Jon Stene

Paternal age effect in Down's syndrome.

Increasing incidence of Downs syndrome with advancing paternal age for given maternal age has been demonstrated. Comparisons are made between an almost complete Downs syndrome sample from the Copenhagen Metropolitan Area and a randomly selected sample of births from the same area and the same time period. Men above 55 years have a significantly increased risk of getting children with Downs syndrome.

Incidence study of Down's syndrome in Copenhagen, 1960-1971; with chromosome investigation.

The aim of the study was to obtain incidence figures for Downs syndrome throughout a period where a considerable change in the age distribution of child-bearing mothers has taken place and to study if the expected fall in incidence has occurred. In parts of the Copenhagen Metropolitan area 235 liveborn patients with Downs syndrome were ascertained in the period 1960 to 1971 in a population of 1-2 million with a total of 204771 births. All patients available were examined cytogenetically (75%). In 160 (90-4%) a regular trisomy 21 was observed. In 6-2% of the cases translocations and in 2-3% of the cases mosaics were found. Two double trisomies and a double trisomy mosaic were observed. Throughout the period 1960-71 the percentage of women over 30 years delivering children decreased from 23-4% in the beginning of the period to 16-2% at the end of the period. In the first part of the period 52-6% of the cases were born to mothers over 30, at the end of the period 40% of Downs syndrome mothers were of that age. However, the incidence was unchanged throughout the whole period, about 1-15 per 1000 births. For some age groups a steady rise in incidence of trisomy 21 cases was found throughout the whole period. These findings may be explained by better ascertainment of patients at the end of the period; however, environmental factors may also play a role.

Paternal age and Down's syndrome data from prenatal diagnoses (DFG)

SummaryFrom prenatal diagnosis data obtained on mothers aged 35 years and above in the Federal Republic of Germany (DFG data), older fathers are demonstrated to have an increased risk of having trisomy 21 offspring. For paternal ages of 41 years upward, the age effect is quite strong. The risk for a fetus to have any de novo chromosomal aberration increases more with advancing paternal age for older mothers than for younger ones. Thus the ages of both parents have to be taken into account as an indication for prenatal diagnosis. Risk figures for trisomy 21 and for any de novo chromosomal aberration are given, together with preliminary recommendations for prenatal diagnosis for different combinations of parental ages.

Experiences with risk estimates for carriers of chromosomal reciprocal translocations

Midro AT, Stengel‐Rutkowski S, Stene J. Experiences with risk estimates for carriers of chromosomal reciprocal translocations. Clin Genet 1992:41: 113–122.

Familial Wolf's syndrome with a hidden 4p deletion by translocation of an 8p segment. Unbalanced inheritance from a maternal translocation (4;8)(p15.3;p22). Case report, review and risk estimates

This is the case report of a patient with Wolfs syndrome having a monosomy 4pter→p15.3 and an additional trisomy 8pter→p22, derived from a maternal balanced translocation t(4;8)(p15.3;p22) after 2:2 disjunction and adjacent‐1 segregation. The patients phenotype is presumably slightly modified by the trisomic 8p segment. Literature analyses indicate that phenotypic “hybrids” with traits of monosomy 4p and of other autosomal segment trisomies exist.

Detection of Higher Recurrence Risk for Age-Dependent Chromosome Abnormalities with an Application to Trisomy G1 (Down’s Syndrome)

In order to detect a higher recurrence risk for age-dependent chromosome abnormalities, four different types of material are considered. The diiferent types are characterized by their amount of inform

Genetic risks for familial reciprocal translocations with special emphasis on those leading to 9p, 10p and 12p trisomies

An analysis of genetic risks for reciprocal translocations is given. Data from translocation families, ascertained through unbalanced offspring with trisomy 9p, 10p and 12p, were taken from the literature. The translocations were specified according to (1) the type of trisomy, (2) the degree of resulting chromosomal imbalance (partial short arm trisomies, complete short arm trisomies, complete short arm trisomies including long arm segments) and (3) the type of disjunction (2:2 or 3:1) and segregation (adjacent‐1, adjacent‐2; tertiary trisomy, interchange trisomy). The risks for unbalanced liveborn offspring were high for translocations leading to partial short arm trisomies through 2:2 disjunction and adjacent‐1 segregation (25–29%). They were lower for translocations leading to complete short arm trisomies through the same disjunction/segregation mechanism (5–17 %). Low risks were obtained for translocations, leading through 3:1 disjunction to unbalanced offspring (about 2 %). For 2:2 disjunction and adjacent‐2 segregation and for 3:1 disjunction the risk is significantly lower for male than for female carriers. ‐ The frequency of balanced karyotypes compared with normal karyotypes deviated among the phenotypically normal offspring of parental carriers from the theoretical 1:1 ratio, both for translocations ascertained through trisomy 12p and trisomy 10p.– It was demonstrated that the genetic risk for reciprocal translocations depends exclusively on (1) the degree of possibly resulting genetic imbalance and (2) the probability of the disjunction/segregation mechanism leading to this type of imbalance. Both factors can be predicted from position of breakpoints. – The precision of breakpoint localizations and its impact on the risk estimation are also considered. — Finally, general rules for genetic counselling of families with reciprocal translocations are indicated.

Statistical methods for detecting a moderate paternal age effect on incidence of disorder when a maternal one is present

A statistical method is developed for detecting a moderate effect on the incidence of a disorder caused by advancing age of one parent when it is known that advancing age of the other parent is of great aetiological importance. The method is a conditional test procedure given the parental ages, therefore no assumptions about the parental age distributions have to be made. The method is applied on Danish material on Downs syndrome, for which a paternal age effect is demonstrated. Methods used in some well-known previous investigations have been discussed. Several of them, e.g. the classical one of Penrose (1933), could hardly detect any paternal age effect in Downs syndrome on the available data, because these methods are heavily affected by certain fertility patterns not recognized previously.

Statistical inference on segregation ratios for D/G-translocations, when the families are ascertained in different ways

The present paper discusses the estimation of the risk rates for D/G‐transloeation carriers of having offspring which are either (1) mongols or (2) phenotypically normal D/G‐translocation carriers. The analysis is based upon 38 families, most of them taken from the literature; the others are personal communications. For all the sibships in the material only one of the parents is a carrier. The families are ascertained through mongols in different ways which may be classified according to the number of mongols through which the family is ascertained, whether they are in the same or different sibships, and whether the carrier parents are of the same or different sex. There are two levels of observations: (1) the phenotypical level and (2) the cytological level, depending on whether an individual has been investigated cytologically or not. At the phenotypical level it is possible to decide if a person is a mongol or phenotypically normal. At the cytological level it is possible to decide if a person is a D/G‐translocation mongol, phenotypically normal D/G‐translocation carrier or karyotypically normal. Several persons in the families have died or are unavailable for cytological investigations, and the medical diagnosis concerning mongolism has been improved during the last decades.

Genetic counselling in Down's syndrome.

Reliable risk figures are available for regular trisomy G cases and the more common translocation types. In trisomic Down’s syndrome risk figures depend on maternal age. In the maternal age group belo