Chromosome 21 non-disjunction and Down syndrome birth in an Indian cohort: analysis of incidence and aetiology from family linkage data.

We analysed the family linkage data obtained from short tandem repeat (STR) genotyping of 212 unrelated Indian families having a single Down syndrome (DS) baby each, in order to explore the incidence and aetiology of this human aneuploidy in our cohort. The estimated values of maternal meiotic I and meiotic II non-disjunction (NDJ) errors of chromosome 21 (Ch 21) were approximately 78 and approximately 22%, respectively. Within the paternal outcome group, about 47 and 53% were accounted for NDJ at meiosis I and meiosis II, respectively. We estimated only approximately 2% post-zygotic mitotic errors. The comparison of average age of conception between controls and DS-bearing mothers revealed a significant difference (P<0.001) with DS-bearing women were on an average older than controls and meiotic II non-disjoined mothers were oldest among meiotic outcome groups. Our linkage analysis suggested an overall reduction in recombination by more than 50% on meiotic I non-disjoined maternal Ch 21 with error prone to susceptible chiasma formation within the approximately 5.1 kbp segment near the telomeric end. We stratified meiotic I non-disjoined women in three age groups, viz. young (<or=28 years), middle (29-34 years) and old (>or=35 years) and found linear decrease in the frequency of achiasmate meiosis from the young to the old group. In contrary, a linear increase in the multiple chiasma frequency from the young to the old group was observed. Considering these results together, we propose that the risk factors for Ch 21 NDJ are of two types, one being 'maternal age-independent' and the other being 'maternal age-dependent'. Moreover, a comparison of our present Indian dataset with that of other published data of ethnically different populations suggested that the genetics that underlies the NDJ of Ch 21 is probably universal irrespective of racial difference across human populations. The present study is the first population-based report on any DS cohort from the Indian subcontinent and our work will help future workers in understanding better the aetiology of this birth defect.