Genetics of early miscarriage

A miscarriage is the most frequent complication of a pregnancy. Poor chromosome preparations, culture failure, or maternal cell contamination may hamper conventional karyotyping. Techniques such as chromosomal comparative genomic hybridization (chromosomal‐CGH), array-comparative genomic hybridization (array-CGH), fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and quantitative fluorescent polymerase chain reaction (QF-PCR) enable us to trace submicroscopic abnormalities. We found the prevalence of chromosome abnormalities in women facing a single sporadic miscarriage to be 45% (95% CI: 38–52; 13 studies, 7012 samples). The prevalence of chromosome abnormalities in women experiencing a subsequent miscarriage after preceding recurrent miscarriage proved to be comparable: 39% (95% CI: 29–50; 6 studies 1359 samples). More chromosome abnormalities are detected by conventional karyotyping compared to FISH or MLPA only (chromosome region specific techniques), and the same amount of abnormalities compared to QF-PCR (chromosome region specific techniques) and chromosomal‐CGH and array-CGH (whole genome techniques) only. Molecular techniques could play a role as an additional technique when culture failure or maternal contamination occurs: recent studies show that by using array-CGH, an additional 5% of submicroscopic chromosome variants can be detected. Because of the small sample size as well as the unknown clinical relevance of these molecular aberrations, more and larger studies should be performed of submicroscopic chromosome abnormalities among sporadic miscarriage samples. For recurrent miscarriage samples molecular technique studies are relatively new. It has often been suggested that miscarriages are due to chromosomal abnormalities in more than 50%, but the present review has determined that chromosomal and submicroscopic genetic abnormalities on average are prevalent in maximally half of the miscarriage samples. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.     

Cytogenetic abnormalities in Tunisian women with premature ovarian failure

To identify the distribution of chromosome abnormalities among Tunisian women with premature ovarian failure (POF) referred to the department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia), standard cytogenetic analysis was carried out in a total of 100 women younger than 40 affected with premature ovarian failure. We identified 18 chromosomal abnormalities, including seven X-numerical anomalies in mosaic and non-mosaic state (45,X; 47,XXX), four sex reversal, three X-structural abnormalities (terminal deletion and isochromosomes), one autosomal translocation and one supernumerary marker. The overall prevalence of chromosomal abnormalities was 18% in our cohort. X chromosome aneuploidy was the most frequent aberration. This finding confirms the essential role of X chromosome in ovarian function and underlies the importance of cytogenetic investigations in the routine management of POF.     

超声联合染色体检测对胎儿心血管畸形的诊断价值

摘要 目的：探讨超声联合染色体检测对胎儿心血管畸形的诊断价值。方法：2017年6月到2020年12月选择在本院诊治的高危孕妇117例作为研究对象,所有孕妇都给予胎儿心脏超声检查与羊膜穿刺染色体检查,判断胎儿心血管畸形情况。结果：在117例孕妇中,胎儿心脏超声检出胎儿心血管畸形37例,占比31.6%,前三位主要为室间隔缺损、左上腔静脉、右锁骨下动脉。羊膜腔穿刺术检出32例染色体异常胎儿,占比27.4%,其中染色体数目异常30例,染色体结构异常2例,前三位分别为21-三体、13-三体与18-三体。超声检查胎儿心血管畸形37例中,染色体异常30例;超声检查胎儿心血管正常80例中,染色体异常2例,对比差异有统计学 意义(P<0.05)。联合诊断为胎儿心血管畸形39例,随访后确诊为胎儿心血管畸形40例,超声联合染色体检测对胎儿心血管畸形的敏感性与特异性为100.0%(39/39)和98.7%(77/78)。结论：胎儿心脏超声联合染色体检测对胎儿心血管畸形的诊断具有很高敏感性与特异性,可尽最大可能提高出生缺陷儿的检出率,有很好的应用价值。     

Incidence of chromosome aberrations among 11148 newborn children.

Chromosome analysis has been made of 11148 children; 29 had sex chromosome abnormalities (2.60 per 1000) and 64 autosomal abnormalities (5.74 per 1000). The total incidence of major chromosome abnormalities was 8.34 per 1000. The incidence of chromosome variations was 16.8 per 1000. The most common variants were those with variation in size of short arms-satellites in D and G chromosomes and variations in Y chromosome size. So far, very little is known about the significance of such chromosome variations. The incidence of most chromosome abnormalities in liveborn children is well established by now from studies of a total of 54749 consecutively liveborn children in 6 studies as shown in Table 1. More chromosome studies of liveborn children are, however, needed for several purposes such as finding families with chromosome translocations, studying segregation rates and giving genetic advice to families with inheritable chromosome aberrations and an increased risk of getting children with unbalanced chromosome abnormalities, mental retardation and physical abnormalities. One of the main purposes in chromosome examination of newborn children is to study the development of children with different chromosome abnormalities, especially those with sex chromosome abnormalities, and compare then with controls, treat them when needed and give advice to the parents of such children.     

Should the indications for prenatal chromosome analysis be changed?

Amniocentesis for chromosome analysis was performed in 1086 pergnant women, 739 of whom had an increased risk of giving birth to a child with chromosome abnormalities. Such abnormalities were found in almost identical proportions among the fetuses with an increased risk (1.2%) and among those with no increased risk (1.4%). Findings in several other studies seem to confirm that there is no significant difference between the risk groups in the proportion of abnormalities found. This suggests that our current risk groups may not be the right ones, but a much larger study is needed to confirm this.     

X chromosome inactivation pattern in elderly women over 70 years of age

In the present study we have analyzed X chromosome inactivation patterns in 40 women aged from 74 to 85 years (mean age 78 years). The control group was 36 women (mean age 30 years). The most common AR-assay was used to determine X-inactivation patterns (the study of methylation patterns of HpaII site in human androgen receptor gene (HUMARA) by quantative PCR). The age dependence of X-inactivation was not observed. We have detected skewed X-inactivation in three women among 40 (7.5%) elderly women comparing to two women among 36 (5.5%) women from control group. The difference was not found to be statistically significant. We made a suggestion that higher incidence of skewed X-inactivation in elderly women revealed by previous studies could occur due to some experimental ambiguities as heterogeneity of the group studied; inclusion of women having relatives with genetic abnormalities associated with skewed X-inactivation patterns; the difference of X chromosome inactivation skewing determination. We conclude that present study does not show X chromosome inactivation to be age dependent.     

Chromosomal abnormalities and hormonal disorders of primary amenorrhea patients in Egypt

BACKGROUND:

Primary amenorrhea is defined as the absence of menstruation and secondary sexual characteristics in phenotypic women aged 14 years or older. Hormonal disorders are main causes of primary amenorrhea. Common hormonal cause of primary amenorrhea includes pituitary dysfunction and absent ovarian function. The aim of this study was to estimate the incidence and types of chromosomal abnormalities in patients with primary amenorrhea in Egypt.

MATERIALS AND METHODS:

Chromosomal analysis and hormonal assay were carried out on 223 patients with primary amenorrhea that were referred from different parts of Egypt to Cytogenetic laboratory of Genetic Unit, Children Hospital Mansoura University, from July 2008 to December 2010. FISH technique was carried out in some of cases to more evaluation.

RESULTS:

The frequency of chromosomal abnormalities was 46 (20.63%) in primary amenorrhea patients. The chromosomal abnormalities can be classified into four main types. (1) The numerical abnormalities of the X chromosome were detected in 23 (50 %). (2) Structural abnormalities of the X chromosome were detected in 11 (23.91%). (3) Mosaicism of X chromosome was found in 10 (21.74%). (4) Male karyotype 46, XY was presented in 2 (4.35%).

CONCLUSION:

The present study showed that karyotype and FISH are necessary to detect the causes of primary amenorrhea. This study also revealed the incidence of chromosomal abnormalities in women with primary amenorrhea in Egypt is similar to that reported in previous literatures.     

胎儿肢体畸形的超声诊断与染色体异常的相关性分析

目的：总结肢体畸形胎儿的超声诊断与染色体核型诊断结果,分析胎儿肢体畸形时超声诊断与染色体异常的相关性。方法：以孕18—32周的健康自愿者作为对照组（A组）,以同期超声诊断异常者作为观察组（B组）,两组均行超声及染色体检查。对比其染色体核型的检出情况;并以胎儿的超声诊断结果为自变量,以各染色体核型为因变量进行logistic回归分析。结果：A组染色体异常的检出率为2．1,与之相比,B组染色体异常检出率有明显升高,且染色体核型异常以47,XY,＋18、47,XX＋21和47,XXX为主,差异有统计学意义,P〈0．05;logistic分析结果显示,染色体核型异常与胎儿肢体比例失调、四肢短小、肢体非功能位的OR值分别为6．332、7．404、5．98l,P〈0．05,差异显著。结论：胎儿肢体畸形患者染色体异常的诊出率较健康人群明显增高,染色体核型异常与超声诊断为胎儿肢体比例失调、四肢短小、肢体非功能位的比例呈正相关。     

Primary amenorrhoea in a patient with mosaicism for monosomy X and a derivative X-chromosome

Primary amenorrhoea is defined as the absence of menstruation in phenotypic women aged 16 years or older, if secondary sexual characteristics are present. X chromosome abnormalities probably comprise about one half of all cases, including Turner syndrome and X chromosome rearrangements. Conventional banding cytogenetic methods might miss the accurate detection of structural chromosome abnormalities. The fluorescence in situ hybridization (FISH) and multicolor FISH techniques are required to interpret specific chromosomal rearrangement. As far as we know, we report the first case with chromosome mosaicism for monosomy X and terminal deletion of Xq26 with duplication of Xp11-->pter. In spite of the fact that a 45,X karyotype was detected in 46% of lymphocytes, she was tall and her secondary sexual characteristics were moderately developed, including breast, pubic and axillary hair stages. Cytogenetic and FISH analyses should be considered for patients presenting primary amenorrhoea even if there are no other clinical features suggestive of chromosome abnormality.     

Chromosome studies in human in vitro fertilization

Summary The chromosome constitution of 22 human preimplantation embryos from donor oocytes fertilized in vitro by donor sperm was studied to assess the contribution of lethal chromosome anomalies to the high failure rate of implantation of in vitro fertilized embryos after embryo transfer in infertile women. Evidence was found of nondisjunction, resulting in trisomy, monosomy, and nullosomy; structural abnormalities; haploidy; and triploidy. Despite the lethality of their chromosome complements, these embryos could not be distinguished morphologically from those with normal chromosomes.     

Cytogenetic survey of 117 Tunisian patients with de novo myelodysplastic syndrome

Cytogenetic studies were performed on 117 Tunisian patients with de novo myelodysplastic syndromes (MDS). According to the French-American-British (FAB) criteria 40 patients presented with refractory anaemia (RA, 34%), eight with refractory anaemia with ringed sideroblasts (RARAS, 7%), 19 with refractory anaemia with excess of blasts (RAEB, 16%), 16 with refractory anaemia with excess of blasts in transformation (RAEB-t, 14%), 18 had chronic myelomonocytic leukaemia (CMML, 15%) and 16 unclassifiable MDS (14%). Seventy-five were men and forty-two were women. Five were children and 112 were adults with a median age of 58 years. Fifty-five per cent of the patients presented clonal chromosome abnormalities. Rates of abnormality varied from one FAB subtype to the other: 55% in RA, 75% in RARAS, 63% in RAEB, 75% in RAEB-t and 28% in CMML. The most frequent chromosome abnormalities were del(5q) (22 cases), monosomy 7 (12 cases), del(12p) (6 cases), and trisomy 8 (5 cases). Rare abnormalities were also found: ring of chromosome 12 and trisomy 15. Conventional cytogenetics remains the basic technique in identifying chromosomal abnormalities associated with MDS.     

Quinacrine fluorescence of variant and abnormal human Y chromosomes

Quinacrine fluorescence has been used to examine variant and abnormal human Y chromosomes, at interphase and mitosis. The length difference in variant Y chromosomes has been shown to involve the highly fluorescent segment only. Eight abnormalities of the Y chromosome have been positively identified, two isochromosomes of the long arms of the Y, five pericentric inversions, and a dicentric Y chromosome with two long arms. Contributory evidence for two further abnormalities, a ring Y and a dicentric with two short arms, is also given.     

Genome instability is increased in lymphocytes of women with polycystic ovary syndrome and is correlated with insulin resistance

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and reproductive and metabolic abnormalities. The potential genetic contributors to PCOS are unclear. We tested the hypothesis that genomic instability (chromosome malsegregation and DNA damage) is increased in PCOS. METHODS: Overweight age, weight and BMI-matched women with (n=14) and without (n=16) PCOS (age 34.2+/-6.0 years, weight 90.7+/-14.5 kg, BMI 34.0+/-5.6 kg/m(2), mean+/-S.D.) were assessed for chromosome malsegregation (assessed by X chromosome chromogenic in situ hybridisation) and micronucleus frequency (assessed by the cytokinesis block micronucleus index) in lymphocytes. RESULTS: Women with PCOS had significantly elevated genomic instability as demonstrated by a significantly higher number of binucleated lymphocytes containing micronuclei, total number of micronuclei, a higher proportion of aneuploid X chromosome signals (2:1 X and 3:1 X) and a lower proportion of normal X chromosome segregation signals (2:2 X) in binucleated lymphocytes than women without PCOS. Surrogate measures of insulin resistance positively correlated with the proportion of aneuploid cells (2:1; 3:1 X chromosome signals) and inversely with the proportion of normal cells (2:2 X chromosome signals). CONCLUSION: Women with PCOS display increased genomic instability (higher micronuclei and chromosome malsegregation) compared to women without PCOS and this increase may be related to the insulin resistance phenotype.     

Y染色体异常29例分析

本文从1992例遗传咨询病例中收集29例Y染色体异常的病例,其中Y染色体数 目异常(47,XYY)2例;Y染色体结构异常8例:Y/Y易位1例、Yp+3例、de l(Y)3例、嵌合 体dic(Y)1例;Y染色体长度变异19例。对Y染色体这几种异常类型的遗传效应进行分析。 Abstract:Twenty nine cases of Y chromosome abnormalities were found in 1992 patients asking genetic counseling.Different kinds of Y chromosome abnormalitics were detected by G and banding techniques.These were 47,XYY(2 cascs);46,X,del(Y)(3 cascs);46,X,Yp+(3 cases);46,X,t(Y;Y)(1 case);45,X/46,X,dic(Y)(1 case) and length changes of Y chromosome(19 cases).The genetic effects of Y chromosome abnormalities have been analyzed in this report.     

Ethical considerations regarding parental decisions for termination following prenatal diagnosis of sex chromosome abnormalities

Termination rates following prenatal diagnosis of sex chromosome abnormalities have been reported to be in a very wide spectrum (12.7-86.5%) in various studies. The different attitudes in management of prenatal diagnosed sex chromosome abnormalities may depend on several factors as the type of the abnormality, the indication for prenatal testing, the number of previous healthy children and whether the pregnancy was assisted or spontaneous. In the current study, we look at prenatal diagnostic procedures carried out in our department over a period of 5 years (2002-2007). We did not detect sex chromosome abnormalities in the 43 cordocenteses and the 26 chorionic villus samples. Among the 1130 amniocentesis patients, 12 cases (1.06%) were diagnosed as having sex chromosome abnormalities. Five (41.67%) of 12 pregnancies with sex chromosome abnormalities were terminated (one case with 47,XXY, one case with 46,X,del(X), and three cases with 45,X karyotype); whereas seven pregnancies (58.33%) continued. Among the factors influencing parents' decision-making, the attitude of the health-care professional giving the post-diagnosis counseling seems to be the most important, next to the socio-economic and educational status of the parents.     

Chromosome abnormalities found among 34910 newborn children: results from a 13-year incidence study in Århus,Denmark

Summary As part of a larger prospective study of the influence of environmental factors on pregnancy, birth and the fetus, chromosome examinations have been made in 34910 newborn children in Århus over a 13-year period. Klinefelter's syndrome was found in 1 per 576 boys, XYY in 1 per 851 boys, triple-X in 1 per 947 girls and Turner's syndrome in 1 per 1893 girls. Other sex chromosome aberrations were found in 1 per 11637 children. The total incidence of sex chromosome abnormalities was 1 per 426 children or 2.34 per 1000. The most frequent autosomal abnormalities were that of Down's syndrome with 1 per 592 children, and reciprocal translocations with 1 per 712 children. The total incidence of autosomal abnormalities was 1 per 164 children. Chromosome abnormalities were found in 276 liveborn children and in 19 fetuses, who were aborted after prenatal chromosome examination. The combined incidence of sex chromosomal and autosomal abnormalities was 1 per 118 children or 8.45 per 1000 children.     

Observations of de novo clones of cytogentically aberrant cells in primary fibroblast cell strains from phenotypically normal women.

In a recent study of chromosome breakage frequencies in 36 primary fibroblast cell strains derived from skin from 10 phenotypically normal women, we observed seven different clones of cells having consistent chromosomal abnormalities. Five of the stem lines were noted in cultures from "control" women and two in fibroblasts from women taking oral contraceptives. We observed aneuploid clones as well as stem lines bearing structural abnormalities (e.g., translocation, inversions). The various aberrant clones were found in cultures ranging in age from 41 to 144 days and comprised varying percentages of the cell populations ranging from 0.8% to virtually 100%. The possible evolution in culture of clones of cells having aberrant karyotypes should be considered in interpreting findings from fibroblast cultures initiated for clinical evaluation.     

Chromosome studies in a neonatal population

The results of chromosome studies on 6809 consecutive newborn infants are presented. One hundred and one (1.48%) were heterozygous for a marker chromosome, the significance of which is not at present clear. Twenty-two infants (0.32%) had a major chromosome abnormality. Only six of these infants (0.09%) had a clinically recognizable abnormal phenotype (Down''s syndrome). The occult chromosome abnormalities included five sex chromosome abnormalities (one 47,XYY; two 47,XXY; two 47,XXX) and 11 balanced translocations. Seven of these were t(DqDq) and four were reciprocal translocations. The results of the present survey are combined with four other similar neonatal surveys in which a total of 23,328 newborns have been screened. Of these, 117 (0.5%; range 0.65-0.32%) had major chromosome abnormalities. The majority of these (72.7%) would not have been detected at birth without chromosome studies, an important fact in the context of prenatal diagnosis of chromosome disease and the early ascertainment of high-risk families.     

Assessment of X bends in patients with atypical X chromosome phenotypes.

Several patients with X chromosome structural abnormalities have been more severely affected clinically than expected. Since bends at Xq13-21 have been associated with inactivation, the authors scored bends retrospectively in 62 patients with X chromosome aneuploidy and 21 cases with structural abnormalities of the X chromosome. They found that patients with 2 X inactivation sites where one X was structurally abnormal had significantly fewer cells with X bends than normal 46,XX. In addition, these patients also showed X bends on the normal X more often than would be expected if non-random X inactivation of the abnormal X chromosome was occurring. Five of the 6 patients with a short or long arm deletion or paracentric inversion of Xq were mentally retarded or had other congenital anomalies not usually associated with Turner syndrome. This suggests to them that these clinical findings may be related to interference with X inactivation patterns in cells with a structurally abnormal X chromosome.