The clinical and cytogenetic findings associated with mosaicism for trisomy 21/Down syndrome are the focus of this review. The primary topics discussed in this overview of the extant literature include the history of this condition and its diagnosis, the incidence of mosaicism, the meiotic and/or mitotic chromosomal malsegregation events resulting in mosaicism, the observation of mosaicism in the parents of children with the non-mosaic form of Down syndrome, and the variation in phenotypic outcome for both constitutional and acquired traits present in people with mosaicism for trisomy 21/Down syndrome, including cognition, fertility, and overall phenotypic findings. Additional topics reviewed include the social conditions of people with mosaicism, as well as age-related and epigenetic alterations observed in people with mosaicism for trisomy 21/Down syndrome. .

Mosaicism for trisomy 21: a review.

Four children, a girl and three boys, with diploid/trisomic mosaic Down syndrome were studied for the mechanism of origin of mosaics, using Q- and R-banding heteromorphisms as markers. Three mosaic subjects started as a trisomic zygote followed by the loss of a chromosome 21 at an early mitotic division. Of these, one resulted from a maternal first-meiotic error, another resulted from a paternal first-meiotic event, and the third originated from a first-meiotic error in either parent. The remaining subject could have resulted from either a diploid or a trisomic zygote. These findings, together with a higher proportion of trisomic cells in skin fibroblasts than in peripheral blood lymphocytes in the two patients studied, suggest that the extra chromosome 21 in mosaic Down syndrome patients usually has a meiotic origin. At least two, possibly three, of the diploid cell lines in these mosaics consisted of "uniparental" chromosomes 21, namely, both the homologous members were derived from a parent.

The origin of mosaic Down syndrome: four cases with chromosome markers.

The frequently observed familial aggregation of Down syndrome (DS) 47,+21 and other aneuploidies and the phenomenon of double aneuploidy involving DS cannot be accounted for by chance alone. To clarify possible aetiological factors, pedigrees from all 7 affected families with repeated marriages referred to two regional genetics centres were examined. In each case the recurrence of aneuploidy was on the mother's side (p<0.01). Such a pattern suggests cytoplasmic inheritance of a risk factor. The hypothesis that mitochondrial DNA mutations have a role in the aetiology of DS is supported by other observations as well as by theoretical considerations.

Familial Down syndrome: evidence supporting cytoplasmic inheritance

An unusual nucleolar organizer region (NOR) heteromorphism was noted among 13 of 41 parents in whom nondisjunction leading to trisomy 21 was known to have occurred In contrast, only one of these double NOR (dNOR) variants was found among the 41 normal spouses and none were seen among 50 control individuals In two dNOR(+) families, a second child with trisomy 21 was conceived In both families, the extra chromosome in each child was contributed by the parent who carried the dNOR variant and resulted from a recurrent meiosis I error Our data suggest that the dNOR heteromorphism may play a role in meiotic nondisjunction and could be associated with as much as a 20-fold increased risk for having offspring with trisomy 21

Nucleolar organizer region variants as a risk factor for Down syndrome.

The statement that Down syndrome is caused by trisomy of chromosome 21 usually begs two questions: (1) Why do three chromosomes instead of two cause abnormal embryonic development and physiology?; and (2) How does a zygote get three chromosomes? This paper addresses the second question. Trisomy is usually the result of nondisjunction, which can be either maternal or paternal. Meiotic nondisjunction is the cause of trisomy 21 in 97-95070 of all cases of Down syndrome. A summary of studies of the parental origin of nondisjunction showed 118 to be maternal and 37 paternal.' Of the maternal cases of nondisjunction, 89 of 118 were in meiosis I and the remaining 29 were in meiosis 11. For the paternal nondisjunction, the 37 meiotic errors were equally divided between meiosis I and meiosis 11. The next largest cause of trisomy is Robertsonian translocation, which is present in 3-5% of all patients with Down syndrome.2 The 14/21 and 21/21 are the most frequent Robertsonian translocations. Considerably less than 1 percent are caused by reciprocal t ransl~cat ion.~ Since meiotic nondisjunction and Robertsonian translocation are the most common causes of Down syndrome, we are led to the obvious questions: What causes nondisjunction and what causes Robertsonian translocation?

Nucleolus Organizing Genes on Chromosome 21: Recombination and Nondisjunction

A family with trisomy-21 mosaicism in two successive generations and a Down's syndrome child in the third generation is presented. Cytogenetic studies of eight individuals of this family showed a marker chromosome 15ph+ and a heteromorphic chromosome 18 in some members. The standard trisomy 21 in the proband was derived from a trisomy-21 oogonium by secondary nondisjunction in his mother.

Cytogenetic studies of a family with trisomy 21 mosaicism in two successive generations as the cause of Down's syndrome

Three female patients with Turner-syndrome (sexual infantilism, short stature and somatic Turner-stigmata) have been analysed cytogenetically by means of different banding techniques. A deletion of the distal heterochromatic band Yq12 of the Y chromosome was observed in a mosaic with a 45,X-cell line, i.e. the karyotype is 45,X/46,X,del(Y)(q12). In order to get information about the phenotypic expression of the 45,X/46,X,del(Yq) mosaicism all previously published cases have been reviewed. Comparing the phenotypes of all 45,X/46,X,del(Yq) mosaic cases three different phenotype categories of sexual development can be distinguished: female individuals with sexual infantilism and Turner-stigmata, individuals with ambiguous genitals, ranging from clitoris hypertrophy of female genitals to hypospadia of males, male individuals, who are infertile (azoospermic). A comparison of the appearance of external genitals with the status of gonads of all patients revealed an unequivocal relationship between the gonad status and the resulting phenotype category. Furthermore, the role of Y-chromosomal loci determining testicular differentiation (biological function of H-Y antigen) for male development has been emphasized. The effect of the 45,X-cell line on the expression of short stature and somatic Turner-stigmata is independent of sexual development. Considering the great phenotypic variability of the 45,X/46,X,del(Yq) mosaicism it seems impossible to deduce a definitive phenotype. This problem is acute in prenatal diagnosis especially.

[45,X/46,X,del(Yq) sex chromosome mosaicism--analysis of the phenotypic expression].

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Cytogenetic studies of a family with trisomy 21 mosaicism in two successive generations as the cause of Down's syndrome

[45,X/46,X,del(Yq) sex chromosome mosaicism--analysis of the phenotypic expression].