BMP15 and GDF9 gene mutations in premature ovarian failure

Background: Premature ovarian failure [POF] is an ovarian defect characterized by the premature depletion of ovarian follicles before the age of 40, representing one major cause of female infertility. Mutations in bone morphogenetic protein 15 [BMP15] and growth differentiation factor 9 [GDF9] have been shown to be associated with POF

Methods: Genomic DNA was isolated from 52 idiopathic premature ovarian failure patients and 100 normal control individuals. Exons of BMP15 and GDF9 gene were amplified using PCR method and subjected to directed sequencing. Variants were identified by comparing the sequences obtained with normal sequences from NCBI database

Results: Four BMP15 gene variants were identified in 6 patients in heterozygous condition. Out of these 4 variants, 3 variants namely, c.165A>T [p.Glu55Asp], c.538 G>T [p.Aln180 Ser] and c. 510_512 delT were novel variants. In silico analysis using SIFT, Provean and Polyphen 2 score predicted the non-deleterious effect of c.165A>T and c.538 G>T variant. 788insTCT variant was identified in 3 patients. No variant was identified in GDF9 gene in any patients and controls

Conclusion: Although the variant has been identified in BMP15 gene but it may not be associated with the premature ovarian failure

MTRR gene variants may predispose to the risk of Congenital Heart Disease in Down syndrome patients of Indian origin

Background: Down syndrome [DS], also called as trisomy 21, is one of the most leading cause of intellectual disability. DS is associated with a number of phenotypes including Congenital Heart Disease [CHD], Leukemia, Alzheimer's disease, Hirschsprung's disease and others. DS affects about 1 in 700 live births

Objectives: The study aims to investigate the association of MTRR [Methionine synthase reductase] gene polymorphisms [C524T and A66G] with the risk of CHD in DS patients

Methods: PCR and PCR-RFLP methods were used for the genotyping of study samples and results were validated using Sanger's sequencing

Results: MTRR C524T and A66G were significantly associated with the increased risk of CHD in DS. We have also reported two novel polymorphisms, T19775C and 19778_19778delG, in DS with CHD cases with a frequency of 93% and 40%, respectively. These two polymorphisms were not found among DS without CHD group

Conclusion: Results from this study indicate that the MTRR C524T and A66G polymorphisms influence the risk of the occurrence of CHD in DS patients of Indian Origin. This is the first report from India highlighting the potential association of MTRR C524T and A66G polymorphisms with CHD in DS. We are also the first one to report two novel polymorphisms, T19775C and 19778_19778delG in DS with CHD group. Hence these four polymorphisms can be used to evaluate the risk of CHD in DS patients

Do the MTHFR gene polymorphism and down syndrome pregnancy association stands true? a case-control study of Indian population and meta-analysis

Background: Down syndrome, the most common trisomy 21 arises from abnormal chromosomal segregation. The etiology includes genetic and acquired factors. The main genetic factor that is well appreciated for onset of Down syndrome pregnancy is MTHFR gene polymorphism. But till date, no final conclusion has arrived despite multiple studies on this gene polymorphism

Aim: To investigate the risk of MTHFR gene polymorphisms, C677T and A1298C, with Down syndrome pregnancies and a meta-analysis of published literature

Subjects and methodology: PCR-RFLP method was used to genotype C677T and A1298C polymorphism. For meta-analysis the literature was retrieved from PubMed database with the key words, MTHFR polymorphism; C677T; A1298C and Down syndrome

Results: Mothers carrying C677T polymorphism had a risk of 2.48 times compared with control subjects while A1298C polymorphism carriers had 1.60 times and 2.12 times increased risk under assumption of dominant and recessive model. However, meta-analysis of published studies resulted in 1.26 times and 1.32 times increased risk of Down syndrome pregnancies among the C677T carries under the assumption of recessive and dominant models of inheritance. Considering A1298C polymorphism, dominant model predicated no risk; recessive model resulted in 1.34 times increased risk in CC genotype individuals. In subgroup analysis, Indian studies had a risk of 1.61 times and 1.44 times under recessive and dominant model of C677T polymorphism inheritance while A1298C polymorphism carriers had a risk of 1.75 and 1.46 under the assumption of recessive and dominant inheritance

Conclusion: Our study suggests that both C677T and A1298C polymorphisms are significantly associated with the risk of DS pregnancy

Abbreviations: DS, Down syndrome; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase remethylation of homocysteine to methionine; MTRR, methionine synthase reductase; CBS, cystathionine beta-synthase; QF-PCR, Quantitative fluorescent PCR; OR, odds ratio; HWE, Hardy Weinberg equilibrium