Maternal Germinal Trisomy 21 in Down Syndrome

Abstract

It has now been over 50 years since it was discovered that Down syndrome is caused by an extra chromosome 21, i.e., trisomy 21. In the interim, it has become clear that in the majority of cases, the extra chromosome is inherited from the mother, and there is, in this respect, a strong maternal age effect. Numerous investigations have been devoted to clarifying the underlying mechanism, most recently suggesting that this situation is exceedingly complex, involving both biological and environmental factors. On the other hand, it has also been proposed that germinal trisomy 21 mosaicism, arising during the very early stages of maternal oogenesis with accumulation of trisomy 21 germ cells during subsequent development, may be the main predisposing factor. We present data here on the incidence of trisomy 21 mosaicism in a cohort of normal fetal ovarian samples, indicating that an accumulation of trisomy 21 germ cells does indeed take place during fetal oogenesis, i.e., from the first to the second trimester of pregnancy. We presume that this accumulation of trisomy 21 (T21) cells is caused by their delay in maturation and lagging behind the normal cells. We further presume that this trend continues during the third trimester of pregnancy and postnatally, up until ovulation, thereby explaining the maternal age effect in Down syndrome.

Effect of extended oral contraception use on the prevalence of fetal trisomy 21 in women aged at least 35 years

“…T21 oocytes appear to demonstrate slowed maturation in comparison with disomic oocytes . It is likely they could accumulate in the ovaries by escaping apoptotic elimination.…”

“…It is assumed that the accumulation of T21 cells is caused by delayed maturation that lags behind that observed in non‐T21 cells. This tendency continues during the third trimester of pregnancy and, postnatally, until ovulation; consequently, the accumulation of T21 oocytes in the ovarian reserve of women of more advance maternal age could be the background for the maternal‐age effect related to T21. Here, it is suggested that the pathological mechanism could be the same when considering other trisomies.…”

Evidence for the Oocyte Mosaicism Selection model on the origin of Patau syndrome (trisomy 13)

“…They suggested that instead of the meiotic nondisjunction of a normal disomic oocyte, the cause of T21 was an obligate—so‐called secondary—nondisjunction of T21 oocytes due to pre‐meiotic mitotic segregation errors. The number of disomic oocytes then drops faster than the small proportion of trisomic oocytes . The maternal age effect seems to be an accumulation of T21 oocytes in the ovarian reserve of older women due to the delay of these cells in maturation, which lag behind the normal cells .…”

On the Parental Origin of Trisomy 21 Downs Syndrome

“…Thus, if you stop the ovulation cycles, then the queue is halted. It has also been shown that mothers, who have had a child with T21 DS at an early age, themselves have T21 mosaicism in some of their ordinary body tissues [5].…”