Genetic counseling dilemmas: Down syndrome, paternal age, and recurrence risk after remarriage

Abstract

The recent demonstration that about 20&30%of cases of Down syndrome are of paternal origin has again raised interest in the question of the possible contribution of paternal age independent of matcrnal age to a couple's risk of a Down syndrome live birth. In this paper the nature of the available evidence is critically reviewed, interpretations reconciling differences between studies that reached opposite conclusions are presented, and an approach t o genetic counseling in the face of such apparent differences in the literature is discussed. It is not likely that data from ad hoc studies of parental origin of the extra chromosome will be sufficient t o judge the existence or magnitude of patcrnal age-specific risk, and reliance must be made on statistical studies that searched for paternal age effects while controlling for maternal age. The literature is consistent with an apparent doubling of risk for paternal age 5 5 and ovcr, but n o effect at younger paternal ages. With regard to remarriage, it is suggested that if members of a couple with a 47, +21 child remarry it be assumed that the excess risk "travels" t o that new couple which includes the parent in whom nondisjunction occurred in the previous marriage. If parental origin is not known, it is suggested that the risk be calculated on the assumption of a 20-30% likelihood that it was of paternal origin and a 70-807& likelihood that it was of maternal origin, and that the excess ernpiric risks be apportioned accordingly in the new marriages.

Have maternal or paternal ages any impact on the prenatal incidence of genomic copy number variants associated with fetal structural anomalies?

“…Advanced paternal age has been suggested to be a risk factor for an adverse pregnancy outcome (stillbirth, preterm birth and low birthweight), for structural anomalies (encephalocele and microcephalia, cleft lip and palate, neural tube defects and cardiac defects) and for some childhood disorders (autism spectrum disorder, schizophrenia or cancer) [5][6][7][8][9][10]. Regarding chromosomal anomalies, most of de novo structural aberrations are paternal in origin, in contrast to aneuploidies that are mainly of maternal origin.…”

Origin of human trisomy 21 mosaicism

“…Hook (1980Hook ( , 1981 concluded that the then available literature suggested a doubling of risk for men over 55, but no effect for younger men. Stene,et al (198la) analyzed parental ages of 65 cases of trisomy 21 that were found among amniocenteses of women who were 35 or older.…”