Comprehensive Genetic Evaluation of Children With Syndromic Craniosynostosis by a Combination of Cytogenetics, Multiplex Ligation-dependent Probe Amplification and Array-based Comparative Genomic Hybridisation

Abstract Syndromic craniosynostosis (SC) is a genetically determined premature closure of one or more of the cranial sutures, which may result in severe dysmorphism, increased intracranial pressure along with many other clinical manifestations. The considerable risk of complications along with significant incidence makes these cranial deformations an important medical problem. Despite the efforts to clarify the pathogenesis of SC in recent years, its genetic aspects remain largely unknown.Aiming to elucidate the complex genetic etiology of syndromic craniosynostosis, we conducted an investigation of 39 children, screened systematically with a combination of conventional cytogenetic analysis, multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridisation (aCGH).Pathological findings were established in 15.3% (6/39) of the cases using aCGH, in 7.7% (3/39) using MLPA and 2.5% (1/39) using conventional karyotyping. About 12.8% (5/39) of the patients with normal karyotype carried submicroscopic chromosomal rearrangements. Duplications were found to be more common than deletions.Conclusion: The systematic genetic evaluation of children with SC revealed a high prevalence of submicrosopic chromosomal rearrangements (most commonly duplications and gain-of-function variations). This suggests the leading role of those defects in the pathogenesis of syndromic craniosynostosis. The genetic complexity of SC was reaffirmed by the discovery of pathological findings in various chromosomal regions. Certain genes were discussed in conjunction with craniosynostosis.

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Microarray‐based comparative genomic hybridisation reveals additional recurrent aberrations in adult patients evaluated for myelodysplastic syndrome with normal karyotype

British Journal of Haematology ◽

10.1111/bjh.15068 ◽

2018 ◽

Vol 184 (2) ◽

pp. 282-287

Author(s):

Ines Ouahchi ◽

Luduo Zhang ◽

Ramon Benitez Brito ◽

Rudolf Benz ◽

Rouven Müller ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Normal Karyotype ◽

Adult Patients ◽

Comparative Genomic Hybridisation ◽

Comparative Genomic

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Comparative genomic hybridisation in mentally retarded patients with dysmorphic features and a normal karyotype

Clinical Genetics ◽

10.1034/j.1399-0004.2001.600307.x ◽

2001 ◽

Vol 60 (3) ◽

pp. 212-219 ◽

Cited By ~ 33

Author(s):

G Joly ◽

J-M Lapierre ◽

C Ozilou ◽

P Gosset ◽

A Aurias ◽

...

Keyword(s):

Normal Karyotype ◽

Mentally Retarded ◽

Comparative Genomic Hybridisation ◽

Comparative Genomic ◽

Dysmorphic Features

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High-Resolution Genomic Profiling of Myelodysplasia (MDS) by Microarray Comparative Genomic Hybridization (CGH).

Blood ◽

10.1182/blood.v108.11.2645.2645 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2645-2645

Author(s):

Noor Esoof ◽

Aristoteles Giagounidis ◽

Mario Cazzola ◽

Luca Malcovati ◽

Carlo Aul ◽

...

Keyword(s):

Copy Number ◽

Genomic Dna ◽

Normal Karyotype ◽

Comparative Genomic Hybridisation ◽

Comparative Genomic ◽

Bac Clones ◽

Conventional Cytogenetic Analysis ◽

Copy Number Changes ◽

Normal Controls ◽

Microarray Cgh

Abstract Myelodysplasia (MDS) is a heterogeneous group of clonal disorders of hematopoietic stem cells characterised by ineffective hematopoiesis and a variable risk of transformation to acute myelogenous leukaemia. We have used Comparative Genomic Hybridisation (CGH) microarray analysis, a technology that represents a significant improvement in resolution over conventional cytogenetic analysis, to screen genomic DNA from MDS patients for the identification of genome-wide Copy-Number Changes (CNCs). We have studied genomic DNA obtained from the neutrophil population of 48 MDS patients and 40 normal controls. Of the 48 MDS patients 10 had the 5q- syndrome, 32 were assigned normal karyotype and 6 had complex karyotypes. Comparative Genomic Hybridisation (CGH) microarray analysis was performed using microarrays containing 3500 BAC clones at 1Mb intervals over the whole human genome. Furthermore we used a whole genome tiling-path (27 000 overlapping BAC clones) array to profile 9 5q-syndrome patients and for 3 of those patients the T-cell DNA were also profiled to act as constitutional control. The patient DNA and a pool of normal reference DNA was labelled with different fluorochromes and cohybridised to the microarray. The normalised ratio of signal intensities was calculated and log2 ratios between −0.4 and 0.4 were considered normal. Ratios below or above the normal range were interpreted as loss or gain of genetic material, respectively. The deletions on chromosome 5q were precisely mapped by array-CGH in the patients with the 5q- syndrome but no additional CNCs were detected. One of the 5q deletions, however, displayed a discontiguous pattern with the tiling resolution array. Copy-number changes (CNCs) that escaped conventional cytogenetic detection were identified in the MDS patients originally reported with normal bone marrow karyotypes. 8 out of those 32 patients displayed CNCs that were not detected in the 40 normal controls and as such were considered as disease-related changes (non-polymorphic). Many of those CNCs were single-clone abberrations that were validated by dye-swap experiments and some were confirmed by quantitative PCR. Microarray CGH data confirmed all abnormalities reported by conventional cytogenetic analysis in the MDS patients with complex karyotypes and previously undetected abnormalities were uncovered. Several genes involved in either the initiation or progression of hematological malignancies are known to map within the cryptic abnormalities identified in the patients studied. For example, one patient with an apparently normal karyotype showed a small deletion at 17q11 which encompasses the NF1 gene. Further work will determine whether particular abnormalities detected by microarray CGH are recurrent and the nature of the genes involved. However, the promise of microarray CGH in the diagnostic work up of MDS particularly in those patients with normal karyotypes is clear.

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Clinical and Cytogenomic Characterization of De Novo 11p14.3-p15.5 Duplication Associated with 18q23 Deletion in an Egyptian Female Infant

Journal of Pediatric Genetics ◽

10.1055/s-0040-1708554 ◽

2020 ◽

Author(s):

Hanan H. Afifi ◽

Ghada Y. El-Kamah ◽

Alaa K. Kamel ◽

Sally G. Abd Allah ◽

Sayda Hammad ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Ductus Arteriosus ◽

Chromosomal Rearrangements ◽

Clinical Manifestations ◽

Brain Magnetic Resonance Imaging ◽

Comparative Genomic ◽

Septal Hypertrophy

AbstractPaternal microduplication of 11p14.3-p15.5 causes the clinical manifestations of Beckwith–Wiedemann syndrome (BWS), while microdeletion of 18q23-ter is clinically characterized by short stature, congenital malformations, and developmental delay. We describe a 15-month-old girl presenting with protruding tongue, dysmorphic facial features, moderate developmental delay, umbilical hernia, hypotonia, mild-to-moderate pulmonary hypertension, small patent ductus arteriosus, and mild ventricular septal hypertrophy. Brain magnetic resonance imaging showed mild atrophic changes. Chromosomal analysis revealed 46, XX, add(18)(q23). Fluorescence in situ hybridization using subtelomere 18q and whole chromosome painting 18 showed subtelomere deletion in 18q, and the add segment was not derived from chromosome 18. Microarray-based comparative genomic hybridization detected a 22 Mb duplication of chromosome 11p15.5p14.3 and a 3.7 Mb deletion of chromosome 18q23. The phenotype of the chromosomal rearrangements is probably resulted from a combination of dosage-sensitive genes. Our patient had clinical manifestations of both 18q deletion and BWS.

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