Andrew D. Carothers

Heteromorphic X chromosomes in 46,XX males: Evidence for the involvement of X-Y interchange

SummaryG- and R-banded chromosome preparations from eight of twelve 46,XX males, with no evidence of mosaicism or a free Y chromosome, were distinguished in blind trials from preparations from normal 46,XX females by virtue of heteromorphism of the short arm of one X chromosome. Photographic measurements on X chromosomes and on chromosome pair 7 in cells from twelve 46,XX males, eight 46,XX females, and four 46,XY males revealed a significant increase in the size of the p arm of one X chromosome in the group of XX males, independently characterised as being heteromorphic for Xp. No such differences were observed between X chromosomes of normal males and females or between homologues of chromosome pair 7 in all groups. The heteromorphism in XX males is a consequence of an alteration in shape (banding profile) and length of the tip of the short arm of one X chromosome, and the difference in size of the two Xp arms in these 46,XXp+ males ranged from 0.4% to 22.9%. From various considerations, including the demonstration of a Y-specific DNA fragment in DNA digests from nuclei of one of three XX males tested, it is concluded that the Xp+ chromosome is a product of Xp-Yp exchange. These exchanges are assumed to originate at meiosis in the male parent and may involve an exchange of different amounts of material. The consequences of such unequal exchange are considered in terms of the inheritance of genes located on Yp and distal Xp. No obvious phenotypic difference was associated with the presence or absence of Xp+. Thus, some males diagnosed as 46,XX are mosaic for a cryptic Y-containing cell line, and there is now excellent evidence that maleness in others may be a consequence of an autosomal recessive gene. The present data imply that in around 70% of 46,XX males, maleness is a consequence of the inheritance of a paternal X-Y interchange product.

The Power to Detect Disease Associations with Mitochondrial DNA Haplogroups

Genetic variation of mitochondrial DNA (mtDNA) has been linked to a number of multifactorial diseases, but there is currently no tool available to predict the optimal size for these investigations. We used a simulation-based (Monte Carlo) permutation test to generate power curves for European mtDNA haplogroup studies, to derive a universal equation to enable power calculations for prospective studies across the globe, and to show that very large cohorts are required to reliably detect an association with complex human diseases. In some populations, geographical variation in haplogroup frequencies will prevent the reliable detection of subtle haplogroup associations with uncommon disorders.

Estimating psychiatric morbidity by logistic regression: application to post-natal depression in a community sample

The use of logistic regression to estimate the prevalence of psychiatric morbidity in community samples is illustrated here with data from a study of post-natal depression in 702 primiparous Cambridge mothers. The method is also used to validate the primary screening instrument (in this case the Edinburgh Postnatal Depression Scale--EPDS), and to estimate the effects of cofactors, such as maternal age, previous psychiatric history and social class.

Klinefelter's syndrome in Sardinia and Scotland

SummaryData on 151 non-mosaic 47,XXY males from Sardinia, previously reported by Filippi (1986), were analysed for associations with parental ages at birth, sib order and sex ratio among siblings. The results confirm those of earlier Scottishbased studies in that: (1) there was a significant increase in risk of 47,XXY livebirths at advanced parental ages; (2) maternal age, and maternal age alone, was sufficient to explain the effect; (3) there were no independent effects of paternal age or sib order once maternal age had been taken into account; (4) there was no evidence of any distortion of the sex ratio among siblings. Estimates of relative risk at different maternal ages were compatible with those from the Scottish studies, and pooled estimates are therefore derived. They suggest, for example, that the risk at maternal age 40 years is 2–3 times that at age 30 years. In 33 cases, the parental origin of the supernumerary X chromosome was determined by analysing the segregation of genetic markers. The mean parental ages of 19 ‘maternal’ cases were significantly raised above those of controls, whereas those of 14 ‘paternal’ cases were slightly, and marginally significantly, reduced. The conclusions were essentially unaffected by whether the Sardinian population, the siblings of cases or a group of 94 unrelated Sardinian males were used as controls.

Elevated maternal age‐specific rates of Down syndrome liveborn offspring of women of Mexican and Central American origin in California

Maternal age‐specific rates of Down syndrome livebirths are widely utilized in personal and policy decisions concerning provision of and election of prenatal cytogenetic diagnostic services. The only extensive reference data available are on those of primarily European ancestral origin. In the absence of definitive evidence of any ethnic, racial or environmental influence upon rates (other than those associated with age) these rate schedules have been widely applied to those of all national origins.

An aetiological study of 290 XXY males, with special reference to the role of paternal age

SummaryData on 290 non-mosaic 47,XXY males have been analysed for possible associations with parental ages at birth, season of birth, sex ratio among sibs, and twinning. Comparison with matched population controls revealed a highly significant association with parental age, which was fully explained by dependence on maternal age and maternal age alone. The maternal age effect was determined with greater precision than in an earlier study of the same material, in which siblings were used as controls, and was estimated to result in an increased risk of between 5% and 10% per annum (p.a.). The estimated independent effect of paternal age, after fitting maternal age, was marginally (but not significantly) negative, and excluded an increased risk in excess of 3% p.a. Paternal age therefore appears to have little if any independent significance in the aetiology of 47,XXY. After correcting for seasonal variations in the population birth rate and smoothing, there was a peak of XXY births in March and a trough in November. Though not statistically significant, the pattern resembled that reported in previous studies, and was similar for both younger and older mothers. The twinning rate for both the XXYs and their sibs, and the sex ratio among the latter, were close to the corresponding population values.

An aetiological study of isochromosome-X Turner's syndrome

In an attempt to resolve conflicting evidence from the literature concerning the existence of a paternal age effect in 46,X,i(Xq) Turners syndrome, we have analysed data on all known cases ascertained in the main population centres of Scotland and on others ascertained in England, using population controls matched for year of birth. There was a significant (P = 0.02) increase of 2.3 years in the mean paternal age of the Scottish cases, and a smaller and non‐significant increase in their mean maternal age. Logistic regression analysis confirmed that the primary association was with paternal, rather than maternal, age. For the English cases, however, there were small and non‐significant decreases in their mean maternal and paternal ages. The differences between the two groups were also significant, but cannot be explained by any likely source of ascertainment bias. We therefore conclude that there is no evidence for a universal paternal age effect in this condition, but that at least one mechanism of origin, occurring with variable frequency, may be associated with increased paternal age. Using data from this and earlier published studies, we estimate the incidence of individuals with a 46,X,i(Xq) cell line to be between 3.3 and 13 per 105 female livebirths.