Mysore R. Savitha

De novo isochromosome 18p in a female dysmorphic child

Isochromosome 18p results in tetrasomy 18p. Most of the i(18p) cases reported so far in the literature are sporadic due tode novo formation, while familial and mosaic cases are infrequent. It is a rare chromosomal abnormality, occurring once in every 140 000 livebirths, affecting males and females equally. In the present investigation, we report ade novo i(18p) in a female dysmorphic child. The small metacentric marker chromosome was confirmed as i(18p) in the proband by cytogenetic and FISH analysis [47,XX + i(18p)]. Cytogenetic investigations in the family members revealed normal chromosome numbers, indicating the case as ade novo event of i(1 8p) formation. It could be due to the somewhat advanced maternal age (32 years) and/or expression of recessive genes in the proband, who is the progeny of consanguineous marriage, which could have led to misdivision and nondisjunction of chromosome 18 in meiosis I, followed by failure in the chromatid separation of 18p in meiosis II and by inverted duplication.

A Maiden Report on CRELD1 Single-Nucleotide Polymorphism Association in Congenital Heart Disease Patients of Mysore, South India

Cardiac malformations contribute greatly to cardiovascular disease in the young, constituting a major portion of clinically significant birth defects. Congenital heart disease (CHD) is a common congenital cardiac birth defect, affecting nearly 1% of all live births. Although significant advances have been made in understanding mechanisms controlling heart formation, the causes of most CHD in humans remain undefined in the vast majority of cases. Of the several genes identified for CHD, CRELD1 is an important cell adhesion molecule crucial in cardiac development, which is known to cause atrioventricular septal defect in Down syndrome and also in sporadic forms of atrioventricular septal defect. With informed consent, 100 clinically diagnosed CHD patients and 50 healthy controls in Mysore, South India, were recruited for single-nucleotide polymorphism (SNP) genotyping. MassARRAY analysis of five prominent SNPs of CRELD1 was performed. The analysis revealed the occurrence of the SNP c.985 C>T of CRELD1 in two of CHD patients and not in controls. This SNP shows a change from arginine to cysteine in the second calcium-binding epidermal growth factor (EGF) domain, leading to change in the β-sheet in the secondary structure. Therefore, the SNP c.985 C>T of CRELD1 is involved in causing CHD in patients of Mysore, South India.

Missense mutation G296S in GATA4 is not responsible for cardiac septal defects.

BACKGROUND: The most common type of congenital heart disease is the cardiac septal defects, which has reported to be caused by a missense mutation (G296S) in exon 3 of the GATA4 gene. AIMS: The present study was undertaken to find out whether GATA4 gene is the prime cause of the septal defects in Mysore population. MATERIALS AND METHODS: GATA4 gene analyses were undertaken on 21 confirmed CHD cases by PCR and DNA sequencing. RESULTS AND CONCLUSION: Analysis of this particular mutation in 21 septal defect patients revealed that none of the patients had the mutation, indicating that this mutation is population specific or septal defect in Mysore population is caused due to mutations in other regions of the GATA4 gene.

GATA4 Specific Nonsynonymous Single-Nucleotide Polymorphisms in Congenital Heart Disease Patients of Mysore, India

Congenital heart disease (CHD) is the most common type of birth defect, affecting 1% of all live births. The recent exponential increase in the knowledge of medical genetics has revolutionized the understanding of CHDs during the past few decades. GATA4, a transcription factor, is involved in heart development. There are many contradictory reports on involvement of single-nucleotide polymorphisms (SNPs) of GATA4 in the manifestation of CHD. In view of this, an attempt has been made to analyze the known SNPs of GATA4 in Mysore patients with CHD. Of the 308 CHD patients recruited, 100 were screened for SNPs of GATA4 by MassARRAY, which identified 11 SNPs, of which 6 were found in both CHD cases and controls. The other 5 SNPs, c.278G>C (G93A), c.1207C>A (L403M), c.1232C>T (A411V), c.1295T>C (L432S), and c.1180C>G (P394A), were found only in CHD patients. Secondary structure analysis revealed that mutant proteins with the SNPs G93A, L403M, and L432S showed structural changes in their helix, sheet, and turn. Thus, these findings suggest the involvement of specific SNPs of GATA4 in the manifestation of CHD, reported for the first time in an Indian scenario. However, screening for a larger number of CHD patients would help us to establish genotype-phenotype correlation.

Chromosomal Anomalies and Congenital Heart Disease in Mysore, South India

Abstract Congenital heart disease (CHD) is the most common form of human birth defects accounting for about 30% of the total anomalies. The prevalence of CHD worldwide is found to range between 1.0 – 150/ 1000 live births. The causes for CHD can be categorized into three major groups such as, chromosomal (0.4 - 26.8%), single gene disorders (10-15%) and multiple factors (85-90%). Here we report the association of chromosomal variations with CHD in Mysore. A total of 192 confirmed CHD cases were considered for the present study whose age ranged from 1 day to 23 years. After written consent was obtained from the family members, 136 CHD patients were subjected for conventional cytogenetic studies and some of them for FISH analysis. Of these, 18 patients were with numerical abnormalities, 3 patients with structural abnormalities, one patient with both numerical and structural abnormalities and remaining 114 patients with normal chromosomes. Thus, the present findings are the maiden report from Mysore, which have contributed richly towards the association of chromosomal anomalies with CHD and pointing out chromosome 9 a possible killer chromosome for the cause of CHD.

Advanced Maternal Grandmother Age is a Risk Factor in Causing Sex Chromosomal Aneuploidy

Abstract Majority of the chromosomal abnormalities are incompatible with embryonic or fetal survival but trisomy 21 and sex chromosomal trisomies have a much higher viability surviving to term. In India, increased numbers of children with sex chromosomal aneuploidy are born to young mothers. Therefore, detailed analysis of the families with sex chromosomal aneuploidy is needed to find out the possible causative factors for nondisjunction. Twenty five families of suspected sex chromosomal aneuploidy children were investigated for cytogenetic analysis and pedigrees were constructed for these families. As controls 100 randomly selected families belonging to different religions were used. Of the 25 sex chromosomal aneuploidy cases studied, 16 were Turners with 45, XO chromosomes and 9 were Klinefelters with 47, XXY chromosomes. The number of sex chromosomal aneuploidy births was greater for the young mothers than the advanced age mothers. The logistic regression of case-control study of sex chromosomal aneuploidy children revealed that the odds ratio for the age of maternal grandmother was significant when all the four variables were used once at a time. However, the effect of age of mother and father was smaller than the effect of age of maternal grandmother. For every year of advancement of age of the maternal grandmother, the risk (odds) of births of sex chromosomal aneuploidy children increases by 36%. Therefore, the age of the maternal grandmother at the time of birth of mother is a risk factor for the occurrence of sex chromosomal aneuploidy.