GLN1233* nonsens-mutation and ARG326GLN polymorphism of MYBPC3 gene in patients with hypertrophic cardiomyopathy in Belarus

Relevance . In many populations of patients with hypertrophic cardiomyopathy (HCM), mutation of р.Gln1233* (rs397516037) and р.Arg326Gln (rs34580776) substitution in MYBPC 3 have been identified with different frequency. The published data of these genetic changes differ in the interpretation of their pathogenicity. The founder effect has been described for р.Gln1233* for some populations. The aim was to assess the incidence of rs397516037 and rs34580776 substitution in MYBPC 3 in Belarusian patients with HCM and in control group; to test the hypothesis about the effects of the founder for р.Gln1233* mutation, and to describe clinical features of the disease in the group of patients with this mutation. Materials and methods . Genetic analysis was made by NGS for 85 individuals. A guided search for a р.Arg326Gln substitution by PCR-RFLP was made in 250 non-related individuals, 13 proband relatives with р.Gln1233* mutations and 127 controls. The р.Gln1233* mutation identification was made using automated sequencing method in all carriers of р.Arg326Gln , and in 113 individuals without the substitution. In those carriers with at least one substitution, р.Val849Val (c.2547C>T, rs3729953) and р.Glu1096Glu (c.3288G>A, rs1052373) loci were genotyped by PCR-RFLP to identify the haplotype. Results . In 5.37% (18 of 335) Belarusian individuals with HCM, р.Gln1233* nonsense-mutation and р.Arg326Gln substitution in cis-arrangement were established. No р.Gln1233* mutation in the controls suggested its diagnostic significance concerning the development of HCM. The р.Arg326Gln substitution without present р.Gln1233* mutation was established in 5.07% (17 of 335) individuals and in 3.94% controls of the sample suggesting the insignificance of this polymorphism in the development of the condition. The effect of the founder for р.Gln1233* mutation for Belarus has been established. Clinical characteristics of HCM has been proposed for probands and closest relatives who have this mutation. Conclusions . р.Gln1233* nonsense-mutation (rs397516037) is the most frequent mutation among mutations identified in Belarusian individuals diagnosed with HCM. The course of the disease in p.Gln1233* carriers varied from mildly symptomatic at a younger age (18 to 40 y.o.) to severe with malignant prognosis including fatal outcome due to CHF progression.

гипертрофическая кардиомиопатия, мутация р.Gln1233* и замена р.Arg326Gln в гене MYBPC3, гаплотип, эффект основателя, клинические проявления, hypertrophic cardiomyopathy, р.Gln1233* mutation and р.Arg326Gln substitution in MYBPC3, haplotype, founder effect, clinical features

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