Y-chromosomal microdeletions among infertile Finnish men.

BACKGROUND: Microdeletions in the Y-chromosome are known to cause a significant proportion of azoo- and oligozoospermia in men. The reported frequency of deletions varies greatly between the studies. Probable reasons for this variation are different selection criteria and number of patients included, and possibly also methodological aspects, whereas the contribution of environmental and genetic factors is not known. The aim of this study was to determine the incidence of Y-chromosome microdeletions among infertile Finnish men. METHODS: Two hundred and one men showing azoospermia (n=68) or severe oligozoospermia (n=133) were included. Multiplex polymerase chain reaction method was used to amplify specific sequence tagged sites (STS) along the Y chromosome. RESULTS: Microdeletions were observed in 18 men (9%), of whom four were azoospermic and 14 oligozoospermic. CONCLUSIONS: The incidence of Y-deletions in the study population of infertile Finnish men falls within the range published in other countries.

[Sex-linked mental retardation]. / Geslachtsgebonden mentale retardatie.

It has long been known that among patients with mental retardation males outnumber females. This is the result of mutations in X-chromosomal genes: X-linked mental retardation. Its prevalence has been estimated as 1.8/1000 males with a carrier frequency of 2.4/1000 females. X-linked mental retardation is divided into syndromic and non-specific types. At present there are about 135 syndromic forms known of 26 of which the responsible genes and mutations have been found. 8 genes are known in which mutations have been found in non-specific X-linked mental retardation. It is estimated that about 100 genes are involved in the latter. These genes are in particular involved in the function of the central nervous system. The development of a complete genetic map of the X-chromosome and the introduction of microarray techniques will in the short term enormously enhance the elucidation of X-linked mental retardation.

Patterns of pregnancy loss, perinatal mortality, and postneonatal childhood deaths in families of girls with Rett syndrome.

Rett syndrome is a neurodevelopmental disorder that occurs predominantly in girls and results in severe physical and intellectual handicap. A popular genetic mechanism is an X-linked dominant disorder, lethal in males. A case control study design was used to investigate fetal wastage as indicated by reported miscarriage and stillbirth prevalence, and the prevalence and cause of reported neonatal and other childhood deaths. There was no disturbance in the sibling sex ratio when case and control families were compared. In the parental generation and in the proband generation miscarriages were reported in similar proportions in case and control families. The reported stillbirth rates in case families was almost double that in control families and reported perinatal loss was more common on the maternal side in case families than in control families. Stillbirths and neonatal deaths affected slightly more boys in the parental and proband generations of case families (19 of 30) than in control families (10 of 21). Childhood deaths also occurred a little more commonly in Rett syndrome families. Sudden infant death syndrome was reported in three siblings of Rett syndrome probands but in no control siblings. Confirmation of this pattern of perinatal loss and infant mortality could indicate an alternative expression of the Rett syndrome gene.

Low rates of pregnancy termination for prenatally diagnosed Klinefelter syndrome and other sex chromosome polysomies.

Over the past 9 years we counseled 55 couples whose unborn child was found to carry a sex chromosome polysomy. We performed a survey of postcounseling parental decisions about continuation or termination of these pregnancies. Of the 55 embryos or fetuses, 23 had the karyotype 47,XXY, 10 had 47,XYY, and 12 had 47,XXX. In addition, there were 10 instances of true mosaicism, i.e. 47,XXY/46,XY (n = 5), 47,XYY/46,XY (n = 2), or 47,XXX/46,XX (n = 3). Mean gestational age (+/-standard deviation) at diagnosis was 18.3+/-3.0 weeks. After comprehensive genetic counseling 48 (87.3%) of these pregnancies were carried to term. In seven cases (12.7%) the parents elected a pregnancy termination. Two of 31 pregnancies (6.5%) primarily ascertained at our center were aborted, whereas amongst the 24 referred cases, 5 couples (20.8%) opted for a termination. The mean gestational age of the terminated pregnancies was 19.7 weeks. The overall termination rate of 12.7% appears low in comparison with literature data. Most reports from other institutions present termination rates between 32 and 66%. The reason for the low rate of induced abortions in our study cohort is not clear. Cultural differences in parental perception of sex chromosomal polysomies may be of importance, and peculiarities of genetic counseling at our institution could also play a role. Although counseling was nondirective, we did put emphasis on providing prospective parents with information from unbiased follow-up studies of children with Klinefelter syndrome and other sex chromosome polysomies.

Age-specific incidences of chromosome abnormalities at the second trimester amniocentesis for Japanese mothers aged 35 and older: collaborative study of 5484 cases.

The aim of this study was to calculate the expected incidences of chromosome abnormalities found at amniocentesis in Japanese women aged 35 and older. From four clinics in Japan, we gathered genetic amniocentesis data on 5484 pregnant women at risk only due to their advanced age, 35 years and older. We analyzed the data using the logistic regression model. Of the 5484 fetuses, 117 (2.1%) were diagnosed with a chromosome abnormality. The abnormal karyotypes included 42 cases of trisomy 21; 13 of trisomy 18; 7 of trisomy 13; 10 of 47,XXY; 4 of 47,XXX; 1 of 47,XYY; 27 with various structural aberrations; and 13 with various types of mosaicism. The incidences of trisomy 21, lethal autosomal aneuploidies (trisomy 18 and trisomy 13), and sex-chromosome abnormalities (XXY, XXX, XYY) increased with maternal age. Parameters of the regression equations with their standard errors were calculated and the expected incidences of chromosome abnormalities at each maternal age were derived. The expected incidences of chromosome abnormalities obtained in this study are the first data published for Japan and will be useful for the counseling of pregnant women. The incidence of trisomy 21 is not different from the rates published previously for Western countries. The incidences of chromosome abnormalities are not affected by race or by geographic factors.

Cytogenetic survey of 1,007 infertile males.

The aim of this study was to investigate the influence of a chromosome abnormality on male infertility. The subjects consisted of 1,007 males with the chief complaint of infertility. Karyotyping was conducted mainly by G banding. Major chromosome abnormalities were observed in 62 patients (6.2%) in total and consisted of sex chromosome abnormalities were observed in 62 patients (6.2%) in total and consisted of sex chromosome abnormalities in 38 patients (3.8%) and autosomal chromosome abnormalities in 24 (2.4%). Among the patients with sex chromosome abnormalities, 28 cases were 47, XXY, 3 were 47,XYY, and 7 cases had a Y chromosome abnormality. Autosomal chromosome abnormalities comprised 10 cases of reciprocal translocation, 8 cases of Robertsonian translocation, 5 cases of inversion, and 1 case of ring chromosome. In patients with a sperm density < 5 x 10(6)/ml, a total motile sperm count < 1 x 10(6), a follicle-stimulating hormone value > or = 30.1 mIU/ml, a luteinizing hormone value > or = 8.9 mIU/ml, a testosterone value < or = 2.69 ng/ml, or an average testis volume < or = 8 ml, the incidence of major chromosome abnormalities was significantly higher. These findings suggest that patients who need microinsemination should undergo chromosome analysis. We should counsel patients about obtaining adequate information on each chromosome abnormality.

Survey of the fragile X syndrome and the fragile X E syndrome in a special education needs population.

To begin to understand the population dynamics of the fragile X (FRAXA) mutation and to learn more about the fragile X E (FRAXE) syndrome, we have initiated a surve of children in special needs education programs in the public school system. With respect to the FRAXA syndrome, we found approximately 1/1,000 full mutations among males. No large alleles at the FRAXE locus were observed among 462 individuals. The allele distributions at the two loci among Caucasians and among African Americans were examined as well as the level of heterozygosity. We found a significant difference in the FRAXA allele distribution among the two ethnic groups; the major difference was due to the lack of smaller alleles among the African Americans. No difference was found for the FRAXE allele distribution among the two groups. The level of heterozygosity was less than predicted by the allele distribution at both loci. This is probably due to unidentified large alleles among females with a test result of a single band. Alternatively, this excess may indicate that the population is not at equilibrium.

Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy.

Genes on the long arm of Y (Yq), particularly within interval 6, are believed to play a critical role in human spermatogenesis. Cytogenetically detectable deletions of this region are associated with azoospermia in men, but are relatively uncommon. It has been hypothesized that microdeletions of Yq may account for a significant proportion of men with infertility. The objective of this study was to validate a sequence-tagged site (STS)-mapping strategy for the detection of Yq microdeletions and to use this method to determine the proportion of men with idiopathic azoospermia or severe oligozoospermia who carry microdeletions in Yq. STS mapping of a sufficiently large sample of infertile men should also help further localize the putative gene(s) involved in the pathogenesis of male infertility. Genomic DNA was extracted from peripheral leukocytes of 16 normal fertile men, 7 normal fertile women, 60 infertile men (50 of whom had azoospermia and 10 of whom had severe oligozoospermia with no other recognizable cause of infertility), and 15 patients with the X-linked disorder, ichthyosis. PCR primers were synthesized for 26 STSs that span Yq interval 6. None of the 16 normal men of known fertility had microdeletions. Seven normal fertile women failed to amplify any of the 26 STSs, providing evidence of their Y specificity. No microdeletions were detected in any of the 15 patients with ichthyosis. Of the 60 infertile men typed with 26 STSs, 11 (18%; 10 azoospermic and 1 oligozoospermic) failed to amplify 1 or more STS. Interestingly, 4 of the 11 patients had microdeletions in a region that is outside the Yq region from which the DAZ (deleted in azoospermia gene region) gene was cloned. In an additional 3 patients, microdeletions were present both inside and outside the DAZ region. In 3 subjects, the microdeletions were verified by Southern analysis using labeled PCR products corresponding to the deleted STSs as probes. These data suggest a high prevalence (18%) of Yq microdeletions in men with idiopathic azoospermia/severe oligospermia. The physical locations of these microdeletions provide further support for the concept that a gene(s) on Yq deletion interval 6 plays an important role in spermatogenesis. The presence of deletions that do not overlap with the DAZ region suggests that genes other than the DAZ gene may also be implicated in the pathogenesis of some subsets of male infertility.

Genetic referrals of Middle Eastern origin in a western city: inbreeding and disease profile.

Inbreeding or consanguineous marriage is a common traditional practice in Middle Eastern cultures. Studies from various countries and communities of this region showed that the frequencies range from 20% to greater than 70%. Inbreeding is known to have adverse effects on morbidity and mortality, in particular with respect to autosomal recessive disorders. This study examined 200 couples representing all referrals of Middle Eastern origin seen at a large Clinical Genetics Unit in Montreal. They were compared with a similar sized group of different cultural backgrounds from among the same referrals. The rate of intercultural marriages and inbreeding was found to be 24% and 23.5% respectively in the Middle Eastern group, while they were 22.5% and 5% in the comparison group. Excluding the referrals for consanguinity only, the rate of inbreeding among the study group was 16.4%. Within the Middle Eastern group, autosomal recessive disorders were more than twice as common in the inbred than in the non-inbred families, the pattern of which is consistent with previous observations.

Trisomy X: ACLF (Association des Cytogénéticiens de Langue Française) retrospective study.

A retrospective study of patients with trisomy X was carried out by the Association des Cytogénéticiens de Langue Française (ACLF). One hundred and ninety observations were collected from 18 cytogenetic laboratories. Variability in presentation is the most striking feature. Results must be treated with some caution, since they concern only individuals referred for karyotyping.

Incidence of congenital heart disease: II. Prenatal incidence.

The incidence of congenital heart disease appears to be about 1 per 100 liveborn infants. In infants who die before term, however, there is a much higher incidence of congenital heart disease, with a tendency for an excess of complex lesions. Some but not all of these lesions are associated with gross chromosomal abnormalities, which occur frequently in first-trimester abortions. Most of these chromosomal abnormalities are associated with such maldevelopment of many organ systems that fetal death occurs in utero. Monosomy X (45, XO), has a high association with congenital heart disease. Most fetuses with this abnormality die in utero, but because the abnormality is not inevitably lethal a small increase in survival of these fetuses would cause a large increase in the total incidence of congenital heart disease.

The karyotype of fetuses with anomalies detected by second trimester ultrasonography.

OBJECTIVE: To determine the incidence of abnormal karyotype among fetuses with anomalies detected by detailed second trimester ultrasonography. STUDY DESIGN: A total of 573 patients underwent amniocentesis following the detection of anomalies by detailed second trimester ultrasonography. RESULTS: Thirty-six (6.3%) fetuses with abnormal karyotype were detected. The most common abnormal karyotypes were: trisomy 18, 11 cases; trisomy 21, 8 cases; 45XO, 7 cases; trisomy 13, 3 cases; and triploidy, 2 cases. Abnormal karyotype was detected in 20/111 (18%) fetuses with more than one anomaly, 15/182 (8.2%) with cystic hygroma, and 1/38 with nuchal thickening. No abnormal karyotype was detected among 108 fetuses with choroid plexus cyst, 58 with hydronephrosis, 25 with ventriculomegaly, 16 with a single umbilical artery, 18 with cardiac anomalies. CONCLUSIONS: (1) Half of the cases with abnormal karyotype occurred in fetuses with more than one anomaly. (2) Cystic hygroma was the isolated malformations most commonly associated with abnormal karyotype. (3) Isolated malformations such as choroid plexus cyst or hydronephrosis were not associated with abnormal karyotype.

[Chromosomal survey of 1001 subfertile males: incidence and clinical features of males with chromosomal anomalies].

A chromosomal survey using the G-banding technique was performed on 1,001 subfertile males examined at Kyoto University Hospital between January, 1985 and April, 1991. Thirty-six of them had major chromosome anomalies (3.6%). The incidence of major anomalies for the 154 azoospermia patients, 326 oligozoospermia patients with a sperm density of less than 20 x 10(6)/ml, and 521 patients with normal sperm density was 10.4, 4.6, and 1.0%, respectively. The major anomalies found in azoospermic patients were associated with the sex chromosome, whereas autosomal anomalies were found in patients with oligozoospermia. The incidence of anomalies for patients with azoo- or oligozoospermia was significantly higher than that for patients with normal sperm density (p = 0.000003). All of the 12 patients with Klinefelter syndrome were azoospermic. However, the serum testosterone levels were within normal range in 10 of these patients. Testicular biopsies showed spermatogenic arrest in 5 of the 12 azoo- or oligozoospermic patients with structural chromosomal anomalies. Except for one patient, treatments such as varicocelectomy or medication were not effective in the patients with structural chromosomal anomalies. Chromosome studies are important in the evaluation of subfertile male patients with sperm densities less than 20 x 10(6)/ml. Disorders of the spermatogenic process may be directly related structural chromosomal anomalies in some of the patients.

Cytogenetics of müllerian agenesis. A case report.

A 38-year-old woman presented with primary infertility and primary amenorrhea. The evaluation revealed müllerian agenesis and mosaicism, 45,X/46,XX/47,XXX.

Y aneuploidy: a further case of a male patient with a 48,XYYY karyotype and literature review.

An adult male with three Y chromosomes is reported. The patient showed some clinical features similar to those of Klinefelter's syndrome. This case represents the 6th instance described in the literature of a 48,XYYY karyotype without recognizable mosaicism. The authors compare the clinical symptoms with those of the five previously reported cases.

Pediatric germ cell and human chorionic gonadotropin-producing tumors. Clinical and laboratory features.

Germ cell tumors may cause various aberrations in pubertal development. In prepubertal boys, these tumors may secrete human chorionic gonadotropin, resulting in precocious puberty. Human chorionic gonadotropin and alpha-fetoprotein are both useful as germ cell tumor markers in the diagnosis and detection of recurrence. Pregnancy-specific beta 1-glycoprotein, another oncoplacental antigen, has been used as a tumor marker for trophoblastic neoplasms, but not previously for human chorionic gonadotropin-producing tumors associated with precocious puberty. Patients with germ cell tumors may also have abnormal karyotypes. Herein, we describe six male pediatric patients with germ cell tumors and pubertal derangements seen during an 8-year period. We confirm the high incidence of associated sexual precocity, the usefulness of alpha-fetoprotein, human chorionic gonadotropin, and pregnancy-specific beta 1-glycoprotein as tumor markers in the diagnosis and follow-up of these patients, and the occurrence of sex chromosomal abnormalities.