Trisomy 21 Nondisjunction (T21NDJ)

The overall goal of the project is to identify genetic risk factors associated with chromosome 21 nondisjunction in the oocyte. The dataset derives from multi-site collection of live birth probands with Down syndrome due to standard trisomy 21 (T21) and their biological parents. The type of nondisjunction error (NDJ)(maternal or paternal) in all cases has been determined to be maternal in origin based on the chromosome 21 variants contributed from parent to proband. The Center of Inherited Disease with support from NICHD has conducted genome-wide genotyping using the Illuminia Human OmniExpress Plus Exome array on approximately 800 women who have been identified through their offspring with DS and have been characterized as having a maternal meiois I (MI) or meiosis II (MII) nondisjunction error. Genotypes from biological fathers of the offspring with DS can be used with the data on mothers to better define the type of nondisjunction error (MI or MII) and to refine the chromosome 21 recombination profile. We provide the type of nondisjunction error, knowing that this will be updated based on the new panel. We do not provide the recombination profile, as this can be best defined using the new comprehensive set of SNPs in the OmniExpress panel.]]>
Mother's Questionnaire for Live BirthsStudy Description: Trisomy 21 NondisjunctionWomen who have been identified through their offspring with DS as a result of a maternal MI or MI nondisjunction error. Priority was given to those women on whom we had DNA on her offspring with trisomy 21 and their biological father to form a complete trio (i.e., child with DS, mother with NDJ error, and father). If a trio was available, all self-reported race/ethnic groups were included. If only the case mother was available, only Caucasians were included.]]>
The importance of understanding the causes of NDJ and the maternal age effect cannot be over-stated. Many women are electing to bear children in their mid-thirties and beyond, the very time at which NDJ rates increase dramatically. Moreover, the clinical consequences of NDJ cannot be over-stated; again, NDJ is the leading cause of pregnancy loss and, among live births, the leading genetic cause of intellectual and developmental disabilities and birth defects. Our proposed studies will enable us to tease apart the susceptibility of human NDJ into its individual liability factors. Altered recombination is a risk factor for NDJ Absent or reduced levels of recombination, along with suboptimally placed recombinant events-- those too close to the centromere or too close to the telomere-increase the likelihood of NDJ. This has been observed in model systems and in human trisomies. Specifically for chr21, we have shown that approximately 40% of maternal MI errors result from no meiotic exchange (i.e., are achiasmate). Among maternal MI cases with a single exchange, the majority occur in the distal 6.5 Mb of chr21. Both of these patterns are independent of maternal age. By contrast, MII errors are highly associated with pericentromeric exchanges, irrespective of the number of exchanges along the chromosome. With increasing maternal age, the association with pericentromeric exchanges increases. Examination of genome-wide recombination patterns in oocytes with nondisjoined chr21 Most recently, again with the help of CIDR, we extended our previous work to further explore whether the genome-wide recombination (GWR) patterns are altered in oocytes with a nondisjoined chr21. We examined the effect leading to a correlation of the number or placement of recombinants among chromosomes within a gamete, and the effect that leads to a correlation of recombination patterns among oocytes from a single mother. These effects have been observed in normal meiotic outcomes. We used the Golden Gate linkage panel on our extended DS proband f amilies (trios, maternal grandparents and siblings) to obtain GWR profiles. Based on 94 proband families with an MI error, we found evidence for overall reduced GWR counts, irrespective of the number of chr21 recombinants and weakened recombination control in oocytes with a nondisjoined chromosome. Although we are cautious with our interpretation of the data to date, we speculate that there may be dysregulation of recombination genome-wide in the oocytes with a nondisjoined chromosome.]]>