Myotonia congenita type Becker in Bulgaria: First genetically proven cases and mutation screening of two presumable endemic regions.
Myotonia congenita type Becker is an autosomal recessive nondystrophic skeletal muscle disorder, caused by mutations in the CLCN1 gene. The disease is characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Here we report the results from molecular genetic testing of 6 families, referred for sequencing of the CLCN1 gene. The disease causing mutations were detected in 5 of the cases, representing diverse type of nucleotide changes: nonsense (p.Arg894*), splice-site (c.1471+1G>A), missense (p.Val273Met; p.Tyr524Cys). Two additional changes were detected in an asymptomatic individual (c.2284+5C>T and p.Phe167Leu). Two of the detected mutations are interesting from population point of view. The novel missense mutation p.Tyr524Cys was found in a large Bulgarian family with affected individuals in both vertical and horizontal pedigree directions, all of them carrying the mutation in homozygous form. They populate a village located in the northwest part of the country. Endogamous marriages are very unusual for the Bulgarian population, supposing a high carrier frequency in this subpopulation. Screening of 154 residents of the corresponding region showed a significant carrier frequency for the p.Tyr524Cys mutation of about 0.65% (1/154). The second interesting region in the context of Myotonia congenita type Becker is the southwest part of the country, where we found a large family of Bulgarian Turkish origin. The disease causing missense mutation p.Val273Met was again present in homozygous state. Surprisingly, the genetic testing of newborns from southwest Bulgaria showed an even higher carrier status of about 2.6% (3/116), disproving our initial hypothesis of endogamous marriages (traditionally common in this subpopulation) being the cause of the disease in these patients. However the probability of consanguineous marriages being the cause for further exaggeration of the anyway very high carrier frequency cannot be excluded.
Department of Medical Chemistry and Biochemistry, Medical University Sofia, 2 Zdrave Str., Sofia, Bulgaria; Genetic Medico-Diagnostic Laboratory "Genica", 90 Tsar Asen Str., Sofia, Bulgaria. Electronic address: savina.tincheva@gmail.com.
Savina
S
Tincheva
Department of Medical Chemistry and Biochemistry, Medical University Sofia, 2 Zdrave Str., Sofia, Bulgaria.
Bilyana
B
Georgieva
Genetic Medico-Diagnostic Laboratory "Genica", 90 Tsar Asen Str., Sofia, Bulgaria.
Tihomir
T
Todorov
Department of Obstetrics and Gynecology, Faculty of Medicine, National Genetic Laboratory, Medical University Sofia, 2 Zdrave Str., Sofia, Bulgaria.
Alexey
A
Savov
Genetic Medico-Diagnostic Laboratory "Genica", 90 Tsar Asen Str., Sofia, Bulgaria.
Slavena
S
Tsaneva
Department of Neurology, University Pediatric Hospital, Medical University, 11 Acad. Ivan Evstatiev Geshov Str., Sofia, Bulgaria.
Ivan
I
Litvinenko
Department of Medical Chemistry and Biochemistry, Medical University Sofia, 2 Zdrave Str., Sofia, Bulgaria.
Vanyo
V
Mitev
Department of Medical Chemistry and Biochemistry, Medical University Sofia, 2 Zdrave Str., Sofia, Bulgaria; Genetic Medico-Diagnostic Laboratory "Genica", 90 Tsar Asen Str., Sofia, Bulgaria.
Albena
A
Todorova
D000328:Adult; D002031:Bulgaria / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D019353:Endemic Diseases; D005190:Family; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D009154:Mutation; D009224:Myotonia Congenita / Q000453:epidemiology / Q000235:genetics*
C086321:CLC-1 channel; D018118:Chloride Channels
CLCN1 gene; Endemic regions; First Bulgarian cases; Myotonia congenita type Becker; Novel mutation