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Human Molecular Genetics Apr 2010Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic...
Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1-3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.
Topics: Aneuploidy; Chimerism; Humans; Meiosis; Monosomy; Mosaicism; Polymorphism, Single Nucleotide; Sex Chromosomes; Trisomy; Uniparental Disomy
PubMed: 20053666
DOI: 10.1093/hmg/ddq003 -
Clinical Epigenetics 2018Monosomy of the X chromosome is the most frequent genetic abnormality in human as it is present in approximately 2% of all conceptions, although 99% of these embryos are... (Review)
Review
BACKGROUND
Monosomy of the X chromosome is the most frequent genetic abnormality in human as it is present in approximately 2% of all conceptions, although 99% of these embryos are spontaneously miscarried. In postnatal life, clinical features of Turner syndrome may include typical dysmorphic stigmata, short stature, sexual infantilism, and renal, cardiac, skeletal, endocrine and metabolic abnormalities.
MAIN TEXT
Turner syndrome is due to a partial or total loss of the second sexual chromosome, resulting in the development of highly variable clinical features. This phenotype may not merely be due to genomic imbalance from deleted genes but may also result from additive influences on associated genes within a given gene network, with an altered regulation of gene expression triggered by the absence of the second sex chromosome. Current studies in human and mouse models have demonstrated that this chromosomal abnormality leads to epigenetic changes, including differential DNA methylation in specific groups of downstream target genes in pathways associated with several clinical and metabolic features, mostly on autosomal chromosomes. In this article, we begin exploring the potential involvement of both genetic and epigenetic factors in the origin of X chromosome monosomy. We review the dispute between the meiotic and post-zygotic origins of 45,X monosomy, by mainly analyzing the findings from several studies that compare gene expression of the 45,X monosomy to their euploid and/or 47,XXX trisomic cell counterparts on peripheral blood mononuclear cells, amniotic fluid, human fibroblast cells, and induced pluripotent human cell lines. From these studies, a profile of epigenetic changes seems to emerge in response to chromosomal imbalance. An interesting finding of all these studies is that methylation-based and expression-based pathway analyses are complementary, rather than overlapping, and are correlated with the clinical picture displayed by TS subjects.
CONCLUSIONS
The clarification of these possible causal pathways may have future implications in increasing the life expectancy of these patients and may provide informative targets for early pharmaceutical intervention.
Topics: Chromosomes, Human, X; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Monosomy; Trisomy; Turner Syndrome
PubMed: 29636833
DOI: 10.1186/s13148-018-0477-0 -
Blood Jun 2018Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q))... (Review)
Review
Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models. (sterile α motif domain 9) and (SAMD9-like) encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile myelodysplastic syndrome (MDS) harboring monosomy 7. Because MDS develops in -deficient mice over their lifetime, / are likely responsible for sporadic MDS with -7/del(7q) as the sole anomaly. (enhancer of zeste homolog 2) and (mixed lineage leukemia 3) encode histone-modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to /, loss of or likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying -7/del(7q).
Topics: Animals; Chromosome Deletion; Chromosomes, Human, Pair 7; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes
PubMed: 29615405
DOI: 10.1182/blood-2017-12-822262 -
American Journal of Medical Genetics.... Feb 2023Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American...
Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.
Topics: Humans; Chromosomes, Human, Pair 1; Muscle Hypotonia; Down Syndrome; DiGeorge Syndrome; Intellectual Disability; Microcephaly; Chromosome Deletion; Phenotype; Epilepsy
PubMed: 36369750
DOI: 10.1002/ajmg.a.63041 -
Journal of Medical Genetics Sep 1999We have reviewed published reports on patients with segmental aneusomy for chromosome 1p36 to help geneticists and other health professionals in the recognition of this... (Review)
Review
We have reviewed published reports on patients with segmental aneusomy for chromosome 1p36 to help geneticists and other health professionals in the recognition of this emerging chromosomal syndrome. Terminal deletions of the short arm of chromosome 1 are associated with hypotonia and developmental delay (usually severe), growth abnormalities (growth retardation, microcephaly, obesity), and craniofacial dysmorphism with a large anterior fontanelle, prominent forehead, deep set eyes, flat nasal bridge and midface hypoplasia, ear asymmetry, a pointed chin, and orofacial clefting. Minor cardiac malformations, cardiomyopathy, seizures, and ventricular dilatation are the more common additional findings. Sensorineural hearing loss and variable ophthalmological anomalies have also been frequently observed. Although the deletions can be detected by high resolution cytogenetic studies, confirmation by fluorescence in situ hybridisation is required in most cases. The majority of deletions are maternally derived. Molecular characterisation of 1p36 deletions has been undertaken in several cases, and it is likely that this condition is a contiguous gene deletion syndrome.
Topics: Adolescent; Adult; Child; Child, Preschool; Chromosome Aberrations; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 1; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Syndrome
PubMed: 10507720
DOI: No ID Found -
Ophthalmology Oct 2023To report a previously unrecognized choroidal melanoma clinical feature termed tumor-associated retinal pigmentation (TARP) and determine any correlation with tumor...
PURPOSE
To report a previously unrecognized choroidal melanoma clinical feature termed tumor-associated retinal pigmentation (TARP) and determine any correlation with tumor biology.
DESIGN
Imaging and histologic analysis of a retrospective cohort of patients.
PARTICIPANTS
Patients with choroidal melanoma identified as having TARP on funduscopy at the Liverpool Ocular Oncology Centre (LOOC), United Kingdom, from January 2020 through January 2023.
METHODS
Clinical and imaging characteristics of patients diagnosed with choroidal melanoma and exhibiting TARP on fundoscopy were documented. Details of these choroidal melanomas were collated and correlated with histopathology and molecular genetic reports. The chromosome 3 status of each tumor was assessed. In enucleated samples, immunostaining was undertaken to determine the nature of the TARP using specific markers (CD68 and MelanA).
MAIN OUTCOME MEASURES
Features of TARP on widefield fundus color imaging, fundus autofluorescence (FAF), and OCT were described. Tumor chromosome 3 status and the immunoprofile of the TARP also were collated.
RESULTS
Tumor-associated retinal pigmentation had a prevalence rate of 7.47 per 100 cases of choroidal melanoma at the LOOC. Twenty-three eyes with TARP were analyzed, with a mean age of 71.4 years (range, 51-88 years). The median largest basal diameter was 16.10 mm (range, 9.17-21.32 mm), and the mean tumor thickness was 8.04 mm (range, 1.40-13.80 mm). Tumor-associated retinal pigmentation was observed on widefield color fundus imaging, with hypofluorescence on FAF images and represented hyperreflective foci located in intraretinal and subretinal spaces on OCT scans. Seventeen patients (73.9%) underwent enucleation, and 6 patients (26.1%) underwent globe-sparing treatment. Molecular genetic analysis of 20 choroidal melanomas (after enucleation or radiotherapy biopsy) revealed monosomy 3 in 18 tumors (90%). Immunostaining of the TARP in enucleated eyes showed CD68+ melanophages in all 17 patients appearing as scattered cells and aggregates; MelanA findings were negative.
CONCLUSIONS
Tumor-associated retinal pigmentation represents tumor-associated macrophages, not melanocytes, within intraretinal and subretinal spaces of larger choroidal melanomas. Radiation treatments need not involve this area in the treatment plan, minimizing radiation-related complications. This novel clinical sign seems to be linked to tumors of high metastatic-risk clinical and genetic characteristics, with a preponderance having monosomy 3 anomalies.
FINANCIAL DISCLOSURE(S)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Topics: Humans; Aged; MART-1 Antigen; Retrospective Studies; Choroid Neoplasms; Melanoma; Pigmentation; Monosomy; Fluorescein Angiography
PubMed: 37182744
DOI: 10.1016/j.ophtha.2023.05.009 -
European Journal of Medical Genetics Jun 2023Phelan-McDermid syndrome (PMS) is a 22q13.3 deletion syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes... (Review)
Review
Phelan-McDermid syndrome (PMS) is a 22q13.3 deletion syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities like seizures. The epilepsy manifests itself in a variety of seizure semiologies. Further diagnostics using electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) are important in conjunction with the clinical picture of the seizures to decide whether anticonvulsant therapy is necessary. As part of the development of European consensus guidelines we focussed on the prevalence and semiology of epileptic seizures in PMS associated with a pathogenic variant in the SHANK3 gene or the 22q13 deletion involving SHANK3, in order to then be able to make recommendations regarding diagnosis and therapy.
Topics: Humans; Chromosome Disorders; Chromosome Deletion; Epilepsy; Seizures; Chromosomes, Human, Pair 22
PubMed: 36967043
DOI: 10.1016/j.ejmg.2023.104746 -
Orphanet Journal of Rare Diseases Feb 2008Monosomy 18p refers to a chromosomal disorder resulting from the deletion of all or part of the short arm of chromosome 18. The incidence is estimated to be about... (Review)
Review
Monosomy 18p refers to a chromosomal disorder resulting from the deletion of all or part of the short arm of chromosome 18. The incidence is estimated to be about 1:50,000 live-born infants. In the commonest form of the disorder, the dysmorphic syndrome is very moderate and non-specific. The main clinical features are short stature, round face with short philtrum, palpebral ptosis and large ears with detached pinnae. Intellectual deficiency is mild to moderate. A small subset of patients, about 10-15 percent of cases, present with severe brain/facial malformations evocative of holoprosencephaly spectrum disorders. In two-thirds of the cases, the 18p- syndrome is due to a mere terminal deletion occurring de novo, in one-third the following are possible: a de novo translocation with loss of 18p, malsegregation of a parental translocation or inversion, or a ring chr18. Parental transmission of the 18p- syndrome has been reported. Cytogenetic analysis is necessary to make a definite diagnosis. Recurrence risk for siblings is low in de novo deletions and translocations, but is significant if a parental rearrangement is present. Deletion 18p can be detected prenatally by amniocentesis or chorionic villus sampling and cytogenetic testing. Differential diagnosis may include a wide number of syndromes with short stature and mild intellectual deficiency. In young children, deletion 18p syndrome may be vaguely evocative of either Turner syndrome or trisomy 21. No specific treatment exists but speech therapy and early educational programs may help to improve the performances of the children. Except for the patients with severe brain malformations, the life expectancy does not seem significantly reduced.
Topics: Abnormalities, Multiple; Chromosome Disorders; Chromosomes, Human, Pair 18; Diagnosis, Differential; Face; Female; Genetic Counseling; Genotype; Holoprosencephaly; Humans; Incidence; Intellectual Disability; Male; Monosomy; Phenotype; Prenatal Diagnosis; Prognosis; Sex Distribution
PubMed: 18284672
DOI: 10.1186/1750-1172-3-4 -
Genetics and Molecular Research : GMR Feb 2016The major clinical features of monosomy 1p36 deletion are developmental delay and hypotonia associated with short stature and craniofacial dysmorphisms. The objective of... (Meta-Analysis)
Meta-Analysis Review
The major clinical features of monosomy 1p36 deletion are developmental delay and hypotonia associated with short stature and craniofacial dysmorphisms. The objective of this study was to review the cases of 1p36 deletion that was reported between 1999 and 2014, in order to identify a possible correlation between the size of the 1p36-deleted segment and the clinical phenotype of the disease. Scientific articles published in the (National Center for Biotechnology Information; NCBI http://www.ncbi.nlm.nih.gov/pubmed) and Scientific Electronic Library Online (www.scielo.com.br) databases were searched using key word combinations, such as "1p36 deletion", "monosomy 1p36 deletion", and "1p36 deletion syndrome". Articles in English or Spanish reporting the correlation between deletion sizes and the respective clinical phenotypes were retrieved, while letters, reviews, guidelines, and studies with mouse models were excluded. Among the 746 retrieved articles, only 17 (12 case reports and 5 series of cases), comprising 29 patients (9 males and 20 females, aged 0 months (neonate) to 22 years) bearing the 1p36 deletions and whose clinical phenotypes were described, met the inclusion criteria. The genotype-phenotype correlation in monosomy 1p36 is a challenge because of the variability in the size of the deleted segment, as well as in the clinical manifestations of similar size deletions. Therefore, the severity of the clinical features was not always associated with the deletion size, possibly because of the other influences, such as stochastic factors, epigenetic events, or reduced penetration of the deleted genes.
Topics: Adolescent; Child; Child, Preschool; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 1; Female; Humans; Infant; Infant, Newborn; Male; Phenotype; Young Adult
PubMed: 26910004
DOI: 10.4238/gmr.15017942 -
Haematologica Feb 2024Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in...
Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).
Topics: Humans; Child; Child, Preschool; Infant; Remission, Spontaneous; Chromosome Deletion; Myelodysplastic Syndromes; Disease Progression; Transcription Factors; Monosomy; Chromosomes, Human, Pair 7; Intracellular Signaling Peptides and Proteins
PubMed: 37584291
DOI: 10.3324/haematol.2023.283591