Margit
M
Serban
Mary Ellen
ME
Conley
Luigi D
LD
Notarangelo
C I Edvard
CI
Smith
Jacques
J
van Dongen
Mirjam
M
van der Burg
László
L
Maródi
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D003710:Demography; D005060:Europe / Q000453:epidemiology; D040181:Genetic Diseases, X-Linked / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D015995:Prevalence; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics; D044465:White People / Q000235:genetics*
D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human