Investigation of factors associated with paternal nondisjunction of chromosome 21

Abstract

Previous studies on relatively small samples of individuals with trisomy 21 caused by paternally derived errors have shown that: (1) advanced paternal age is not a risk factor for chromosome 21 nondisjunction (NDJ), (2) absence of recombination, but not the location of recombination is associated with paternal NDJ and (3) there is an excess of males among live-births with paternally derived trisomy 21. An excess of males is also observed among all individuals with trisomy 21. Using 128 families that had a child with trisomy 21 due to a paternally derived error, we examined: paternal age, recombination and the male/female sex ratio. We genotyped STRs along 21q to identify the origin of the error and the location of recombination on the paternal chromosome. Results showed that 32% of paternal meiotic errors occurred in meiosis I (MI) and 68% in meiosis II (MII). We confirmed the lack of a paternal age association with either type of error (mean paternal age for controls, MI, and MII errors: 31.3 ± 6.6, 32.2 ± 6.3, 30.6 ± 6.5, respectively). However, contrary to previous findings, we did not find altered patterns of recombination among paternal MI or MII errors. We found an increased male/female sex ratio among paternal (1.28, 95% CI: 0.68–1.91) and maternal (1.16, 95% CI: 1.02–1.33) meiotic errors. While the sex ratio among individuals with paternal errors was not statistically significant, these findings suggest that selection against female fetuses with trisomy 21 may contribute to the excess of males observed among all individuals with trisomy 21.

Meiotic non-disjunction mechanisms in human fertile males

“…In accordance with our results, other meiotic studies in fertile male donors reported G-group and sex chromosomes as the most susceptible to having no chiasmata at MI (Skakkebaek et al, 1973;Uroz et al, 2011) or no recombination foci at pachytene (Sun et al, 2006) (reviewed by Tempest, 2011). The absence of chiasmata has been correlated with an abnormal chromosome segregation in meiosis I both in trisomic 21 (Savage et al, 1998;Oliver et al, 2009) and 47,XXY conceptuses (Hassold et al, 1991;Lorda-Sanchez et al, 1992;Thomas et al, 2000). In the present work, chromosomes X, Y and 21 were the most commonly implicated in disomy in spermatocytes II, corroborating the results reported in spermatozoa from healthy men using FISH (reviewed by Templado et al, 2005Templado et al, , 2011.…”

SNaPshot Assay in Quantitative Detection of Allelic Nondisjunction in Down Syndrome

“…Although we observed increased paternal meiosis-I errors in our sample, in contrast to previous reports of increased nondisjunction in paternal meiosis-II (Savage et al, 1998;Oliver et al, 2009), it is important to note that chromosome 21, which has one chaisma, is generally more prone to nondisjunction in normal males (Soares et al, 2001).…”

Noninvasive prenatal screening at low fetal fraction: comparing whole-genome sequencing and single-nucleotide polymorphism methods

“…The expected deviation in allele frequencies caused by aneuploidies in the SNP method differs based on the parental‐ and meiotic‐stage of origin of the aneuploidy (Figure ; Supplemental Figure S7), the rates of which vary substantially: 70% of nondisjunction events occur during maternal meiosis phase I (M1), leading to fetal inheritance of both maternal chromosomes, while 20% occur during meiosis phase II (M2), causing fetal inheritance of two copies of a single maternal chromosome . The remaining nondisjunctions are paternal in origin, with 3% originating from M1, and 7% from M2 (Figure a).…”

“…Sensitivity of the SNP method at each fetal fraction was calculated by simulating 10,000 samples for each of the four types of meiotic nondisjunction and determining the proportion of trisomic samples for which the trisomy hypothesis had log‐odds ratio (LOR) below the threshold at which 99.87% of disomic samples would be called disomic (corresponding to the same specificity as the WGS test). The aggregate sensitivity of the SNP method was determined by calculating the weighted expectation of the sensitivity of detection of each fetal ploidy hypothesis multiplied by its prevalence …”