True polyploid meiosis in the human male.

Polyploidy does not usually occur in germinal cells of mammals and other higher vertebrates. We describe a unique example of mosaic autotetraploidy in the meiosis of a human male. Although the original observations were made in the late 1960s, we did not publish them at that time, because we expected to detect further examples that could be described together. However, this did not occur and we have now decided to make the observations available to demonstrate that polyploidy in mammalian male meiosis can arise at a higher frequency than expected by random polyploidization of individual meiotic cells, by either DNA duplication or cell fusion prior to synapsis. This is the first description of a population of primary spermatocytes exhibiting multivalent formation at leptotene /diakinesis in human spermatogenesis, with ring, chain, frying pan and other types of quadrivalents, typical of autotetraploidy. As many of the polyploid configurations showed apoptotic breakdown, it is likely that diploid and/or aneuploid spermatozoa would have rarely or never resulted from this mosaic autotetraploid meiosis.

Impact of prenatal technologies on the sex ratio in India: an overview.

The fact that techniques of prenatal diagnosis are used in India and China to selectively eliminate females is widely known. It has been extensively reported in the international media and in scientific publications since the 1990s. The publication of the Census of India 2011 shows that the ratio of girls to boys below the age of 6 years continues to decline at an alarming rate. Following that publication, this topic has again received international attention. The aim of this article is to better inform the human genetics community of the magnitude of this practice and its consequences in India.In this overview, we examine the impact of prenatal technology on the sex ratio in India. We present facts and figures from the Census of India and other publications that show that the practice is wide spread throughout India, in urban and rural areas, among the rich and the poor, and among the educated and the illiterate. We also briefly discuss the possible causes, consequences, and solutions.

Balanced complex chromosome rearrangements: reproductive aspects. A review.

This review examines the reproductive consequences for carriers of a balanced complex chromosome rearrangement (CCR). It is based on an analysis of CCRs in 103 adults referred for reproductive problems, including male infertility. The main focus is on reproductive risks based on data from 84 CCRs. Carriers of balanced CCRs have a high risk of an abortion and/or a chromosomally unbalanced child. I have identified roughly four different types of CCRs (I-IV); most (44%) belong to Type I with a simple 3-way or 4-way exchange of segments and risk factors similar to those for reciprocal translocations. There were only three CCRs (4%) of type II, which involve an inversion. Type III CCRs (21%) involve one or more insertions with ∼35% risk of a child with a duplication or a deletion of the inserted segment. Type IV CCRs (31%) involve a "middle segment" in a derivative chromosome with segments from at least three chromosomes. In ∼35% of these CCRs, recombination occurs in this segment, which can produce imbalance but in many cases it changes a CCR into a simpler balanced rearrangement in the next generation. Balanced CCRs, which have been often considered together in one group, can now be split into four types, each with a risk of a different type of imbalance. This analysis provides a better understanding of the reproductive consequences for carriers of balanced CCRs and should be useful in prenatal diagnosis and genetic counseling.

Natural human chimeras: A review.

The term chimera has been borrowed from Greek mythology and has a long history of use in biology and genetics. A chimera is an organism whose cells are derived from two or more zygotes. Recipients of tissue and organ transplants are artificial chimeras. This review concerns natural human chimeras. The first human chimera was reported in 1953. Natural chimeras can arise in various ways. Fetal and maternal cells can cross the placental barrier so that both mother and child may become microchimeras. Two zygotes can fuse together during an early embryonic stage to form a fusion chimera. Most chimeras remain undetected, especially if both zygotes are of the same genetic sex. Many are discovered accidently, for example, during a routine blood group test. Even sex-discordant chimeras can have a normal male or female phenotype. Only 28 of the 50 individuals with a 46,XX/46,XY karyotype were either true hermaphrodites or had ambiguous genitalia. Blood chimeras are formed by blood transfusion between dizygotic twins via the shared placenta and are more common than was once assumed. In marmoset monkey twins the exchange via the placenta is not limited to blood but can involve other tissues, including germ cells. To date there are no examples in humans of twin chimeras involving germ cells. If human chimeras are more common than hitherto thought there could be many medical, social, forensic, and legal implications. More multidisciplinary research is required for a better understanding of this fascinating subject.

Multiple genomic aberrations in a patient with mental retardation and hypogonadism: 45,X/46,X,psu dic(Y) karyotype, thyroid hormone receptor beta (THRB) mutation and heterozygosity for Wilson disease.

We report on multiple genomic aberrations in a patient with mental retardation. In addition, he had hypogonadism, elevated thyroid hormone levels, hearing loss, delayed speech development and mild dysmorphic features. First, we identified a mosaic karyotype, 45,X/46,X,psu dic(Y). The pseudo-dicentric Y chromosome has three short arm segments. Second, we found a germline mutation (Pro453Thr) of the thyroid hormone receptor beta (THRB) which is associated with resistance to thyroid hormone. Third, he was found to be a carrier of a heterozygous ATP7B mutation (c.2575 + 5G > C), the Wilson disease gene. Even though an array-CGH (with a density of approximately 1 Mb) did not reveal any further genomic gains or losses, we cannot exclude that all contributing factors have been identified. However, this case report shows that with increasing technological possibilities we can find more than one cause for developmental problems in a single patient. The identification of multiple causes in a single patient may complicate explaining the disorder and genetic counseling.

An urgent need for a change in policy revealed by a study on prenatal testing for Duchenne muscular dystrophy.

Prenatal diagnosis for Duchenne muscular dystrophy (DMD) was introduced in the Netherlands in 1984. We have investigated the impact of 26 years (1984-2009) of prenatal testing. Of the 635 prenatal diagnoses, 51% were males; nearly half (46%) of these were affected or had an increased risk of DMD. As a result 145 male fetuses were aborted and 174 unaffected boys were born. The vast majority (78%) of females, now 16 years or older, who were identified prenatally have not been tested for carrier status. Their average risk of being a carrier is 28%. We compared the incidences of DMD in the periods 1961-1974 and 1993-2002. The incidence of DMD did not decline but the percentage of first affected boys increased from 62 to 88%. We conclude that a high proportion of families with de novo mutations in the DMD gene cannot make use of prenatal diagnosis, partly because the older affected boys are not diagnosed before the age of five. Current policy, widely accepted in the genetic community, dictates that female fetuses are not tested for carrier status. These females remain untested as adults and risk having affected offspring as well as progressive cardiac disease. We see an urgent need for a change in policy to improve the chances of prevention of DMD. The first step would be to introduce neonatal screening of males. The next is to test females for carrier status if requested, prenatally if fetal DNA is available or postnatally even before adulthood.

Selective chromosome analysis in couples with two or more miscarriages: case-control study.

OBJECTIVE: To identify additional factors, such as maternal age or factors related to previous reproductive outcome or family history, and the corresponding probability of carrying a chromosome abnormality in couples with two or more miscarriages. DESIGN: Nested case-control study. SETTING: Six centres for clinical genetics in the Netherlands. PARTICIPANTS: Couples referred for chromosome analysis after two or more miscarriages in 1992-2000; 279 carrier couples were marked as cases, and 428 non-carrier couples served as controls. MAIN OUTCOME MEASURES: Independent factors influencing the probability of carrier status and the corresponding probability of carrier status. RESULTS: Four factors influencing the probability of carrier status could be identified: maternal age at second miscarriage, a history of three or more miscarriages, a history of two or more miscarriages in a brother or sister of either partner, and a history of two or more miscarriages in the parents of either partner. The calculated probability of carrier status in couples referred for chromosome analysis after two or more miscarriages varied between 0.5% and 10.2%. CONCLUSIONS: The probability of carrier status in couples with two or more miscarriages is modified by additional factors. Selective chromosome analysis would result in a more appropriate referral policy, could decrease the annual number of chromosome analyses, and could therefore lower the costs.

Cerebellar hypoplasia, zonular cataract, and peripheral neuropathy in trisomy 17 mosaicism.

Trisomy 17 mosaicism in liveborns is an extremely rare chromosomal abnormality, with only three cases reported in the literature. Here we describe a 7-year-old boy with trisomy 17 mosaicism. The chromosome abnormality was detected by amniocentesis and was confirmed postnatally in cultured skin fibroblasts. The main clinical features were mental retardation and growth reduction, peripheral motor and sensory neuropathy, hypoplastic cerebellar vermis, zonular cataract, and body asymmetry. In our patient, and in the three earlier described cases, the additional chromosome 17 was detected in skin fibroblasts, not in peripheral lymphocytes. Molecular investigations excluded uniparental disomy of chromosome 17 in our patient. The extra chromosome 17 probably originated from a postzygotic mitotic nondisjunction of the maternal chromosome 17. In most cases of trisomy 17 mosaicism detected in amniocytes the chromosome abnormality seems to be confined to extra-embryonic tissues and clinically normal children are born. If, however, there are also ultrasound abnormalities, the possibility of fetal trisomy 17 mosaicism should certainly be considered. If postnatal karyotyping is limited to blood the diagnosis of trisomy 17 mosaicism could easily be missed. Therefore, we recommend chromosome analysis to be based on cultured skin fibroblasts in all cases where mental retardation is accompanied by postnatal growth retardation, body asymmetry, peripheral neuropathy, and cerebellar hypoplasia or zonular cataract.