Pranami Bhaumik

Epidemiology of Down Syndrome: New Insight Into the Multidimensional Interactions Among Genetic and Environmental Risk Factors in the Oocyte

Down syndrome birth is attributable to multiple maternal risk factors that include both genetic and environmental challenges, but there is limited understanding of the complicated interactions among these factors. In the present study, a case-control analysis of approximately 400 infants with or without suspected Down syndrome reported between 2003 and 2009 and their parents in and around Kolkata, India, was conducted. Maternal exposure to 2 environmental risk factors (smokeless chewing tobacco and oral contraceptive pills) was recorded, and families were genotyped with microsatellite markers to establish the origin of nondisjunction errors as well as recombination patterns of nondisjoined chromosome 21. With logistic regression models, the possible interactions among all of these risk factors, as well as with maternal age, were explored. Smokeless chewing tobacco was associated with significant risk for meiosis II nondisjunction and achiasmate (nonexchange) meiosis I error among young mothers. By contrast, the risk due to oral contraceptive pills was associated with older mothers. Study results suggest that the chewing tobacco risk factor operates independently of the maternal age effect, whereas contraceptive pill-related risk may interact with or exacerbate age-related risk. Moreover, both risk factors, when present together, exhibited a strong age-dependent effect.

Maternal Telomere Length and Risk of Down Syndrome: Epidemiological Impact of Smokeless Chewing Tobacco and Oral Contraceptive on Segregation of Chromosome 21

Background: We have previously demonstrated a relationship between children born with Down syndrome and maternal telomere length. Similarly, exposure to tobacco and oral contraceptives has been explored in one of our earlier studies as a risk factor for Down syndrome. Objective: In the present study, we consider the interactions among these risk factors associated with Down syndrome in a population from Kolkata, India, using analyses stratified by maternal age. Methods: We estimated the telomere length of women with children with Down syndrome by restriction enzyme/Southern blot methods. Linear regression was employed to estimate telomere shortening as an indicator of the maternal age of conception. Interactions among the various factors were analyzed by logistic regression. Result: We found an association between the use of smokeless chewing tobacco and shorter telomere length among women who experienced meiosis I nondisjunction at gametogenesis; the effect is seen across all maternal age groups. In contrast, oral contraceptive use alone did not exhibit a statistically significant association with maternal telomere length, but there was an interaction with the use of smokeless chewing tobacco in the older mothers who experienced meiotic II nondisjunction. Conclusion: Environmental/habitual factors interact with molecular components of the oocyte, which ultimately increases the risk of chromosome 21 nondisjunction and subsequently of giving birth to a child with Down syndrome.

Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect

To explore the role of CRELD1 variants on congenital heart defects, we sequenced the entire reading frame of CRELD1 in the samples from Kolkata and adjoining areas. Nearly, 400 participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD, and euploid without AVSD. A significant association was found between AVSD and three polymorphisms, namely rs9878047 (c.1049‐129T > C), rs3774207 (c.1119C > T), and rs73118372 (c.1136T > C) among the Down syndrome and euploid individuals. The polymorphism rs73118372, involves a transition (c.1136T > C) that leads to change in amino acid methionine to threonine which alters protein secondary structure as confirmed by the bioinformatics software SOPMA. In addition, two haplotypes, C‐T‐C and C‐T‐T, in the order of loci rs9878047‐rs3774207‐rs73118372 were associated with incidence of AVSD among euploid and Down syndrome, with a slightly higher odds ratio in the later group. We hypothesize that these haplotypes increase the risk of AVSD, and the susceptibility is exacerbated in DS, possibly due to the trisomy 21 genetic background. Moreover, we report for the first time on an interaction between the mutant alleles of rs3774207 and rs73118372 which could disrupt the delicate balance between different CRELD1 isoforms.

Telomere length analysis in Down syndrome birth

Human reproductive fitness depends upon telomere chemistry. Maternal age, meiotic nondisjunction error and telomere length of mother of trisomic child are someway associated. Reports exhibiting maternal inheritance of telomere length in Down syndrome child are very scanty. To investigate this, we collected peripheral blood from 170 mothers of Down syndrome child and 186 age matched mothers of euploid child with their newly born babies. Telomere length was measured by restriction digestion - southern blotting technique. Meiotic nondisjunction error was detected by STR genotyping. Subjects are classified by age (old >35 years and young ˂35 years) and by meiotic error (MI and MII). Linear regression was run to explore the age - telomere length relationship in each maternal groups. The study reveals that with age, telomere erodes in length. Old MII mothers carry the shortest (p˂0.001), control mothers have the longest telomere and MI lies in between. Babies from older mother have longer telomere (p˂0.001) moreover; telomeres are longer in Down syndrome babies than control babies (p˂0.001). To conclude, this study represents not only the relation between maternal aging and telomere length but also explore the maternal heritability of telomere length in families with Down syndrome child.

A Rare Intronic Variation of Presenilin-1 (rs201992645) is Associated withAlzheimerâÂÂs Disease and Down Syndrome Birth

Background and objective: Presenilin-1 (PSEN-1) gene is a potent candidate that relates Alzheimer’s disease (AD) to Down syndrome (DS). Genetic variation of PSEN-1 could be a risk factor that predisposes individual for both AD and DS and may contribute the common etiology of both the disorders. Methods: We sequenced exon 8 of PSEN-1 with flanking introns in 136 DS patients with their parents, 96 AD patients, 173 age-matched controls. Results were analysed in-silico to anticipate the damaging effect at molecular level. Results: A rare polymorphism rs201992645 was identified within intron 8 and in silico analysis revealed the variation as ‘potentially damaging’ at the transcript splicing level. The genotypic frequencies of mutant heterozygotes were 0.031, 0.029 and 0.029 for AD, DS and mother of DS respectively. Conclusions: We have suggested that this variation may cause AD manifestation in mothers of DS patients and is the potential marker for predisposition testing of both disorders.

COL6A1 loss of function mutation underlie atrioventricular septal defects in down syndrome patients

Materials and methods We sequenced the entire reading frame of COL6A1 in the samples from Kolkata and adjoining areas. Four hundred participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD and euploid without AVSD. DNA of Down syndrome individual with atrioventricular septal defect and Down syndrome individuals without AVSD were sequenced for the SNP analysis of COL6A1 gene.

Rare Intronic Variations in TP73 Gene Found in Patients with Alzheimer’s Disease

ABSTRACT TP73 gene encodes p73 transcription factor, crucial for neurogenesis and neuronal health maintenance. In aging brain, p73 haploinsufficiency increases deposition of tau aggregates, hallmark pathology of Alzheimer’s disease. Thus, TP73 gene can be an important candidate for studying Alzheimer’s disease susceptibility. To explore the role of nucleotide variations in regulatory region of TP73 on Alzheimer’s disease, the region encompassing exon 2 of 80 Alzheimer’s patients and 123 age-matched controls was sequenced. Prediction of functional impact of found variations were done by software like ‘SpliceAid’, ‘mutation t@sting’ and ‘RegRNA2.0’.Two rare variations rs5031052 (NG_017035.2: g.34771C>T) and rs141679680 (NG_017035.2:g.34875G>A) were found in Alzheimer’s patients in only heterozygous condition with minor allelic frequencies 0.01875 and 0.0125 respectively, significantly higher than global MAF count (p value of z test 0.04 and 0.01 respectively), but totally absent in the control group. In silico analysis reveals the importance of these variations in splicing and microRNA binding. These variations not only introduce intronic spicing enhancer motif but also modulate splicing factor recruitment. Moreover, they regulate microRNA binding by creating or destroying miRNA binding site. Thus, the researchers report, for the first time that these two rare variations may involve in manifestation of Alzheimer’s disease in our cohort.

Recent Advances in Research on Down Syndrome

Down syndrome (DS) or trisomy 21 is one of the most important genetic causes of mental retardation. Sincere and significant attempts have been made towards understanding the congenital diseases that affect DS patients. Better understanding of gene networks associated with such malformations will help to predict the complex genetic trait behind congenital disease in DS and will also provide the basis for tailored gene therapies that could begin to heal or prevent such malformation without the need to resort to invasive surgery. Further, susceptible mutation screening in women will also be helpful for both prenatal diagnosis of DS birth and assessing the risk of predisposition to Alzheimer’s disease and congenital heart disease. Stress condition and neurodegeneration are two important markers in Down syndrome patients and mtDNA variation can also be used as an important biomarker. It has been suggested that nutraceuticals which reduce reactive oxygen species (ROS) level may be used to treat trisomy 21 condition. As mitochondria play a crucial role in the regulation of free radicals, only a detail analysis will reveal the origin of phenotypic characteristics among trisomy 21 DS patients. On the other hand, several mechanisms are responsible for neurodegeneration as well as altered cognition. It includes impaired neurogenesis leading to hypocellularity in the cortex, hippocampus and cerebellum, altered dendritic morphology, altered synapses, increased inhibition and neurodegeneration. The new knowledge of the pathogenic mechanisms in DS individuals has been acquired from mouse model. These studies provide the basis for developing new drugs for clinical trials in DS individuals and to sustain the hope that some of these drugs will be useful in treating intellectual disability in DS individuals.

An intronic rare mutation in Presenilin-1 (PSEN-1) gene may be involved in the developement of Alzheimer’s disease

Background The Presenilin-1 gene (PSEN-1) encodes a protein component of gamma-secretase complex which is involved in processing of amyloid precursor protein (APP). The PSEN-1 is involved in many cardinal mechanisms in several molecular pathway which when impaired leads to the manifestation of Alzheimer’s disease (AD). The aim of the study was to investigate the role of PSEN-1 gene in the developement of AD in Indian Bengali population.