scholarly journals Ανίχνευση υπομικροσκοπικών χρωμοσωμικών διαταραχών σε ασθενείς με αυτιστικές διαταραχές με την μέθοδο μικροσυστοιχιών συγκριτικού γενωμικού υβριδισμού array-CGH

2017 ◽  
Author(s):  
Βασίλης Οικονομάκης
Keyword(s):  
Copy Number ◽  
Array Cgh ◽  
De Novo ◽  
Copy Number Variations ◽  
Genomic Variants ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

Οι Διαταραχές Αυτιστικού Φάσματος (ΔΑΦ) ή αυτισμός είναι μία ομάδα ετερογενών ισόβιων νευροαναπτυξιακών διαταραχών που συνήθως αναπτύσσονται κατά την παιδική ηλικία και χαρακτηρίζονται από δυσκολία στην επικοινωνία, τις κοινωνικές αλληλεπιδράσεις και από επαναλαμβανόμενη συμπεριφορά, μέσα σε ένα στενό εύρος ενδιαφερόντων. Ως ηλικία έναρξης των πρώτων συμπτωμάτων ορίζεται συνήθως εκείνη πριν από τα τρία έτη με τη διάγνωση των ΔΑΦ να βασίζεται σε κριτήρια συμπεριφοράς και στη λεπτομερή κλινική εξέταση και καταγραφή των συμπτωμάτων. Το 2012, οι πιο πρόσφατες εκτιμήσεις για τον επιπολασμό στις ΗΠΑ, τοποθετούν τη συχνότητα των ΔΑΦ στο γενικό πληθυσμό σε 1/68 παιδιά ηλικίας οκτώ ετών (1,5%). Οι ΔΑΦ ανήκουν στις λεγόμενες πολυπαραγοντικές διαταραχές για τις οποίες έχουν ενοχοποιηθεί γενετικοί, επιγενετικοί, μεταβολικοί, ορμονικοί, ανοσολογικοί, νευροανατομικοί, νευροφυσιολογικοί καθώς και γαστρεντερικοί παράγοντες καθώς και άλλες συστηματικές διαταραχές και συννοσηρότητες ως πιθανοί παθογενετικοί μηχανισμοί. Η γενετική συμβολή είναι καθοριστικής σημασίας στην αιτιοπαθογένεια του αυτισμού και στην παρούσα διατριβή περιγράφονται αναλυτικά τα διάφορα μοντέλα που έχουν προταθεί για να εξηγήσουν την αυξημένη συχνότητα του αυτισμού σε συγκεκριμένες οικογένειες, καθώς επίσης και οι κύριοι νευροβιολογικοί μηχανισμοί που οδηγούν στον συγκεκριμένο φαινότυπο .Η Χρωμοσωμική Ανάλυση Μικροσυστοιχιών (ΧΑΜ) θεωρείται πλέον ως πρώτη επιλογή διαγνωστικής δοκιμασίας για την διερεύνηση ιδιοπαθών περιπτώσεων ΔΑΦ, Αναπτυξιακών Διαταραχών (ΑΔ) και Νοητικής Υστέρησης (ΝΥ). Για την παρούσα εργασία χρησιμοποιήθηκαν μικροσυστοιχίες υψηλής διακριτικής ικανότητας για τον εντοπισμό χρωμοσωμικών περιοχών αλλαγής αντιγράφων (Copy Number Variations - CNVs) σε 195 ασθενείς ΔΑΦ ελληνικής καταγωγής (126 άρρενα, 69 θήλεα). Η ΧΑΜ είχε σαν αποτέλεσμα τον εντοπισμό 65 παθολογικών CNVs, χωρίς να ληφθούν υπόψιν οι πολυμορφικές αλλαγές αριθμού αντιγράφων (Copy Number Polymorphisms - CNPs), που αλληλεπικαλύπτονται με αλληλουχίες στην ηλεκτρονική βάση δεδομένων Database of Genomic Variants (DGV), σε 51/195 ασθενείς (26,1%). Ο έλεγχος γονεϊκών γονιδιωμάτων σε 20/51 ασθενείς αποκάλυψε ότι 15 CNVs ήταν de novo, 3 ήταν πατρικής προέλευσης ενώ 2 μητρικής.Η πλειοψηφία των 65 CNVs αφορούσε μικροελλείμματα (66.1%), από τα οποία 5 βρέθηκαν στο χρωμόσωμα Χ, ενώ οι μικροδιπλασιασμοί, 7 εκ των οποίων βρέθηκαν στο χρωμόσωμα Χ, ήταν σπανιότεροι, με συχνότητα 33.8%. Τα 51 από τα 65 CNVs που βρέθηκαν στο δείγμα ελέγχου έχουν μεγάλη διαγνωστική αξία και είναι σαφώς περιγεγραμμένα στη διεθνή βιβλιογραφία, ενώ 14 CNVs (8 μικροελλείμματα και 6 μικροδιπλασιασμοί) χαρακτηρίστηκαν ως αλλαγές άγνωστης κλινικής σημασίας (Variants of Unknown Significance - VOUS) και χρήζουν περαιτέρω διερεύνησης. Από τους 51 ασθενείς 39 έφεραν ένα παθολογικό CNV, 10 έφεραν δύο παθολογικά CNVs και δύο ασθενείς έφεραν τρία παθολογικά CNVs.Επιπρόσθετα, έγινε εκτίμηση της ΧΑΜ ως διαγνωστική δοκιμασία και διερευνήθηκε η κλινική της εγκυρότητα και χρησιμότητα.

scholarly journals The Cytoscan HD Array in the Diagnosis of Neurodevelopmental Disorders

2018 ◽  
Vol 7 (3) ◽  
pp. 28 ◽  
Author(s):  
Francesca Scionti ◽  
Maria Di Martino ◽  
Licia Pensabene ◽  
Valentina Bruni ◽  
Daniela Concolino
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Snp Array ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Clinical Diagnostic Laboratory ◽  
Diagnostic Laboratory ◽  
Unknown Significance ◽  
Pathogenic Cnvs ◽  
Line Test

Submicroscopic chromosomal copy number variations (CNVs), such as deletions and duplications, account for about 15–20% of patients affected with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. Most of CNVs are de novo or inherited rearrangements with clinical relevance, but there are also rare inherited imbalances with unknown significance that make difficult the clinical management and genetic counselling. Chromosomal microarrays analysis (CMA) are recognized as the first-line test for CNV detection and are now routinely used in the clinical diagnostic laboratory. The recent use of CMA platforms that combine classic copy number analysis with single-nucleotide polymorphism (SNP) genotyping has increased the diagnostic yields. Here we discuss the application of the Cytoscan high-density (HD) SNP-array for the detection of CNVs. We provide an overview of molecular analyses involved in identifying pathogenic CNVs and highlight important guidelines to establish pathogenicity of CNV.

scholarly journals Relevance of Copy Number Variation at Chromosome X in Male Fetuses Inherited from the Mother May Be Ascertained by Including Male Relatives from the Maternal Lineage in Addition to Trio Analyses

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 979
Author(s):  
Ming Chen ◽  
Wan-Ju Wu ◽  
Mei-Hui Lee ◽  
Tien-Hsiung Ku ◽  
Gwo-Chin Ma
Keyword(s):  
Genetic Counseling ◽  
Copy Number ◽  
Copy Number Variations ◽  
Chromosome X ◽  
Genetic Changes ◽  
Monogenic Disorders ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Number Variation ◽  
Extended Analysis

Chromosome microarray analysis has been used for prenatal detection of copy number variations (CNVs) and genetic counseling of CNVs has been greatly improved after the accumulation of knowledge from postnatal outcomes in terms of the genotype-phenotype correlation. However, a significant number of CNVs are still regarded as variants of unknown significance (VUS). CNVs at the chromosome X (X-CNVs) represent a unique group of genetic changes in genetic counseling; X-CNVs are similar to X-linked recessive monogenic disorders in that the prognosis in males is expected to be poor. Trio analysis is typically advised to patients with X-CNVs but such an approach may be inadequate in prenatal settings since the clinical relevance is sometimes uninformative, particularly for the maternally inherited X-CNVs in male fetuses. Here, we reported four healthy women whose male fetuses were found to have X-CNVs inherited from the mothers. The X-CNVs were initially recognized as VUS or likely pathogenic in males according to the publicly available information. After extending genetic analyses to male relatives of the maternal lineages, however, the relevance of the X-CNVs was reconsidered to be likely benign. The results highlight that an extended analysis to include more relatives, in addition to the parents, provides further information for genetic counseling when X-CNVs are encountered in prenatal settings.

High-resolution genome-wide array-CGH reveals copy number variations associated with premature ovarian failure

Placenta ◽  
2011 ◽  
Vol 32 ◽  
pp. S282
Author(s):  
Paola Scaruffi ◽  
Sara Stigliani ◽  
Annamaria Jane Nicoletti ◽  
Pier Luigi Venturini ◽  
Gian Paolo Tonini ◽  
...  
Keyword(s):  
High Resolution ◽  
Premature Ovarian Failure ◽  
Copy Number ◽  
Array Cgh ◽  
Copy Number Variations ◽  
Ovarian Failure ◽  
Genome Wide

scholarly journals Lessons Learned from CNV Analysis of Major Birth Defects

2020 ◽  
Vol 21 (21) ◽  
pp. 8247
Author(s):  
Alina Christine Hilger ◽  
Gabriel Clemens Dworschak ◽  
Heiko Martin Reutter
Keyword(s):  
Birth Defects ◽  
Copy Number ◽  
Congenital Malformations ◽  
De Novo ◽  
Copy Number Variations ◽  
Lessons Learned ◽  
Organ System ◽  
Molecular Karyotyping ◽  
The Past ◽  
Single Organ

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

scholarly journals A Case With 4 de Novo Copy Number Variations With Clinical Features That Overlap 1q43q44 Microdeletion and 3q29 Microduplication Syndromes

2018 ◽  
Vol 5 ◽  
pp. 2329048X1879820
Author(s):  
Miriam Kessi ◽  
Jing Peng ◽  
Lifen Yang ◽  
Haolin Duan ◽  
Yulin Tang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Corpus Callosum ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variations ◽  
Language Delay ◽  
Global Developmental Delay ◽  
Recurrent Infections ◽  
Dental Anomalies ◽  
Microdeletion Syndrome

1q43q44 microdeletion syndrome is characterized by intellectual disability/global developmental delay, epilepsy, dysmorphic facies, stereotypic movement, language delay, recurrent infections, dental anomalies, and hand and foot anomalies. Microcephaly and corpus callosum dysplasia are present in some cases depending on gene content. 3q29 microduplication syndrome is characterized by intellectual disability, language delay, microcephaly, and dental anomalies. We report the first case with 4 de novo copy number variations with clinical features which overlap 1q43q44 microdeletion and 3q29 microduplication syndromes. Our case presented with global developmental delay, epilepsy, recurrent infections, stereotypic movements, speech delay, microcephaly, facial dysmorphism, bilateral clinodactyly, and small puffy feet with metatarsus varus; however, she had no corpus callosum dysplasia. Our case highlights the role of multiple copy number variations in the occurrence of a certain phenotype. Moreover, it supports the theory that the loss of HNRNPU gene function cannot explain the occurrence of microcephaly and abnormalities of the corpus callosum in 1q43q44 microdeletion syndrome.

scholarly journals Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 698 ◽  
Author(s):  
Rossella Elisei ◽  
Alessia Tacito ◽  
Teresa Ramone ◽  
Raffaele Ciampi ◽  
Valeria Bottici ◽  
...  
Keyword(s):  
Genetic Screening ◽  
De Novo ◽  
Germline Mutations ◽  
Pathogenic Role ◽  
Medullary Thyroid ◽  
Variants Of Unknown Significance ◽  
The Family ◽  
Unknown Significance ◽  
Hereditary Medullary Thyroid Carcinoma ◽  
Sporadic Cases

Background: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. Methods: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. Results: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were “de novo” and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. Conclusions: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype–phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.

Array CGH Discovers Novel Genomic Signatures in De Novo Acute Myeloid Leukemia (AML): Results of Children’s Oncology Group (COG) Study POG #9421.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2771-2771
Author(s):  
Dennis J. Kuo ◽  
Norman J. Lacayo ◽  
Don Hoang ◽  
Dejan Juric ◽  
Susana C. Raimondi ◽  
...  
Keyword(s):  
Copy Number ◽  
Myeloid Leukemia ◽  
Array Cgh ◽  
De Novo ◽  
Gene Copy Number ◽  
Chromosome 8 ◽  
Gene Copy ◽  
Chromosome 6 ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease. Risk factors such as karyotype, FAB subtype, FLT3 status and response to induction therapy are determinants of outcome with current therapies. We hypothesize that array comparative genomic hybridization (CGH) will identify gene copy number changes that are determinants of outcome. Array CGH was performed on diagnostic bone marrow samples from patients on the COG study POG #9421. In order to determine regions of altered gene copy number, labeled genomic DNA samples were hybridized together with sex-matching normal human reference DNA to cDNA microarrays with 41,751 features (corresponding to 24,473 unique Unigene cluster IDs), arrays were obtained from the Stanford University Microarray Core Facility. Control hybridizations were performed to assess intra- and inter-experimental variability. We studied 70 samples with adequate high-quality DNA. Circular binary segmentation was used to distinguish discrete gene copy number transition points from chance noise events and to transform primary clone-by-clone data into genomic regions of equal copy number. Using gain/loss threshold, based on two-standard deviation range of control self-to-self distribution, novel gene amplifications and deletions were found in profiled samples. The highest alteration recurrence was observed for gains of chromosome 8 (21%) and losses of chromosome 6 (29%). The area of chromosome 8 which was found to be gained is notable for the presence of potential oncogenes such as ERK8. The deleted area of chromosome 6 is notable for the presence of potential regulators of oncogenesis: MDC1, DDR1, NFKBIL1, TNF, and BRD2. In summary, array CGH has identified novel areas of gene copy number gain and loss in this population of pediatric de novo AML patients. Further studies are needed to assess whether these genes are associated with outcome, known risk factors and whether they will provide insight into the heterogeneity of de novo AML.

scholarly journals CNVDetector: locating copy number variations using array CGH data

2008 ◽  
Vol 24 (23) ◽  
pp. 2773-2775 ◽  
Author(s):  
Peng-An Chen ◽  
Hsiao-Fei Liu ◽  
Kun-Mao Chao
Keyword(s):  
Copy Number ◽  
Array Cgh ◽  
Copy Number Variations

scholarly journals Characteristics of Highly Polymorphic Segmental Copy-Number Variations Observed in Japanese by BAC-Array-CGH

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Norio Takahashi ◽  
Yasunari Satoh ◽  
Keiko Sasaki ◽  
Yuko Shimoichi ◽  
Keiko Sugita ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Copy Number ◽  
Array Cgh ◽  
Artificial Chromosome ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Bac Clones ◽  
Japanese Cohort ◽  
The Individual ◽  
Chromosome Microarray

Segmental copy-number variations (CNVs) may contribute to genetic variation in humans. Reports of the existence and characteristics of CNVs in a large Japanese cohort are quite limited. We report the data from a large Japanese population. We conducted population screening for 213 unrelated Japanese individuals using comparative genomic hybridization based on a bacterial artificial chromosome microarray (BAC-aCGH). We summarize the data by focusing on highly polymorphic CNVs in ≥5.0% of the individual, since they may be informative for demonstrating the relationships between genotypes and their phenotypes. We found a total of 680 CNVs at 16 different BAC-regions in the genome. The majority of the polymorphic CNVs presented on BAC-clones that overlapped with regions of segmental duplication, and the majority of the polymorphic CNVs observed in this population had been previously reported in other publications. Some of the CNVs contained genes which might be related to phenotypic heterogeneity among individuals.

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