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PubMed1994

Mosaicism with a normal cell line and an autosomal structural rearrangement.

Over three decades, 12 cases of mosaicism for an autosomal rearrangement were recognised in the major cytogenetics laboratories in New Zealand, eight of which were studied between 1990 and 1992. One case inferentially involved the gonad, eight the soma, and three both gonad and soma. This mosaicism could have arisen as a postzygotic event either in a conceptus that was initially normal, with the generation of an abnormal cell line, or in a conceptus having a supernumerary chromosome which was lost at a subsequent mitosis, thereby restoring a normal cell line. Three of the 12 cases involved a presumed direct duplication, an otherwise very uncommon rearrangement. This may indicate a propensity for direct duplications to arise at mitosis rather than at meiosis; unequal sister chromatid exchange is a plausible mechanism. Mosaicism has clinical relevance for genetic counselling, as an intragonadal cell line carrying a rearrangement could generate multiple unbalanced gametes. Mosaicism for an autosomal rearrangement my be very much more common that is, or ever could be, recognised.

Adolescent↗
PubMed1994

Asymmetry and skin pigmentary anomalies in chromosome mosaicism.

We report six persons mosaic for a chromosome anomaly. All were mentally retarded and dysmorphic. Unilateral or asymmetrical features were found in all cases, in one an unusual transverse terminal limb anomaly, and in the others various degrees of hemiatrophy of the left side of the body. Five of the subjects had skin pigmentary anomalies which were distributed in the lines of Blaschko. The abnormal cell lines found were ring chromosome 22, trisomy 22, a large acrocentric marker, a deletion of 18q, a deletion of 8q, and triploidy. In four cases the clinical diagnosis was only confirmed by skin biopsy. In one case low level mosaicism in blood was fortuitously detected because of cytogenetic fragile X screening and confirmed in a skin biopsy. The sixth case was of dynamic mosaicism of a non-mosaic deletion 18q with a chromosome 18 derived marker present in a proportion of cells. Chromosome mosaicisn may cause subtle and asymmetrical clinical features and can require repeated cytogenetic investigations. The diagnosis should be actively sought as it enables accurate genetic counselling to be given.

Abnormalities, Multiple↗
PubMed1996

Confined placental mosaicism.

In most pregnancies the chromosomal complement detected in the fetus is also present in the placenta. The detection of an identical chromosomal complement in both the fetus and its placenta has always been expected as both develop from the same zygote. However, in approximately 2% of viable pregnancies studied by chorionic villus sampling (CVS) at 9 to 11 weeks of gestation, the cytogenetic abnormality, most often trisomy, is confined to the placenta. This phenomenon is known as confined placental mosaicism (CPM). It was first described by Kalousek and Dill in term placentas of infants born with unexplained intrauterine growth restriction (IUGR). Contrary to generalised mosaicism, which is characterised by the presence of two or more karyotypically different cell lines within both the fetus and its placenta, CPM represents tissue specific chromosomal mosaicism affecting the placenta only. The diagnosis of CPM is most commonly made when, after the diagnosis of chromosomal mosaicism in a CVS sample, the second prenatal testing (amniotic fluid culture or fetal blood culture analysis) shows a normal diploid karyotype.

Chorionic Villi Sampling↗
PubMed2003

Clinical aspects, prenatal diagnosis, and pathogenesis of trisomy 16 mosaicism.

INTRODUCTION: Analysis of data from cases of trisomy mosaicism can provide insight for genetic counselling after prenatal diagnosis and for the elucidation of the pathogenesis of trisomy during pregnancy. METHODS: Statistical analysis was carried out on data from 162 cases of pregnancies with prenatal diagnosis of trisomy 16 mosaicism. RESULTS: The majority of cases resulted in live birth (66%) with an average gestational age of 35.7 weeks and average birth weight of -1.93 standard deviations from the population mean. Among the live births 45% had at least one malformation, the most common being VSD, ASD, and hypospadias. The level of trisomy on direct CVS (cytotrophoblast) was associated with more severe intrauterine growth restriction (IUGR) and higher risk of malformation, while the level of trisomy on cultured CVS (chorionic villous stroma) was associated only with more severe IUGR. Similarly, the presence of trisomy on amniocentesis (amniotic fluid) was associated with both IUGR and malformation, while the presence of trisomy in the amniotic mesenchyme was associated only with IUGR. Surprisingly, the degree of trisomy in placental tissues appeared to be independent of the degree of trisomy in amniotic fluid and amniotic mesenchyme. The sex of the fetus was not associated with any outcome variables, although there was an excess of females (sex ratio = 0.45) that may be explained by selection against male mosaic trisomy 16 embryos before the time of CVS (approximately 9-12 weeks). CONCLUSION: The levels of trisomy in different fetal-placental tissues are significant predictors of some measures of outcome in mosaic trisomy 16 pregnancies.

Chromosomes, Human, Pair 16↗
PubMed2006

Triploidy and mosaicism in Liolaemus chiliensis (Sauria: Tropiduridae).

A remarkable diversity of ploidy, i.e., diploidy, triploidy, and diploid-triploid mosaicism, was found among the somatic and testicular cells in a natural population of the lizard Liolaemus chiliensis from central Chile. Intra pop ulation, intersexual, and intraindividual ploidy variation is reported. In contrast with other species of polyploid reptiles, 86% of L. chiliensis males were mosaics (2n/3n) and 14% were diploids; 33% of females were triploid, 57.1% were mosaics, and 9.5% were diploid. Among 21 specimens, no triploid males were found in this sample. In the mosaic males, the diploid and triploid spermatogonia both enter meiosis, producing both reduced and unreduced metaphase II spermatocytes, most of them euploids. We discuss the origin for this ploidy in this iguanid lizard.

Animals↗
PubMed2026

CRISPR-Cas9-induced genetic mosaicism in three species of the microcrustacean Daphnia.

Genetic mosaicism can arise from in vivo CRISPR-Cas9 gene editing, especially in the embryos. This study evaluates the extent of genetic mosaicism resulted from CRISPR-Cas9-mediated knockout for 11 genes in the freshwater microcrustacean Daphnia magna, Daphnia pulex, and Daphnia sinensis. Based on extensive genotyping data of the asexually produced progenies of successfully edited females, we find strong evidence of mosaicism in 9 of these genes. The genotyping data also suggest that the gene editing activity can take place as early as the one-cell embryo stage and extends into the 32-cell and later stages. This study establishes genetic mosaicism as an important feature of Cas9-mediated gene editing in Daphnia.

Animals↗
PubMed1976

A technique for the differential isolation of hop mosaic virus and hop latent virus.

Two rod-shaped viruses of similar length occurring in hops were isolated from a mixed infection. One (hop mosaic virus) infected Nicotiana clevelandii, produced mosaic symptoms in mosaic-sensitive hop cultivars, and did not infect Chenopodium murale. The other (hop latent virus) infected C. murale but not N. clevelandii and did not produce mosaic symptoms in hops. Neither N. clevelandii nor C. murale developed distinct symptoms after infection with the respective virus. Both viruses produced a systemic chlorotic flecking in Cluster hop seedling clones.

Methods↗
PubMed1998

Pathogenetics of 45,X/46,XY gonadal mosaicism.

Five patients with 45,X/46,XY mosaicism ranging from 8% to 66% of 46, XY lymphocytes in the peripheral blood were studied. Their age when chromosome studies were performed ranged from a few days to 37 yr. The phenotypic presentations were two females with gonadal dysgenesis and Turner syndrome features (cases 1 and 2), two males with ambiguous genitalia and mixed gonadal dysgenesis (cases 3 and 4), and an infertile male with an atrophic testis (case 5). Fluorescence in situ hybridization (FISH) using dual-color X and Y probes on paraffin-embedded sections of the gonads was performed to assess mosaicism. A mosaic cell line with a Y chromosome was present in the streak ovary, dysgenetic gonad, and testis. In the mixed gonadal dysgenesis cases (cases 3 and 4), the testis had a higher percentage (greater than two fold) of XY cells than the ovary had. However, the highest ratio of cells with a Y chromosome was in the atrophic testis of the infertile male (case 5). The distribution of mosaic clones in the different gonadal cell types was examined. Both females (cases 1 and 2) with dysgenetic gonads had scant ovarian stroma and nests of Leydig or hilus cells. In FISH studies, the coelomic epithelial cells were predominantly 46,XY; in comparison, the Leydig and hilus cells had a lower percentage and the ovarian stroma the least number of cells with a Y signal. A mixed gonadal dysgenesis case (case 3) possessed a right testis with an XY complement in approximately 21% of Sertoli cells and approximately 14% of Leydig cells. The infertile male had an atrophic testis with interstitial hyperplasia (case 5). His testis contained Sertoli cells but no evidence of spermatogenesis. FISH detected a Y signal in about 50-60% of the Sertoli and Leydig cells.

Adolescent↗
PubMedDate not supplied

Correlation of confined placental mosaicism with fetal intrauterine growth retardation. A case control study of placentas at delivery.

OBJECTIVE: Our purpose was to determine if the frequency of confined placental mosaicism in newborns with unexplained intrauterine growth retardation (IUGR) was higher compared with infants with appropriate growth in utero and the outcome of these pregnancies. STUDY DESIGN: A total of 20 cases with unexplained IUGR and 20 cases with appropriate growth for gestational age has been studied. Amnion, chorion and villi biopsy specimens were obtained from growth-retarded cases and controls at delivery. Cord blood specimens for 48-hour lymphocyte cultures were obtained from all infants with IUGR. RESULTS: Karyotype analysis revealed confined placental mosaicism in two of 20 (10%) cases with IUGR. In one growth retarded case and one appropriate growth for gestational age case, mosaicism was also confirmed in the amnion. Cytogenetic analysis from peripheral blood of newborns showed normal karyotype in all cases. Three pregnancies in the group of fetuses with IUGR (15%) ended with fetal death compared with normal fetal surveillance of all cases from the control group. CONCLUSION: Confined placental mosaicism was detected two times more frequently from placentas of growth- retarded infants compared with those of newborns with appropriate growth. The fetal loss was significantly higher in the group of cases with IUGR compared with the control group.

Case-Control Studies↗
PubMed2002

Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction.

Fanconi anemia (FA) is a genetically and phenotypically heterogenous autosomal recessive disease associated with chromosomal instability and hypersensitivity to DNA crosslinkers. Prognosis is poor due to progressive bone marrow failure and increased risk of neoplasia, but revertant mosaicism may improve survival. Mechanisms of reversion include back mutation, intragenic crossover, gene conversion and compensating deletions/insertions. We describe the types of reversions found in five mosaic FA patients who are compound heterozygotes for single base mutations in FANCA or FANCC. Intragenic crossover could be shown as the mechanism of self-correction in the FANCC patient. Restoration to wildtype via back mutation or gene conversion of either the paternal or maternal allele was observed in the FANCA patients. The sequence environments of these mutations/reversions were indicative of high mutability, and selective advantage of bone marrow precursor cells carrying a completely restored FANCA allele might explain the surprisingly uniform pattern of these reversions. We also describe a first example of in vitro phenotypic reversion via the emergence of a compensating missense mutation 15 amino acids downstream of the constitutional mutation, which explains the reversion to MMC resistance of the respective lymphoblastoid cell line. With one exception, our mosaic patients showed improvement of their hematological status during a three- to six-year observation period, indicating a proliferative advantage of the reverted cell lineages. In patients with Fanconi anemia, genetic instability due to defective caretaker genes sharply increases the risk of neoplasia, but at the same time increases the chance for revertant mosaicism leading to improved bone marrow function.

Adolescent↗
PubMed1992

True hermaphroditism in 45,X/46,XY mosaicism.

This report discusses the clinical findings on two patients with 45,X/46,XY mosaicism, two boys presented with penile hypospadias and cryptorchidism. A dysgenetic ovary and a testis were found in one boy, and a dysgenetic ovary in the other. Both patients can be considered to be true hermaphrodites on the basis of histology and clinical and hormonal observations. 45,X/46,XY mosaics have a wide range of phenotypic appearances and their gonadal morphology can also show great differences. However, the incidence of true hermaphroditism in individuals with 45,X/46,XY mosaicism is low and the reports in the literature rare. It is likely that males with 45,X/46,XY who suffer only mild maldevelopment of the external genitalia will not be recognized. In all patients with penoscrotal hypospadias and cryptorchidism with 45,X/46,XY mosaicism, the possibility of true hermaphroditism should be considered.

Child↗
PubMed1993

Somatic mosaicism for partial paternal isodisomy in Wiedemann-Beckwith syndrome: a post-fertilization event.

Genomic imprinting has been implicated in the aetiology of an overgrowth cancer-prone syndrome, the Wiedemann-Beck-with syndrome (WBS). We have demonstrated uniparental disomy (UPD) for paternal chromosome 11p markers in 5 out of 25 sporadic cases (20%). Delineation of the extent of the disomy region may help in understanding the mechanism and the stage, meiotic or mitotic, of disomy formation in this disease and in associated tumours. Our current studies in WBS patients with seventeen 11p and one 11q markers reveal paternal isodisomy, not heterodisomy, in the five cases. For one case we demonstrate unambiguously that partial isodisomy for 11p and somatic mosaicism for UPD resulted from a post-fertilization event. The restriction of isodisomy to part of 11p in another case, and somatic mosaicism for UPD in three other cases, suggest a mitotic recombinational event that must have occurred after fertilization. Mosaic phenotypes reflect the timing of their origin and the fate of the cells involved, as well as the cell-specific pattern of imprinting. Somatic mosaicism for UPD in four cases may thus explain the incomplete forms of WBS. The association of hemihypertrophy in sporadic WBS and even some cases of isolated hemihypertrophy. This is in agreement with a recent report of paternal isodisomy for 11p markers in a patient with hemihypertrophy, Wilms' tumour and adrenocortical carcinoma. Moreover, the risk of developing a tumour seems higher (50%) for patients with paternal 11p UPD than for WBS patients in general (7.5%).

Adult↗
PubMed2024

Single-cell sequencing shows mosaic aneuploidy in most human embryos.

Mammalian preimplantation embryos often contain chromosomal defects that arose in the first divisions after fertilization and affect a subpopulation of cells - an event known as mosaic aneuploidy. In this issue of the JCI, Chavli et al. report single-cell genomic sequencing data for rigorous evaluation of the incidence and degree of mosaic aneuploidy in healthy human in vitro fertilization (IVF) embryos. Remarkably, mosaic aneuploidy occurred in at least 80% of human blastocyst-stage embryos, with often less than 20% of cells showing defects. These findings confirm that mosaic aneuploidy is prevalent in human embryos, indicating that the process is a widespread event that rarely has clinical consequences. There are major implications for preimplantation genetic testing of aneuploidy (PGT-A), a test commonly used to screen and select IVF embryos for transfer. The application and benefit of this technology is controversial, and the findings provide more cause for caution on its use.

Pregnancy↗
PubMed2004

Piecing together the puzzle of cutaneous mosaicism.

Autosomal dominant disorders of the skin may present in a pattern following the lines of embryologic development of the ectoderm. In these cases, the surrounding skin is normal, and molecular studies have shown that the causative mutation is confined to the affected ectodermal tissue (type 1 mosaicism). Rarely, an individual shows skin lesions that follow the pattern of type 1 mosaicism, but the rest of the skin shows a milder form of the disorder (type 2 mosaicism). A new study provides the molecular basis for type 2 mosaicism.

Body Patterning↗
PubMed2004

Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel.

Activating mutations in the KCNJ11 gene encoding for the Kir6.2 subunit of the beta-cell ATP-sensitive potassium channel have recently been shown to be a common cause of permanent neonatal diabetes. In 80% of probands, these are isolated cases resulting from de novo mutations. We describe a family in which two affected paternal half-siblings were found to be heterozygous for the previously reported R201C mutation. Direct sequencing of leukocyte DNA showed that their clinically unaffected mothers and father were genotypically normal. Quantitative real-time PCR analysis of the father's leukocyte DNA detected no trace of mutant DNA. These results are consistent with the father being a mosaic for the mutation, which is restricted to his germline. This is the first report of germline mosaicism in any form of monogenic diabetes. The high percentage of permanent neonatal diabetes cases due to de novo KCNJ11 mutations suggests that germline mosaicism may be common. The possibility of germline mosaicism should be considered when counseling recurrence risks for the parents of a child with an apparently de novo KCNJ11 activating mutation.

Adenosine Triphosphate↗
PubMed2006

Normal female phenotype and ovarian development despite the ovarian expression of the sex-determining region of Y chromosome (SRY) in a 46,XX/69,XXY diploid/triploid mosaic child conceived after in vitro fertilization-intracytoplasmic sperm injection.

CONTEXT: Diploid/triploid mosaicism (mixoploidy) is a rare chromosomal abnormality characterized by mental and growth retardation, hypotonia, and dysmorphic features such as facial asymmetry, low-set ears, and syndactyly. All 46,XX/69,XXY cases fall into three phenotypic groups: male with testicular development, ovotestis disorder of sex development (DSD), or undervirilized male DSD. All phenotypic females with diploid/triploid mosaic reported so far had 46,XX/69,XXX karyotype. PATIENT: We report an 8-year-old girl conceived after in vitro fertilization-intracytoplasmic sperm injection with normal internal/external genital and ovarian development despite 46,XX/69,XXY mosaicism and normal expression of sex-determining region of Y chromosome (SRY) in her gonads. INTERVENTION: Because of the increased risk of gonadoblastoma resulting from Y chromosome mosaicism, her ovaries were removed by laparoscopy. Ovarian tissue was analyzed histologically as well as by fluorescence in situ hybridization, PCR, and RT-PCR amplification to determine the localization of Y chromosome and expression of SRY and DAX1 mRNA. Methylation-specific PCR was used to assess the inactivation pattern of X chromosomes. RESULTS: By laparoscopy, internal female genital anatomy appeared to be normal. Cytogenetic and molecular methods confirmed the presence of intact and functionally active Y chromosome in the ovary. Strikingly, histological assessment of the gonads showed normal ovarian architecture with abundant primordial follicles despite the presence of the Y chromosome in ovarian follicles and the expression of SRY mRNA in gonadal tissue. CONCLUSION: This case illustrates that normal ovarian development is possible in the presence of Y chromosome in ovarian follicles and despite the expression of SRY in ovarian tissue. Furthermore, this is the first documented case of mixoploidy after in vitro fertilization-intracytoplasmic sperm injection and the only phenotypic female with 46,XX/69,XXY karyotype.

Child↗
PubMed1995

Nested polymerase chain reaction study of 53 cases with Turner's syndrome: is cytogenetically undetected Y mosaicism common?

Turner's syndrome patients with Y mosaicism face a high risk of developing gonadoblastoma. Cytogenetic analysis can fail to detect rare cells bearing a normal or structurally abnormal Y chromosome (low level Y mosaicism). We screened 53 individuals with Turner's syndrome for presence of sex-determining region Y (SRY), the testis-specific protein, Y encoded, gene, and the Y centromeric DYZ3 repeat using nested polymerase chain reaction (PCR). Thirty girls (57%) had the 45,X karyotype, determined through standard analysis of blood lymphocytes. The remaining 23 girls (43%) were mosaics and/or had structural abnormalities in 1 X-chromosome. Genomic DNA from blood leukocytes was amplified using 2 rounds of PCR. This method was sensitive enough to detect 0.0001% male DNA on a female background. None of 53 Turner's syndrome cases was positive for Y-specific loci after the first round of PCR. After the second round, 2 of 53 Turner's syndrome cases were positive for SRY mapping to the distal short arm of chromosome Y. In 1 SRY-positive subject, the karyotype was 45,X, and in the other, it was 46,Xi(Xq). None of 53 Turner's syndrome individuals, including the 2 SRY-positive subjects, were positive for the testis-specific protein, Y encoded, gene on the proximal short arm of chromosome Y or the centromeric DYZ3 repeat. These data exclude low level Y mosaicism in almost all Turner's syndrome cases tested.

Base Sequence↗
PubMed1999

45,X/46,XY mosaicism: report of 27 cases.

OBJECTIVES: There exist substantial differences between prenatally and postnatally diagnosed cases of 45,X/46,XY mosaicism. Ninety percent of prenatally diagnosed cases show a normal male phenotype, whereas the postnatally diagnosed cases show a wide spectrum of phenotypes. This 10% risk of an abnormal outcome in prenatally diagnosed cases requires further attention. The purpose of the present study is to provide more information on the postnatally diagnosed 45,X/46,XY mosaicism cases. To date, only a few series have been reported. An accurate diagnosis in these patients is essential not only to their follow-up, but also to providing appropriate genetic counselling and subsequent prenatal diagnosis to their parents. METHODS: The clinical, cytogenetic, endocrinologic, histologic and molecular biological findings of 27 patients with 45, X/46,XY mosaicism are analyzed. RESULTS: The reported cases showed a wide spectrum of phenotypes as Turner syndrome, mixed gonadal dysgenesis (MGD), male pseudohermaphroditism (MPH) and apparently normal male. However, Ulrich-Turner stigmata were the most common features found in this series. Patients with MGD or MPH presented with various degrees of sex reversal such as hypospadias and/or abnormal internal genitalia. No correlation between the proportion of the 45,X/46,XY cell lines in the blood or the fibroblasts and the phenotype was found. Mild mental retardation was present in 4 of the patients and 2 patients showed signs of autism. CONCLUSIONS: Two major points are emphasized in this series: 1) the presence in 7 histologically analyzed streak gonads of a homogeneous 45,X chromosomal complement suggests that the invasion of the primitive genital ridge by a such a cell line may induce abnormal gonadal development; 2) 3 males, apparently normal at birth, developed late onset abnormalities such as dysgenetic testes leading to infertility, Ulrich-Turner stigmata, dysmorphic features, and mild mental retardation. These data indicate the importance of an accurate clinical and histologic evaluation of any patient presenting with 45, X/46,XY mosaicism.

Disorders of Sex Development↗