Population-based trends in the prenatal diagnosis of sex chromosome aneuploidy before and after non-invasive prenatal testing.

OBJECTIVE: To assess the impact of non-invasive prenatal testing (NIPT) on trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) in a population with >73,000 annual births. METHOD: Retrospective population-based cohort study from 1986-2016 of all women undergoing prenatal diagnosis before 25 weeks gestation in the Australian state of Victoria. Statistical significance was tested using the chi-square test for trend or proportions. RESULTS: There were 2,043,345 births and 842 SCA diagnoses from 1986-2016. The percentage of prenatal diagnostic tests leading to a SCA diagnosis increased significantly from 0.95% in 2010 to 2.93% in 2016 (p < 0.001) but due to a concurrent decline in testing, the annual prenatal diagnosis rate of SCA remained stable at 4.4/10,000 births. Among confirmed fetal SCAs the most common indication for testing in 1986 was advanced maternal age (63%); in 2016 it was high risk NIPT (49%). CONCLUSION: SCAs now make up an increasing proportion of prenatal diagnostic results but due to the overall decline in diagnostic testing, the prenatal prevalence as a percentage of births remained steady. The ascertainment of fetal SCA has evolved from an incidental finding after testing for increased risk of trisomy 21, to a diagnosis obtained after suspected SCA on NIPT.

Autism Spectrum Disorder in Males with Sex Chromosome Aneuploidy: XXY/Klinefelter Syndrome, XYY, and XXYY.

OBJECTIVE: Neurodevelopmental concerns in males with sex chromosome aneuploidy (SCA) (XXY/Klinefelter syndrome, XYY, XXYY) include symptoms seen in autism spectrum disorder (ASD), such as language impairments and social difficulties. We aimed to: (1) evaluate ASD characteristics in research cohorts of SCA males under DSM-IV compared to DSM-5 criteria, and (2) analyze factors associated with ASD diagnoses in SCA. METHODS: Evaluation of participants with XXY/KS (n=20), XYY (n=57) and XXYY (n=21) included medical history, cognitive/adaptive testing, Social Communication Questionnaire, Social Responsiveness Scale, Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, and DSM ASD criteria. Clinical impressions of ASD diagnostic category using the ADOS and DSM-IV criteria were compared to ADOS-2 and DSM-5 criteria. T-tests compared cognitive, adaptive, SES and prenatal vs. postnatal diagnoses between ASD and no ASD groups. RESULTS: ASD rates in these research cohorts were 10% in XXY/KS, 38% in XYY, and 52% in XXYY using ADOS-2/DSM-5, and were not statistically different compared to DSM-IV criteria. In XYY and XXYY, the ASD group had lower verbal IQ and adaptive functioning compared to those without ASD. Many children without ASD still showed some social difficulties. CONCLUSION: ASD rates in males with SCA are higher than reported for the general population. Males with Y chromosome aneuploidy (XYY and XXYY) were 4.8 times more likely to have a diagnosis of ASD than the XXY/KS group, and 20 times more likely than males in the general population (1 in 42 males, CDC 2010). ASD should be considered when evaluating social difficulties in SCA. Studies of SCA and Y-chromosome genes may provide insight into male predominance in idiopathic ASD.

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.

Chromosomal abnormalities in patients with oligozoospermia and non-obstructive azoospermia.

PURPOSE: To assess the frequency and types of chromosomal abnormalities in 204 Ukrainian patients with non-obstructive azoospermia and oligozoospermia and 87 men with normozoospermia. METHODS: Cytogenetic studies were performed on peripheral blood lymphocyte samples of 164 men with oligozoospermia, 40 men with non-obstructive azoospermia and 87 men with normozoospermia attending infertility clinic. RESULTS: Chromosomal abnormalities were detected in 17% of patients with sperm disorders: in 35% of men with azoospermia and in 12.7% of men with oligozoospermia. The frequency of chromosomal abnormalities in patients with sperm disorders was significantly higher, than in patients with normozoospermia (P = 0.0001). An increase in the incidence of chromosomal abnormalities with the decrease of sperm count was observed. Chromosomal abnormalities were detected in 1.1% of patients with normozoospermia, 6.5% of patients with mild oligozoospermia (sperm count 5-15 × 10(6)/ml), 18.4% of patients with severe oligozoospermia (sperm count <5 × 10(6)/ml) and 35% of patients with azoospermia. A significant increase in the frequency of chromosomal abnormalities in patients with severe oligozoospermia was observed when compared to mild oligozoospermia (P = 0.01). A statistically significant association (P = 0.02) of chromosomal abnormalities and sex chromosome abnormalities (P = 0.0001) with azoospermia when compared to oligozoospermia was observed. CONCLUSIONS: Our results highlight the importance of cytogenetic studies in patients with oligozoospermia (both mild and severe) and non-obstructive azoospermia. The presence of chromosomal abnormalities influences significantly the fertility treatment protocols, as well as provides a definite diagnosis to couples suffering from infertility.

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.

El diagnóstico citogenético prenatal aquí y ahora. Validez actual y futura del cariotipo / The cytogenetic prenatal diagnosis nowadays. Present and future value of karyotype

El cariotipo convencional obtenido mediante las técnicasde bandas es considerado como el gold standard deldiagnóstico prenatal citogenético; nos da la información detodos los cromosomas, es decir de todo el genoma, con un nivelde resolución limitado pero aceptable. Está incorporado en lapráctica asistencial de la mayoría de hospitales de tercer nivelde nuestro país, así como en centros sanitarios y laboratoriosprivados. En buena parte de ellos se aplican además otrastécnicas complementarias de citogenética molecular paracompletar algún diagnóstico concreto.Durante estos últimos años se han ido desarrollando técnicasmoleculares que permiten superar determinados inconvenientesdel cultivo celular y análisis citogenético, como laduración del cultivo (Quantitative Fluorescent PolymeraseChain Reaction [QF-PCR]) o el limitado poder de resolución delos cromosomas bandeados (técnicas de Array Genomic Hybridization[AGH]). Sin embargo, estas técnicas también tienensus desventajas con respecto al cariotipo: resultados parciales,coste económico elevado, falta de información de las reorganizacionescromosómicas (fundamental para el consejo genéticode la gestante y su familia), y problemas de interpretaciónde los resultados debido a la existencia de Copy Number Variants(CNV) polimórficas o benignas, con el agravante de contarsolamente con el examen ecográfico del «paciente».A corto plazo, por su relación coste-beneficio, el futurodel cariotipo como técnica básica de diagnóstico prenatalcitogenético parece asegurado. El empleo de técnicas complementariasmoleculares o citogenético-moleculares, paracompletar los análisis en los casos que lo requieran, va a sercada vez más necesario...(AU)

The conventional karyotype, obtained using bandingtechniques, is considered the «gold standard» in prenatal cytogeneticdiagnosis: it gives genome-wide information (from allthe chromosomes), with limited but acceptable resolution.Most of the great public hospitals of our country, as well asmany private sanitary centres and laboratories, offer conventionalkaryotype as routine prenatal diagnosis, and in most ofthem, complementary molecular-cytogenetic techniques arealso available for application in special cases.New molecular techniques have been developed duringthe last years, which overcome certain drawbacks of cellculture and cytogenetic analysis, such as the duration of theculture (Quantitative Fluorescent Polymerase Chain Reaction[QF-PCR]) or the limited resolution of the banded chromosomes(Array Genomic Hybridization [AGH] techniques).However, these techniques also have disadvantages with respectto the karyotype: partial results, high costs, lack of informationabout chromosome rearrangements (essential forthe genetic counselling to the pregnant woman and herfamily), and interpretation problems of results due to theexistence of benign Copy Number Variants (CNV) and difficultiesto correlate the findings with the fetal phenotype,only visible through echography.In the near future, the karyotype will remain as the basictool in cytogenetic prenatal diagnosis, due to its costbenefitrelation. The use of complementary molecular ormolecular-cytogenetic techniques in special cases will becomemore and more frequent.In the distant future, with the rising technological advances,the karyotype will probably become the complementary technique, but it will be also necessary in most casesfor validation (Fluorescence in Situ Hybridization [FISH])and, above all, as an essential tool for genetic counselling(AU)

Estudio de incidencia de trisomía 21 en Gran Canaria / Incidence of trisomy 21 in Gran Canaria (Spain)

Objetivos: Conocer la incidencia de la trisomía 21 en nuestra población y la tasa de detección prenatal con el actual método de cribado poblacional. Material y método: Estudio observacional, longitudinal, retrospectivo, entre el 1 de enero de 1995 y el 31 de diciembre de 2002. Resultados: La incidencia global de la trisomía 21 en nuestro medio es de 2,09 cada 1.000 recién nacidos. Uno de cada 3 casos de trisomía 21 se diagnostica en mujeres no añosas. La tasa de detección de la edad materna en nuestro medio es del 45,66 por ciento. El 58,18 por ciento de los diagnósticos posnatales de síndrome de Down se realizaron en gestantes menores de 35 años, en quienes sólo se diagnosticó prenatalmente el 13,51 por ciento de las trisomías 21. Conclusiones: El cribado poblacional de la trisomía 21 en nuestro medio es insuficiente. Proponemos un cribado secuencial, que combina la edad materna y la translucencia nucal con cribado bioquímico entre las semanas 11 y 14 (AU)

XYY chromosome anomaly and schizophrenia.

Sex chromosome anomalies have been associated with psychoses, and most of the evidence is linked to the presence of an additional X chromosome. We report a patient with XYY chromosome anomaly who developed schizophrenia.

47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.

Cytogenetic surveys of neonates have found that approximately one boy in 500 is born with an extra sex chromosome. Some of these boys are now being diagnosed when prenatal karyotyping is done for the detection of Down syndrome and other major aneuploidies. This study estimates what proportion of those not detected prenatally will be diagnosed postnatally and what the indications for karyotyping are likely to be. We ascertained all 47,XXY and 47,XYY males detected prenatally and postnatally (during the 4 years 1990-1993) in the three cytogenetic laboratories in the North Thames (West) region. The age at diagnosis and indication for karyotyping were noted for cases diagnosed postnatally. Less than 10 per cent of the estimated number of affected fetuses were detected prenatally. This study suggests that most males born with these chromosome patterns will go through life without being karyotyped, that the commonest indication for a 47,XYY male to be karyotyped will be developmental delay and/or behaviour problems, and that the commonest indication for a Klinefelter male to be karyotyped will be hypogonadism and/or infertility. It would appear that most undiagnosed 47,XXY and 47,XYY males do not look or behave in a manner which prompts testing for a chromosome abnormality.

The frequency of XYY and XXY men among criminal offenders.

Among 1,040 consecutive male criminals remitted for mental examination nine had the karyotype 47,XYY, one 48,XXYY and eleven 47,XXY. The types of crime in the XYY men were much like those in the XXY men, the proportion of sexual crimes possibly being greater than among other criminal offenders. The reasons for these findings are discussed.

[Incidence of 47,XXY and 47,XYY karyotypes among the mentally ill who have committed antisocial acts]. / Rasprostranennost' kariotipov 47,XXY i 47,XYY sredi psikhicheski bol'nykh, sovershivshikh obshchestvenno opasnye deistviia.

A cytogenetic screening of 1868 mentally diseases criminals is performed. 5 man with abnormal karyotypes were found: 2 with the chromosome set 47,XXY; 1--with mosaicism 46,XY/47,XXY and 2--with karyotype 47,XYY. Total frequency of chromosome abnormalities was found to be 0.27% (XXY karyotype--0.16%, XYY--0.11%). Among tall mentally diseased criminals the frequency of XXY set was found to be 0.94%, and of XYY--1.89%. So among tall mentally diseased criminals the frequency of these abnormalities is higher. The frequency of karyotype abnormalities among mentally diseased criminals was not found to be higher than in total population.

Frequency of XYY males in Wisconsin state correctional institutions.

Karotyping of 3011 males at five Wisconsin state correctional institutions revealed that 1% had a chromosome abnormality. The frequency of occurrence of the XYY complement was about 5 times that for newborn males. Approximately the same rate was found among 2556 males in the three penal institutions for adults. The frequency of XYY at the institution for juvenile offenders was about ten times background. The relatively low frequency of XYY (0.38%) found at the mental-penal institution may have been due to previous sampling done there. Of the 16 XYY males discovered, only two were below the 85th percentile for height. A relatively low frequency of XYY was found among black males. Our data contradict the notion that a high rate of XYY among adult males in penal settings may be due to a disproportionately large number of tall men in prisons.

Chromosome survey of newborn infants in Tokyo: follow-up study for XYY.

In order to ascertain the frequency of chromosome aberrations among newborn infants in Japan, a chromosome survey of a large number of newborn infants is in progress. A series of 10,270 consecutive newborn babies, 5,341 male and 4,929 female, have been screened for clinical manifestations of autosomal aberrations and for sex-chromatin and sex-chromosome aberrations. Chromosome studies were carried out on 185 infants with suspected chromosome aberrations. Of these, 23 had abnormal karyotypes, including 2 males with a 47,XXY complement, 1 female with 45,X complement, 3 males with a 47,XYY complement, 2 with trisomy 13 syndrome, 3 with trisomy 18 (including one mosaicism), 10 with Down syndrome (including 1 mosaicism), 1 with B5p partial trisomy, and 1 with Y-D translocation. Developmental studies of four XYY children and one 45,X girl are in progress.

Incidence of 47,XYY karyotype in a consecutive series of newborn males in Tokyo.

A series of 3545 newborn males, born consecutively at a maternity hospital in the western suburbs of Tokyo and with no detectable physical abnormalities, were studied for fluorescent Y-chromatin. Buccal cell smears from each infant were screened. Cases with ambiguous results were subjected to a second test by blood smears, which were found to be more reliable. After the second test, chromosomal analysis was carried out in five infants: three had a 47,XYY karyotype; one, the karyotype 46,XY-D,t(D:Y) (Iijima et al., in preparation); and one, a normal male karyotype. The XYY karyotype occurred in 0.11% of newborn males in this series.

The XYY genotype.

The epidemiological data pertaining to the XYY genotype suggest that there is a three- to fourfold overrepresentation of XYY individuals in mental and penal settings and a twentyfold overrepresentation of mental-penal (special security) settings. The reasons behind the risk for behavioral disability are not known at this time. Tallness and ondulocystic acne are reported frequently to be associated with the genotype. Since much of the available information about the XYY sex chromosome complement is biased, more data is required before definitive statements can be made about the personality characteristics or intelligence of the vast majority of XYY men not appearing in social settings oriented towards behavioral deviancy.