Dataset Information

Are paternal or grandmaternal age associated with higher probability of trisomy 21 in offspring? A population-based, matched case-control study, 1995-2015.

ABSTRACT:

Background

Fetal aneuploidy risk increases with maternal age, but the majority of pregnancies complicated by trisomy 21 occur in younger women. It has been suggested that grandmaternal and/or paternal age may also play a role.

Objectives

To assess the association between grandmaternal and paternal age and trisomy 21.

Methods

For the grandmaternal assessments, we included all offspring with trisomy 21 in a statewide birth defects surveillance system (1995-2015) that could be linked to 3-generation matrilineal pedigrees in the Utah Population Database. Ten sex/birth year-matched controls were selected for each case (770 cases and 7700 controls). For the paternal assessments, our cohort included all trisomy 21 cases (1995-2015) where both the mother and father resided in Utah at the time of birth (1409 cases and 14 090 controls). Ages were categorised by 5-year intervals (reference: 25-29 years). Conditional logistic regression, adjusting for potential confounding factors, was used to model the association between grandmaternal and paternal age and trisomy 21.

Results

No association between grandmaternal age and trisomy 21 was detected, whether age was assessed continuously (adjusted odds ratio [OR] 1.01, 95% confidence interval [CI] 0.98, 1.03) or categorically after adjusting for grandmaternal and grandpaternal race/ethnicity and grandpaternal age. Compared to fathers aged 20-29 years, fathers <20 years (OR 3.15, 95% CI 1.99, 4.98) and 20-24 years (OR 1.39, 95% CI 1.11, 1.73) had increased odds of trisomy 21 offspring, after adjusting for maternal and paternal race/ethnicity and maternal age. Results were consistent after excluding stillbirths, multiples, and trisomy 21 due to translocation or mosaicism.

Conclusions

Maternal age is an important risk factor for trisomy 21 offspring; however, this population-based study shows that that young paternal age is also associated with trisomy 21, after taking into account maternal age and race/ethnicity.

SUBMITTER: Schliep KC

PROVIDER: S-EPMC8058293 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Trisomy of chromosome 21 (T21; Down syndrome, DS) is the most common aneuploidy in live births. Though its etiology has been intensively studied for a half of century, there are surprisingly many problems awaiting their elucidation. Some of the open questions are related directly to germ line mosaicism for T21, other problems include the prevalence of males with non-mosaic trisomy over females (skewed sex ratio, SR), the genetic predisposition to non-disjunction, etc. Studies in families of gonadal mosaicism (GM) carriers might help resolving some of these problems.80 families of carriers of GM, in which the sex of the offspring had been specified, were identified in the literature and in logbooks of two local genetic units. Mothers in these families were relatively young: only 8% of mothers were 35 years old and older at the time of delivery of their first affected offspring while the proportion of grandmothers on the GM carrier's side aged 35 years old and older was significantly higher (39%). Postzygotic rescue of T21 due to error in the meiosis I had been proposed as a mechanism of parental GM formation in 78% of the families with known origin of the T21. For the other 22%, rescue of errors in the meiosis II or postzygotic mitotic non-disjunction was assumed. Mosaicism for T21 in successive generations was reported in at least 12 families. The proportion of mosaics among affected female offspring (14%) is significantly higher compared to that among affected male offspring (0%). Male preponderance (SR = 1.5) is found in non mosaic liveborn offspring with either maternally- or paternally transmitted T21. Among unaffected offspring of male carriers of GM there is a notable excess of females (SR = 0.27).Both direct (results of cytogenetic and molecular study of the origin of trisomic line) and indirect (advanced grandmaternal age on the side of GM carrier) evidences allow to assume that significant proportion of the mosaic parents had been conceived as trisomics. Female-specific trisomy rescue and genetic predisposition to postzygotic non-disjunction has been suggested as mechanisms of formation of both GM and somatic mosaicism. Typical male preponderance in affected non mosaic offspring with either maternally- or paternally transmitted trisomy 21, indicates than meiotic events are not responsible for the skewed sex ratio in DS. However a female excess among unaffected offspring of male carriers of GM might be the result of meiotic non homologous co-orientation of chromosomes 21 and X in spermatogenesis.