We classified females as having X chromosome aneuploidy if they were outliers in both the cohort mean LRR distribution and the expected heterozygous BAF count distribution Supplemental Fig.
The method was validated in a series of Turner syndrome cases tested by cytogenetics see Supplemental Methods and Supplemental Fig. Hypertension and hypothyroidism were tested using logistic regression and household income was tested using ordinal logistic regression.
Variables were inverse normalized to account for skewed distributions. We detected women with whole X chromosome imbalances among the , women from the UK Biobank, with a higher dosage indicating an additional X chromosome and with a lower dosage, suggesting only one X chromosome in some or all cells Fig.
Of the suspected 45,X women there was a range of estimated dosages with mean LRRs ranging from —0. Of these women, 30 had an estimated X chromosome dosage in the lowest quintile, suggesting the majority of cells had only one X, consistent with a 45,X karyotype. No women self-reported having Turner syndrome at their baseline visit. This left 13 individuals who had had an overnight hospital stay, but Turner syndrome was not recorded in HES Supplemental Fig.
S 7 ; and three were not detected by the SNP array method because their SNP array metrics were well within the normal range. These samples were either below the limit of detection or could represent age-related loss of the X, which is not detected by our array method. This protocol modification also identified nine women with an X chromosome deletion of between 15 and 55 megabases in size Supplemental Fig. The 30 women with evidence of nonmosaic 45,X chromosome loss were on average X chromosome dosage is color coded see key for each category tested in the analysis.
Distribution of each trait in controls is shown in gray histogram for a height and b natural menopause age. For the other 14 women with nonmosaic 45,X, menarche ages between 12 and 19 years were recorded. The recruitment ages of the 30 women with nonmosaic 45,X ranged from 42 to 69 years, but only 5 reported a natural menopause age and the odds ratio OR for not reporting an age at natural menopause compared with women with 46,XX was 3. Only 4 of the 30 nonmosaic 45,X cases had ever been pregnant, much fewer than in the remaining 46,XX women with an odds ratio for never being pregnant of Heart defects are a common reported feature of Turner syndrome, but we found few cases of heart defects in 45,X women, based on self-report and ICD codes.
Blood pressure and hypertension risk were elevated e. Women with 47,XXX were 5. Women with trisomy X had normal age at menarche, but an average 5. The availability of more than , adult women with SNP array data in a population-based study enabled us to assess X chromosome aneuploidy phenotypes without the potential ascertainment biases of clinical presentation and with sufficient statistical power to quantify phenotypic effects, including adult-onset diseases. Previous studies have either concentrated on clinically ascertained women, or prenatally ascertained cases numbering in the tens and not followed up into adulthood.
While these studies have provided fundamental clinical descriptions of Turner and XXX syndrome, they have not focused on the penetrance of the genetic anomalies in the general population throughout the life course. This is nearly four times lower than the prevalence we detected in UK Biobank, suggesting that many cases go undiagnosed.
This difference is likely to be due in part to the UK Biobank favoring healthy individuals, but also we may have classified some 45,X cases as mosaic. We observed an association with IQ-related measures in women with 47,XXX, and it is known that individuals with lower IQ were less likely to participate in the study. The most important implication of our data is that many women with a 45,X cell line likely do not require currently recommended interventions.
S 3ah. This group of women went through menarche and menopause at an average age, had an average number of children, were not at increased risk of pregnancy loss, and there was no evidence of increased risk of cardiac complications. Currently any women identified as having a 45,X cell line not thought to be due to age-related loss, would be diagnosed as having Turner syndrome and would be offered extensive monitoring, particularly during pregnancy.
In young women, one of the main concerns will be the likelihood of infertility associated with a diagnosis of Turner syndrome. Women with 45,X had a phenotype that was characteristic of that reported for this chromosomal abnormality, i.
There were no data available on physical characteristics, such as neck webbing, which is a common physical feature in Turner syndrome. These findings are important because they suggest that ascertainment bias has not dramatically influenced the current consensus regarding the 47,XXX phenotype. Traditionally 47,XXX syndrome has been identified by cytogenetic testing, which is costly, labor intensive, and requires fresh tissue to culture dividing cells.
Thus the majority of studies on 47,XXX have been on women tested for a clinical presentation such as learning difficulties, or identified through prenatal testing as an incidental finding. Cohorts of older women with 47,XXX are therefore uncommon.
This effect appears to be limited to the end of reproductive life however, as these women had average menarche age, but went through menopause on average more than 5 years earlier than women with 46,XX, with 10 women meeting the criteria for POI, with menopause before 40 years. We found no evidence for an impact of 47,XXX on reproductive function throughout life, as these women had an average number of pregnancies and no significant increase in pregnancy loss.
Adult height is associated with puberty timing, with earlier puberty resulting in shorter adult height. The 47,XXX effect on adult height is however unlikely to be driven by later puberty timing, as menarche age was not significantly different from the 46,XX women.
It is more likely that the increase in height is caused by dosage-sensitive genes responsible for postpubertal growth. The IQ of girls with 47,XXX is reported to be within the normal range, but approximately 10—15 points below their sibling average.
Lower IQ is also reported in adult cases of 47,XXX, along with psychosocial features, such as low self-esteem, language difficulties, and increased prevalence of psychiatric disorders. We observed an increase in BMI in women with 47,XXX, that is not reported as a typical feature of this chromosome abnormality, and may be related to the observed lower IQ. There was also a reduction in household income in women with 47,XXX.
The association with lower household income was not a consequence of general lower socioeconomic status because Townsend deprivation index was not significantly associated with 47,XXX status. Ability to work and type of employment taken by younger women with 47,XXX has been reported in other studies, but with much smaller sample sizes.
Thus the reduced IQ observed in adolescents with 47,XXX continues into older age and appear to have a lifelong effect on income. The samples tested in this study were from peripheral blood and may not reflect the level present in brain, ovary, or heart, for example.
Nonaneuploid causes of Turner syndrome were not included in our analyses, although we detected cases of apparent isoXq, and X chromosome deletions, but we were unable to verify these cytogenetically. Any cases with Y chromosome material were excluded as sex mismatches.
Our study is biased in favor of healthier individuals with a more benign phenotype. Cases of X chromosome aneuploidy with a severe phenotype may be underrepresented in the Biobank cohort, but our study goes a long way toward redressing the bias seen in many published series of cases ascertained through clinical referrals. While we were not able to karyotype any of the samples from UK Biobank, we did use two array platforms to test an independent series of patients with various levels of 45,X mosaicism and found close correlation between the methods.
Further validation came from finding 16 previously known Turner syndrome cases in UK Biobank among the 30 individuals who we classified as nonmosaic 45,X with the array dosage data. Three previously diagnosed cases of Turner syndrome had a normal 46,XX SNP array profile; this may be a sample mix-up, or a clinical case not confirmed by genetic testing, or a more complex genetic abnormality not detected by the array method. We are confident that the cases we have identified do not include false positives, but there may be X chromosome imbalances that we did not detect.
We have assessed X chromosome aneuploidy phenotypes into adulthood, without the ascertainment biases of clinical presentation. Triple X syndrome: a review of the literature.
Eur J Hum Genet. Article Google Scholar. However, there are some exceptions to this general finding. If you or your child have Turner Syndrome, you should consult your health care team to learn whether you are a patient with classic or mosaic type of the condition. Massachusetts General Hospital. Medical News Today. Mayo Clinic. Hi my sister is a medical mystery the medics say as although my sister had social struggles she was bright articulate and gained average qualifications in education.
Upon receiving growth hormone considered late she became very aggressive and ended up in care. Have you come across any other Turners female like this. Everyone is so puzzled with years of no answers. Kind regards Dany. Turner Syndrome Foundation. Mosaic vs. Classic Classic Turner Syndrome or non-mosaic Turner Syndrome — all cells lack one X chromosome Mosaic Turner Syndrome — cells vary in chromosomal content, with some cells having both X chromosomes and others having an incomplete amount of X chromosomes either with an absent X chromosome; with one full X chromosome and one incomplete X chromosome; or, in few cases, one full X chromosome and and one incomplete Y chromosome Impacts of the Turner Syndrome Variations The type of Turner Syndrome matters, because it can alter the impact of physiological characteristics on the individual.
Share this:. Turner Syndrome Clinic What is Turner syndrome? What is mosaic Turner syndrome? Signs of Turner syndrome and mosaic Turner syndrome Signs of Turner syndrome and Mosaic Turner syndrome can be similar: Height usually under 5 feet Droopy heavy eyelids ptosis Differences in ear shape and position Webbed neck extra skin Arms or feet that are puffy lymphedema Often, broad chest High-arched roof of the mouth Teeth that are crowded Trouble with certain types of math Learning difficulties in school Reduced fertility Delayed or absent periods Women and girls with Mosaic TS tend to have fewer signs and health problems than those with typical TS.
Did you know? Type Patient Education. Topics Women's Health. Turner Syndrome Turner syndrome is a genetic condition that affects women and girls of all ages.
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