DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study.

BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. RESULTS: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. CONCLUSIONS: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.

Current survey of early childhood intervention services in infants and young children with sex chromosome aneuploidies.

Sex chromosome aneuploidies (SCAs) are the most commonly occurring aneuploidies in children with a collective prevalence rate of 1 in 500 live births. Prior research has documented SCAs are associated with an increased risk for early expressive language and gross motor delays, learning disorders, ADHD, autism spectrum disorder, anxiety, and executive function problems. Although SCAs have been historically underdiagnosed in young children, recent advances in noninvasive prenatal testing have resulted in an increasing nationwide cohort of infants with confirmed diagnoses. Consequently, early childhood support systems must prepare for an influx of children with known risks for associated developmental delays and potential school problems. This national survey aimed to update our understanding of current early childhood intervention services for young children with SCA in the United States and to describe parent perspectives and priorities. Descriptive statistics, chi-square tests, and logistic regression models controlling for parent education revealed a majority of respondents reported receiving public early childhood intervention services with speech therapy as the most common service. There were significant differences in early childhood intervention services by timing of diagnosis (prenatal vs. postnatal), number of sex chromosomes (trisomy vs. tetra/pentasomy), and geographic location. Parents described interventions as desirable and effective yet also difficult to obtain due to issues with the SCA phenotype, lack of provider knowledge, and challenges navigating the intervention systems. Results support the need for enhanced provider training in SCAs, policy change for early childhood intervention qualification criteria for SCA conditions, and collaboration between medical and early childhood settings.

Non-Invasive Prenatal Testing for Sex Chromosome Aneuploidy in Routine Clinical Practice.

OBJECTIVES: To assess the accuracy of non-invasive prenatal testing (NIPT) for sex chromosome aneuploidy (SCA) in routine clinical practice and to review counselling and sonographic issues arising in SCA cases. METHODS: Three specialist Australian obstetric ultrasound and prenatal diagnosis practices offering NIPT after 10 weeks' gestation participated in this study. NIPT was reported for chromosomes 21, 18, 13, X, and Y. RESULTS: NIPT screening was performed in 5,267 singleton pregnancies. The odds of being affected given a positive screening result (OAPR) was lowest for SCAs, most notably for monosomy X (20%). Fewer women underwent invasive prenatal testing when counselled regarding a high risk for SCA (65.5%) compared with those who had a high risk for another aneuploidy (85%). The positive screening rate of NIPT including SCA was 2.3%, but 1.2% if only the autosomal trisomies were included in the panel. CONCLUSION: The addition of SCA testing to NIPT doubles the positive screening rate. The OAPR for SCAs (most notably for monosomy X) is reduced compared with the autosomal trisomies. Clinicians need a more extensive discussion with women prior to the inclusion of the X and Y chromosomes in the NIPT panel, given the complexity in counselling regarding further management and the additional anxiety that these abnormal results may cause. A benefit of sex chromosome analysis is an improvement in antenatal diagnosis of some disorders of sexual development.

Screening for Sex Chromosome Aneuploidy by Cell-Free DNA Testing: Patient Choice and Performance.

OBJECTIVE: To study patient choice regarding testing for sex chromosome aneuploidy (SCA) and the performance of cell-free DNA (cfDNA) screening for SCA. METHODS: Patient choice regarding screening for SCA and factors influencing this choice were evaluated in a single center. In a subsequent two-center study, cases that screened positive for SCA were analyzed to determine the positive predictive value (PPV) for each SCA. RESULTS: In all, 1,957 (61.9%) of the 3,162 patients undergoing cfDNA testing opted for SCA screening. Regression analysis demonstrated that independent predictors of a patient's decision for SCA were earlier gestational age, spontaneous conception, and cfDNA chosen as a primary method of screening. A total of 161 cases screened positive for SCA and follow-up data were available for 118 (73.3%). Forty-six of the 61 cases of 45,X were false-positive results and 15 were concordant with the fetal karyotype (PPV = 24.6%). Seventeen of the 22 cases of 47,XXX were false positive and 5 concordant (PPV = 22.7%). Eleven of the 30 cases of 47,XXY were false positive and 19 concordant (PPV = 63.3%). All 5 cases of 47,XYY were correctly identified, thus yielding a PPV of 100%. CONCLUSION: More than half of the patients undergoing cfDNA aneuploidy screening also opted for SCA testing, but they were less likely to do so in the presence of an increased risk of trisomy. SCAs involving the X chromosome had a lower PPV than those involving the Y chromosome.

[Insufficient knowledge of the relationship between sex chromosome abnormalities and psychiatric diagnoses]. / Otillräcklig kunskap om samband mellan könskromosom­­avvikelser och psykiatriska diagnoser - Viktigt att barn och unga utreds och får rätt omhändertagande.

Sex chromosome abnormalities are among the most common genetic changes. The manifestations vary and may include growth abnormalities, specific appearance features, and other endocrinological and physical disorders, but also delayed psychomotor development, learning disabilities, and psychiatric conditions including ADHD and autism spectrum disorders. Increased knowledge about the relationship between sex chromosome abnormalities, development and psychiatric conditions would enable improved care of these patients.

Pregnancy outcomes in prenatally diagnosed 47, XXX and 47, XYY syndromes: a 30-year French, retrospective, multicentre study.

OBJECTIVE: Sex chromosome aneuploidies are frequently detected fortuitously in a prenatal diagnosis. Most cases of 47, XXX and 47, XYY syndromes are diagnosed in this context, and parents are thus faced with an unexpected situation. The objective of the present study was to characterize a French cohort of prenatally diagnosed cases of 47, XXX and 47, XYY and to evaluate the termination of pregnancy (TOP) rate before and after France's implementation of multidisciplinary centres for prenatal diagnosis in 1997. METHODS: This retrospective study identified respectively 291 and 175 cases of prenatally diagnosed 47, XXX and 47, XYY between 1976 and 2012. For each case, the indication, maternal age, karyotype and outcome were recorded. RESULTS: Most diagnoses of the two conditions were fortuitous. The occurrence of 47, XXX was associated with advanced maternal age. The overall TOP rate was higher for 47, XXX (22.9%) than for 47, XYY (14.6%), although this difference was not statistically significant. However, the TOP rates fell significantly after 1997 (from 41.1% to 11.8% for 47, XXX and from 25.8% to 6.7% for 47, XYY). CONCLUSION: The TOP rates after prenatal diagnoses of 47, XXX and 47, XYY fell significantly after 1997, following France's implementation of multidisciplinary centres for prenatal diagnosis. © 2016 John Wiley & Sons, Ltd.

Genetic evaluation of severe male factor infertility in Turkey: a cross-sectional study.

OBJECTIVE: To determine the frequency, types of chromosomal abnormalities and Y chromosome microdeletions in patients with severe male factor infertility, and the association between clinical background and genetic abnormality. STUDY DESIGN: A total of 322 infertile men; 136 men with severe oligozoospermia (sperm count <5 million/ml) and 196 with nonobstructive azoospermia were studied between April 2004 and November 2006 at the Dr. Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey. Blood, semen samples, and testicular biopsies of patients were obtained. Hormonal analysis (follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels), semen analysis, karyotype analysis, and PCR screening for Y chromosome microdeletions were performed. RESULT(S): Forty-eight out of 332 (14%) infertile men had a genetic abnormality. Twenty-four (7.2%) cases with karyotype abnormality were detected. The frequencies of karyotype abnormalities were Klinefelter's syndrome 17/24 (71%), translocation 3/24 (12%), mix gonadal dysgenesis 2/24 (8%), XX male 1/24 (4%), and 46XYY 1/24 (4%). Twenty cases (6%) infertile men had only Y chromosome microdeletions. The frequencies of the deleted areas were azoospermia factor (AZF)c 42%, AZFb 25%, AZFa 21%, AZFb, c 8%, and AZFa, c 4%. Four of the cases with Y chromosome microdeletions also had a concurrent karyotype abnormality. CONCLUSION(S): All patients with nonobstructive azoospermia and severe oligozoospermia (sperm count <5 million/ml) should undergo genetic screening.

Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy.

This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000-2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71-2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46-0.64), 1.04 (95% CI 0.92-1.17) and 0.30 (95% CI 0.24-0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19-5.36 per 1000), proportion prenatally diagnosed (50-100%) and proportion of prenatally diagnosed resulting in TOPFA (13-67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors.

Residential proximity to waste sites and industrial facilities and chromosomal anomalies in offspring.

A few studies have found chromosomal anomalies in offspring associated with a maternal residence near waste sites, but did not examine the effect of living near industrial facilities, and most combined specific anomalies into heterogeneous groups. With a case-control study design, we investigated whether maternal residential proximity to hazardous waste sites or industrial facilities with chemical air emissions was associated with chromosomal anomalies in births. Maternal residences of 2099 Texas births with chromosomal anomalies and 4368 control births without documented malformations were related to boundaries of hazardous waste sites and street addresses of industrial facilities through geographic information systems. With adjustment for maternal age, race/ethnicity, and education, maternal residence within 1mile of a hazardous waste site (relative to farther away) was not associated with chromosomal anomalies in offspring except for Klinefelter variants among Hispanic births (odds ratios (OR) 7.9, 95% confidence interval (CI) 1.1-42.4). Women 35 years or older who lived within 1mile of industries with emissions of heavy metals were two times more likely (95% CI 1.1-4.1) than women living farther away to have offspring with chromosomal anomalies including trisomies 13, 18, or 21 or sex chromosome abnormalities. Among women 40 years or older, maternal residence within a mile of industries with solvent emissions was associated with chromosomal anomalies in births (OR 4.8, 95% CI 1.2-42.8). Study findings suggest some relation between residential proximity to industries with emissions of solvents or heavy metals and chromosomal anomalies in births to older mothers.

Small supernumerary marker chromosomes (sSMC) in patients with a 45,X/46,X,+mar karyotype - 17 new cases and a review of the literature.

Small supernumerary marker chromosomes (sSMC) can appear in a numerically normal 'basic karyotype', but also in a numerically abnormal one like a Turner syndrome karyotype (= sSMC(T)). Here we present 17 new cases with such a mos 45,X/46,X,+mar karyotype. Moreover we reviewed all 512 cytogenetically similar cases available from the literature and supply for the first time data on occurrence, shapes and subgroups of this rare cytogenetic entity. sSMC(T) are very rare in the common population (1:100,000) - however, they can be observed with a 45- and even 60-times higher frequency in infertile and (develop)mentally retarded patients, respectively. Even though sSMC(T) derive from one of the gonosomes in >99% of the cases, there are also exceptional reports on sSMC(T) derived from one of the autosomes. The majority of sSMC(T)(X) form ring chromosomes, while most sSMC(T)(Y) are inverted duplicated/isodicentric chromosomes. Although >500 sSMC(T) are reported, a detailed characterization of the chromosomal breakpoints is only given for a minority. Thus, more cases with detailed (molecular) cytogenetic marker chromosome characterization are needed to provide information on formation and effects of an sSMC(T).

Asociación de síndrome de Down y de Klinefelter / A case of association between Down's and Klinefelter's syndromes

El primer caso de doble aneuploidía (48,XXY,+21) fue diagnosticado por Ford, et al en 1959. Actualmente, la frecuencia de la asociación del síndrome de Down y Klinefelter se estima en 0,7 3 100.000 recién nacidos. La apariencia clínica es de fenotipo Down. La vida media de los pacientes con síndrome de Down varía dependiendo de la existencia de complicaciones asociadas; asimismo, no está descrito que la asociación de ambos síndromes implique un acortamiento del pronóstico vital de estos pacientes

The first case of double aneuploidy was reported in 1959 by Ford and associates, who examined a patient with an XXY and trisomy 21 karyotype. The incidence of combined Klinefelter's and Down's syndromes is estimated to be 0.7 per 100 000 newborns. The phenotype is invariably that of Down's syndrome, and the life expectancy of individuals with this syndrome varies depending on the existence of associated complications. There is no evidence to date that the association of the two syndromes implies a shorter life expectancy

[Results from 10 years of preimplantation-genetic diagnostics in The Netherlands]. / Resultaten van 10 jaar preimplantatiegenetische diagnostiek in Nederland.

OBJECTIVE: To report the data from couples who were referred for preimplantation-genetic diagnostics (PGD) and treatment due to a significantly increased risk of offspring with a serious genetic disorder. DESIGN: Descriptive, prospective. METHOD: Data were collected from couples that underwent PGD in the period 1993/'03 at Maastricht University Hospital. Embryos produced by means of in-vitro fertilisation (IVF) were subjected to genetic tests several days after fertilisation. Subsequently 1 or 2 unaffected embryos were transferred to the uterus. Where there was an increased risk of a male with an X-linked genetic disorder, the gender was determined using fluorescence in-situ hybridisation (FISH). This method was also used to detect structural chromosomal abnormalities. The polymerase chain reaction (PCR) method was used for mutation detection and/or marker analysis of monogenetic disorders. RESULTS: A total of 691 couples were referred for PGD. The most frequent indications were X-linked disorders (30%), in particular Fragile-X syndrome, Duchenne/Becker muscular dystrophy and haemophilia A/B. This was followed by autosomal dominant disorders (26%), such as Huntington's disease and myotonic dystrophy, and then structural chromosomal abnormalities (24%). A total of 120 women underwent 260 PGD cycles. An embryo transfer was possible in 158 of the cycles and this resulted in 45 successful pregnancies. The pregnancy rate was 17% per cycle initiated and 28% per cycle with embryo transfer. Up until december 2003 29 singletons, 8 sets of twins and 1 set of triplets were born. There were no misdiagnoses and none of the babies had congenital abnormalities. CONCLUSION: PGD was a reliable and successful method, with pregnancy rates similar to those of IVF or intracytoplasmatic sperm injection. PGD should be stated as an alternative during the preconception counselling of couples with an increased genetic risk, especially for disorders where PGD can be routinely applied, such as Huntington's disease, myotonic dystrophy, cystic fibrosis, spinal muscular atrophy, Fragile-X syndrome and structural chromosomal abnormalities.

Chromosomal abnormalities in a clinic sample of individuals with autistic disorder.

We examined data from the largest reported sample of autistic individuals who have been karyotyped with the aim of providing additional information in the search for autism disease genes. Individuals seen in the University of Iowa's Child and Adolescent Psychiatry Clinic since 1980 who had been diagnosed with autism were cross-referenced with the University of Iowa's Cytogenetics Laboratory database. We determined the number of individuals referred for cytogenetic testing and, of these, the number found to have gross cytological abnormalities. Medical records were reviewed for all cases with such abnormalities. Between 1980 and 1998, 898 subjects seen in the clinic were diagnosed with autism. Of these, 278 (30.1%) were referred for cytological studies; 25 (9.0%) of these were found to have chromosomal abnormalities. The most common chromosomal abnormalities were Fragile X, other sex chromosome anomalies, and chromosome 15 abnormalities. These data support the contribution of chromosomal abnormalities to a small but significant number of cases of autism, and highlight the involvement of chromosome 15 and the sex chromosomes.