Outcomes in pregnancies with a confined placental mosaicism and implications for prenatal screening using cell-free DNA.

PURPOSE: To assess the association between confined placental mosaicism (CPM) and adverse pregnancy outcome. METHODS: A retrospective cohort study was carried out evaluating the outcome of pregnancies with and without CPM involving a rare autosomal trisomy (RAT) or tetraploidy. Birthweight, gestational age at delivery, fetal growth restriction (FGR), Apgar score, neonatal intensive care admission, preterm delivery, and hypertensive disorders of pregnancy were considered. RESULTS: Overall 181 pregnancies with CPM and 757 controls were recruited. Outcome information was available for 69% of cases (n = 124) and 62% of controls (n = 468). CPM involving trisomy 16 (T16) was associated with increased incidence of birthweight <3rd centile (P = 0.007, odds ratio [OR] = 11.2, 95% confidence interval [CI] = 2.7-47.1) and preterm delivery (P = 0.029, OR = 10.2, 95% CI = 1.9-54.7). For the other RATs, an association with prenatally diagnosed FGR was not supported by birthweight data and there were no other strong associations with adverse outcomes. CONCLUSION: Excluding T16, the incidence of adverse pregnancy outcomes for pregnancies carrying a CPM is low. RATs can also be identified through genome-wide cell-free DNA screening. Because most of these will be attributable to CPMs, we conclude that this screening is of minimal benefit.

Somatic mosaicism of sex chromosomes in the blood and brain.

In the blood, mosaic somatic aneuploidy (mSA) of all chromosomes has been found to be associated with adverse health outcomes, including hematological cancer. Sex chromosome mSA in the blood has been found to occur at a higher rate than autosomal mSA. Mosaic loss of the Y chromosome is the most common copy number alteration in males, and has been found to be associated with Alzheimer's disease (AD) in blood lymphocytes. mSA of the sex chromosomes has also been identified in the brain; however, little is known about its frequency across individuals. Using WGS data from 362 males and 719 females from the ROSMAP cohort, we quantified the relative rate of sex chromosome mSA in the dorsolateral prefrontal cortex (DLPFC), cerebellum and whole blood. To ascertain the functionality of observed sex chromosome mosaicism in the DLPFC, we examined its correlation with chromosome X and Y gene expression as well as neuropathological and clinical characteristics of AD and cognitive ageing. In males, we found that mSA of the Y chromosome occurs more frequently in blood than in the DLPFC or cerebellum. In the DLPFC, the presence of at least one APOE4 allele was associated with a reduction in read depth of the Y chromosome (p = 1.9e-02). In the female DLPFC, a reduction in chromosome X read depth was associated with reduced cognition at the last clinical visit and faster rate of cognitive decline (p = 7.8e-03; p = 1.9e-02). mSA of all sex chromosomes in the DLPFC were associated with aggregate measures of gene expression, implying functional impact. Our results provide insight into the relative rate of mSA between tissues and suggest that Y and female X chromosome read depth in the DLPFC is modestly associated with late AD risk factors and cognitive pathologies.

Higher male prevalence of chromosomal mosaicism detected by amniocentesis.

OBJECTIVE: To present the calculated frequencies, male to female sex-ratio, and modes of ascertainments in different levels of chromosomal mosaicism (CM) detected at amniocentesis. MATERIALS AND METHODS: This's a 10-years retrospective study between January 2008 and December 2017 and there were 13,752 cases of amniocentesis performed in MacKay Memorial Hospital, Taipei, Taiwan. Eight hundred and thirty four cases of CM were collected in this study. We reviewed their types of chromosomal abnormalities of mosaicism, the modes of ascertainment (including: advanced maternal age, abnormal ultrasound findings, abnormal maternal serum screening result, and other reasons), maternal age, gestational age at amniocentesis, fetal gender, and perinatal findings. After amniocentesis, in situ culture was performed and the results of karyotype with CM were divided in to three levels. RESULTS: In our sample of 13,752 amniocentesis, 834 cases with all levels of CM were collected in this study. Of them, there were 562 cases (4.09%) with level I mosaicism, 207 cases (1.51%) of level II mosaicism, and 65 cases (0.47%) of level III mosaicism (Table 1). In the group of advanced of maternal age (AMA), their calculated frequencies, 4.18% in level I, 1.46% in level II and 0.41% in level III, were very similar to those in total cases (p value = 0.206) without statistical significance. In the group of abnormal ultrasound findings, the calculated frequency was much higher in level III (0.87%), however, there was no statistical significance because of the small numbers of level III. In our cases of amniocentesis, the case numbers of male case (50.20%) is very similar to female (49.80%), and the male to female ratio was 1.01. But, we found more cases of male with CM (444 cases) than female (390 cases). The sex-ratio in different levels' calculated frequencies of CM showed similar in level I, and male prevalence was found in level II and III with statistical significance (p value = 0.022). The male prevalence also revealed in both numerical and structural abnormalities in level II and level III, but no difference in the cases of level I. CONCLUSION: In conclusion, our observation showed a novel finding of higher male prevalence of CM in level II and III, and both in numerical and structural abnormalities. It's consistent with the theory of better survival in male embryo after partial self-correction of initial chromosomal aberrations, male-specific selection against chromosomal abnormalities.

The categories of cutaneous mosaicism: A proposed classification.

Mosaic disorders can most easily be studied in the skin. This article presents a comprehensive overview of the different forms of cutaneous mosaicism. Major categories are genomic versus epigenetic mosaicism and nonsegmental versus segmental mosaicism. The class of nonsegmental mosaics includes single point mosaicism as exemplified by solitary benign or malignant skin tumors; disseminated mosaicism as noted in autosomal dominant tumor syndromes such as neurofibromatosis 1; and patchy mosaicism without midline separation as found in giant melanocytic nevus. The class of segmental mosaics includes segmental manifestation of lethal genes surviving by mosaicism as noted in Proteus syndrome; type 1 segmental mosaicism of autosomal dominant skin disorders reflecting heterozygosity for a postzygotic new mutation; type 2 segmental mosaicism of autosomal dominant skin disorders reflecting loss of heterozygosity that occurred at an early developmental stage in a heterozygous embryo; and isolated or superimposed segmental mosaicism of common polygenic skin disorders such as psoriasis or atopic dermatitis. A particular form of genomic mosaicism is didymosis (twin spotting). Revertant mosaicism is recognizable as one or more areas of healthy skin in patients with epidermolysis bullosa or other serious genodermatoses. The category of epigenetic mosaicism includes several X-linked, male lethal disorders such as incontinentia pigmenti, and the patterns of lyonization as noted in X-linked non-lethal disorders such as hypohidrotic ectodermal dysplasia of the Christ-Siemens-Touraine type. An interesting field of future research will be the concept of epigenetic autosomal mosaicism that may explain some unusual cases of autosomal transmission of linear hypo- or hypermelanosis.

Mosaicism and clinical genetics.

With the introduction of increasingly sensitive technologies for mutation detection such as chromosomal microarrays and next-generation sequencing, the importance of mosaicism for human disease is being more fully appreciated. Mosaicism can occur for any type of mutation, either at the chromosomal or DNA sequence level, and while in many cases mosaicism can modify the clinical effects of a syndrome, there are many alterations that can only occur in mosaic form as the mutation is lethal when present in every cell. Mosaicism can have a wide range of effects, from early pregnancy loss, to organ specific pathology, to modification of clinical syndromes. Recent evidence reveals that generation of mosaic alterations is associated with aging, and our ability to detect mosaic alterations sheds light on normal and pathologic changes across the lifespan.

Cutaneous mosaicisms: concepts, patterns and classifications.

A mosaic is an organism composed of two or more genetically distinct cell populations derived from a genetically homogeneous zygote. Cutaneous mosaicisms are the clinical expressions of these disorders. The main event which allows the existence of mosaicism is a genetic mutation, either structural or functional. Cutaneous mosaicisms usually manifest by specific patterns on the skin and the archetypic pattern is the system of Blaschko lines, but others include checkerboard, phylloid, large patches without midline separation and lateralization. Since 1901, when Blaschko lines were first described, the study of mosasicism has helped to elucidate the behavior of numerous genetic diseases, generating therapeutic perspectives for these pathologies, including the promising gene therapy.

Cutaneous mosaicisms: concepts, patterns and classifications / Mosaicismos cutaneos: conceitos, padroes e classificacoes

A mosaic is an organism composed of two or more genetically distinct cell populations derived from a genetically homogeneous zygote. Cutaneous mosaicisms are the clinical expressions of these disorders. The main event which allows the existence of mosaicism is a genetic mutation, either structural or functional. Cutaneous mosaicisms usually manifest by specific patterns on the skin and the archetypic pattern is the system of Blaschko lines, but others include checkerboard, phylloid, large patches without midline separation and lateralization. Since 1901, when Blaschko lines were first described, the study of mosasicism has helped to elucidate the behavior of numerous genetic diseases, generating therapeutic perspectives for these pathologies, including the promising gene therapy.

Um mosaico é um organismo formado por duas ou mais populações de células geneticamente distintas originadas a partir de um mesmo zigoto geneticamente homogêneo. Os mosaicismos são as expressões clínicas dessa desordem, e a mutação gênica seu evento determinante, que pode ser tanto estrutural quanto funcional. Os mosaicismos cutâneos costumam se expressar em padrões específicos, dentre os quais podem ser mencionados as prevalentes linhas de Blaschko, o padrão "checkerboard", o padrão filóide, o padrão em placa sem separação na linha média e o padrão de lateralização, que serão abordados neste artigo. Desde 1901, momento da primeira descrição das linhas de Blaschko, o estudo dos mosaicismos tem contribuído para a elucidação do comportamento de numerosas desordens genéticas, de forma a criar perspectivas terapêuticas para essas doenças, incluindo a promissora terapia gênica.

Bregmatic wormian bone and metopic synostosis.

We present a case of a 14-week-old girl with metopic synostosis and an incidental finding of a large, pentagonal bregmatic wormian bone. No prior photographic evidence of this combination of rare findings exists. An extensive review of the incidence, etiology, and significance of these unusual supernumerary cranial bones is provided in this study.

The clinical and genetic heterogeneity of mixed gonadal dysgenesis: does "disorders of sexual development (DSD)" classification based on new Chicago consensus cover all sex chromosome DSD?

UNLABELLED: Clinical findings illustrate the wide spectrum of the phenotypic manifestations of 45,X/46,XY mosaicism in the sex chromosome disorders of sex differentiation (DSD). The objective of study is to evaluate the characteristics of 45,X/46,XY patients and questioning of their place within the DSD categorization. The clinical findings of 11 patients with 45,X/46,XY mosaicism are described including the presentation, gonadal morphology, genital anatomy, and the hormone levels among 285 patients with DSD evaluated. Sixty-seven patients were diagnosed with sex chromosome DSD (50 Turner, three Klinefelter, ten 45,X/46,XY gonadal disgenesis, one 45X/46,XY ovotesticular DSD, one 47,XYY ovotesticular DSD, and two 46,XX/46,XY ovotesticular DSD). The type and the percentage of patients with 45,X/46,XY mosaicism were as follows: Four cases of mix gonadal dysgenesis, four cases of partial gonadal dysgenesis, two cases of complete gonadal dysgenesis, one case of ovotesticular DSD. On the other hand, another patient that has 45,X/46,XX mosaicism was diagnosed with MGD with the presence of the streak gonad on the right side and the testis on the other side. CONCLUSION: We suggest that sex chromosome DSD categorization can include 45,X/46,XY PGD and 45,X/46,XY CGD. Mixed gonadal dysgenesis may be also placed among the disorders of testicular differentiation of 46,XY DSD subdivision.

A case of gynandromorphism in Hyalomma marginatum Koch, 1844 (Acari: Ixodidae).

Gynandromorphism is a rare, abnormal phenomenon in which both female and male characteristics are simultaneously displayed in an organism. It has been described in many arthropods, including ticks. This unique occurrence is known within several species of Amblyomma, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, and Rhipicephalus. Bipartite protogynander is the most common form of gynandromorphism, whereas gynander intriqué is the rarest type among the ticks. Here, we report the first case of a gynandromorph of Hyalomma marginatum Koch, 1844 collected from a naturally infested human during a tick survey in the Tokat Province of Turkey in 2006. It is an interesting gynander intriqué, with features of a protogynander. The tick described here displays abnormal characters such as an alloscutum with a male consucutum in dorsal view, male and female spiracular plates, female genital aperture under the male genital flap, and adanal plates located on the both side of the anus, whereas accessory plates are on the left side only in ventral view.

Detection of mosaicism for genome imbalance in a cohort of 3,042 clinical cases using an oligonucleotide array CGH platform.

Mosaicism for chromosome imbalance has traditionally been detected by karyotype analysis. The introduction of array CGH into clinical diagnostic laboratories and routine clinical practice has raised concerns as to the ability of this new test to detect the presence of more than one cell line. We present our validation data on the detection of chromosome mosaicism by oligonucleotide array CGH, and the cases detected in a cohort of 3042 clinical referrals. Using an artificial mosaicism series, we found that oligonucleotide array CGH using specific analysis parameters could accurately measure levels of mosaicism down to 10% and that the degree of mosaicism could be predicted from fluorescence ratios. We detected 12 cases of mosaicism in our clinical cohort, in 9 of which there was no previous indication of mosaicism. In two cases, G-banded chromosome analysis had been carried out previously, and had failed to detect the abnormal cell line. Three cases had mosaicism for the X chromosome and 9 involved autosomes, of which 4 were mosaic for whole chromosome trisomies, one for whole chromosome monosomy, and four were mosaic for segmental imbalances. We conclude that oligonucleotide array CGH has the power to detect a range of mosaic abnormalities in clinical diagnostic samples.

Confined placental mosaicism and pregnancy outcome: a distinction needs to be made between types 2 and 3.

OBJECTIVE: To study the influence of types 2 and 3 confined placental mosaicism (CPM) on pregnancy outcome. METHOD: From 13 809 chorionic villus samplings (CVSs), karyotype after long-term cultured villi (LTC-villi) was systematically performed. Next, in case of suspicion of CPM, karyotype after short-term cultured villi (STC-villi) was established to define type 2 CPM (chromosomal abnormality limited to the mesenchymal core) or type 3 CPM (chromosomal abnormality found both in the cytotrophoblast and the mesenchymal core). Confirmatory amniocentesis was performed to exclude fetal mosaicism. Uniparental disomy (UPD) testing was carried out when the abnormal cell line involved chromosomes 5, 6, 7, 15 or 16. RESULTS: Fifty-seven CPM cases were observed (57/13 809 = 0.41%) and of these, 37 were type 2 and 20 were type 3 CPM. Incidence of preterm infants, neonatal hypotrophy and adverse pregnancy outcome were comparable between patients in whom type 2 CPM was demonstrated and the control population. In contrast, for the type 3 CPM the incidence of these factors was higher than for the control population. CONCLUSION: When a CPM is suspected, it appears essential to determine type, since type 2 has no effect on fetal development and type 3 is associated with preterm infants, low birth weight and adverse pregnancy outcome.

Morfea siguiendo líneas de Blaschko estrechas / Morphea Distributed Along Narrow Blaschko Lines

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The frequency of occurrence of abnormal frenal attachment of lips and enamel defects in Turner syndrome.

OBJECTIVE: The aim of the work was to register the frequency of occurrence of abnormal frenal attachment of lips and enamel defects and find the correlation between these anomalies and three types of Turner syndrome. MATERIALS AND METHODS: Fifty patients (aged 20-40 years) were clinically and cytogenetically diagnosed and divided into three groups, according to karyotype: 45,X (17 cases), with structural aberrations of chromosome X (12 cases) and with mosaic karyotype (21 cases). The control group consisted of 51 healthy woman aged 21-40 years. Subjects were screened for developmental anomalies in the labial frenula and enamel defects in three groups of Turner syndrome. RESULTS: Some significant anomalies of soft and hard tissues were found in studied patients: abnormal frenal attachments (42% of cases), enamel opacities (58% of cases) and enamel hypoplasia (38% of cases). Differences in the occurrence of these anomaly in all group with Turner syndrome in comparison with the control group were significantly different. Enamel defects were prevalent in the patients with karyotype 45,X and patients with structural aberrations of chromosome X in comparison with the mosaic karyotype. CONCLUSION: The results of the present study have shown, that abnormal attachment of lips and enamel defects were more frequent in Turner syndrome patients than in the control group. Enamel defects were correlated with the karyotypes of Turner syndrome and abnormal attachment of lips was not correlated with the karyotypes of Turner syndrome.

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.