ABSTRACT
BACKGROUND: Dysferlinopathy has a high prevalence in relatively isolated ethnic groups where consanguineous marriages are characteristic and/or the founder effect exists. However, the frequency of endemic mutations in most isolates has not been investigated. METHODS: The prevalence of the pathological DYSF gene variant (NM_003494.4); c.200_201delinsAT, p. Val67Asp (rs121908957) was investigated in an isolated Avar population in the Republic of Dagestan. Genetic screenings were conducted in a remote mountainous region characterized by a high level of consanguinity among its inhabitants. In total, 746 individuals were included in the screenings. RESULTS: This pathological DYSF gene variant causes two primary phenotypes of dysferlinopathy: limb-girdle muscular dystrophy (LGMD) type R2 and Miyoshi muscular dystrophy type 1. Results indicated a high prevalence of the allele at 14% (95% confidence interval [CI]: 12-17; 138 out of 1518 alleles), while the allele in the homozygous state was detected in 29 cases-3.8% (CI: 2.6-5.4). The population load for dysferlinopathy was 832.3 ± 153.9 per 100,000 with an average prevalence of limb-girdle muscular dystrophies ranging from 0.38 ± 0.38 to 5.93 ± 1.44 per 100,000. CONCLUSION: A significant burden of the allele was due to inbreeding, as evidenced by a deficiency of heterozygotes and the Wright fixation index equal to 0.14 (CI 0.06-0.23).
ABSTRACT
INTRODUCTION: Tyrosinemia type 1 (HT1) (OM IM 276700) is an inborn error of tyrosine catabolism caused be fumarylacetoacetate hedralase deficiency (FAH). In tyrosinemia type I, dietary therapy and nitisinone (Orfandin®), liver transplantation are effective . AIM: We present here the first report on identification of FAH mutation in HT1 Yakut patient from Russia with a novel one. MATERIAL AND METHODS: The material for the clinical study is based on the genetic data of the patient card with tyrosinemia type 1, which is observed in the medical-genetic consultations Republican Hospital â1-National Medical Center of the Republic of Sakha (Yakutia). For molecular genetic analysis has been used venous whole blood, taken with the written consent from the patient, his relatives and 200 healthy Yakuts. All regions of the FAH gene spanning exons were amplified by PCR and mutational analyses was carried out by direct sequencing. Results of sequencing were confirmed by restriction fragment length polymorphism (PCR-RELF) analyses. RESULTS: 1 one-year-old child was identified with a diagnosis hereditary tyrosinemia type Ia, acute form. In exon 13 of the FAH gene a novel mutation c.1090 G>C (GLu364GLn) in the homozygous state was found in patient, and in heterozygous state in both parents. The child is treated Nitisinone therapy. DNA diagnostics of c.1090 G>C mutation frequency in the FAH gene was conducted using PCR and RFLP analysis in 200 unrelated Yakuts. The frequency of heterozygous carrier was 1.0%.
