The Role of the Reanalysis of Genetic Test Results in the Diagnosis of Dysmorphic Syndrome Caused by Inherited Xq24 Deletion including the UBE2A and CXorf56 Genes

Psychomotor delay, hypotonia, and intellectual disability, as well as heart defects, urogenital malformations, and characteristic cranio-facial dysmorphism are the main symptoms of dysmorphic syndrome associated with intergenic deletion in the Xq24 chromosome region including the UBE2A and CXorf56 genes. To date, there is limited information in the literature about the symptoms and clinical course of the Xq24 deletion. Here, we present a case of Xq24 deletion including the UBE2A and CXorf56 genes in a nine-year-old boy, in whom the array comparative genomic hybridization (array-CGH) and whole exome sequencing (WES) tests were performed in 2015 with normal results. The WES results were reanalyzed in 2019. Intergenic, hemizygous deletion in the Xq24 chromosome region including the UBE2A and CXorf56 genes was revealed and subsequently confirmed in the array-CGH study as the deletion of 35kb in the Xq24 region. Additionally, the carriership of deletion in the mother of the child was confirmed.

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Prenatal Diagnosis by Array Comparative Genomic Hybridization in Fetuses with Cardiac Abnormalities

Genes ◽

10.3390/genes12122021 ◽

2021 ◽

Vol 12 (12) ◽

pp. 2021

Author(s):

Katarzyna Kowalczyk ◽

Magdalena Bartnik-Głaska ◽

Marta Smyk ◽

Izabela Plaskota ◽

Joanna Bernaciak ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Comparative Genomic Hybridization ◽

Congenital Heart Defects ◽

Congenital Heart ◽

Array Cgh ◽

Heart Diseases ◽

Heart Defects ◽

Comparative Genomic ◽

Genomic Hybridization ◽

Fetal Ultrasound

Congenital heart defects (CHDs) appear in 8–10 out of 1000 live born newborns and are one of the most common causes of deaths. In fetuses, the congenital heart defects are found even 3–5 times more often. Currently, microarray comparative genomic hybridization (array CGH) is recommended by worldwide scientific organizations as a first-line test in the prenatal diagnosis of fetuses with sonographic abnormalities, especially cardiac defects. We present the results of the application of array CGH in 484 cases with prenatally diagnosed congenital heart diseases by fetal ultrasound scanning (256 isolated CHD and 228 CHD coexisting with other malformations). We identified pathogenic aberrations and likely pathogenic genetic loci for CHD in 165 fetuses and 9 copy number variants (CNVs) of unknown clinical significance. Prenatal array-CGH is a useful method allowing the identification of all unbalanced aberrations (number and structure) with a much higher resolution than the currently applied traditional assessment techniques karyotype. Due to this ability, we identified the etiology of heart defects in 37% of cases.

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First Report of a de novo 10q23.31q23.33 Microdeletion: Obesity, Intellectual Disability and Microcephaly

Molecular Syndromology ◽

10.1159/000515400 ◽

2021 ◽

pp. 1-5

Author(s):

Ayberk Turkyilmaz ◽

Erdal Kurnaz ◽

Atilla Cayir

Keyword(s):

Intellectual Disability ◽

Array Cgh ◽

De Novo ◽

Chromosomal Abnormalities ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Autism Spectrum ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Genetic And Environmental Factors

Intellectual disability (ID) is characterized by limited or insufficient development of mental abilities, including intellectual functioning impairments, such as learning and understanding cause-effect relationships. Some cases have ID as the only finding and are called isolated cases. Conversely, cases accompanied by facial dysmorphism, microcephaly, autism spectrum disorder, epilepsy, obesity, and congenital anomalies are called syndromic developmental delay (DD)/ID. Isolated and syndromic DD/ID cases show extreme genetic heterogeneity. Genetic etiology can be detected in approximately 40% of the cases, whereas chromosomal abnormalities are observed in 25%. Obesity is a multifactorial disease in which both genetic and environmental factors play important roles. The role of heredity in obesity has been reported to be between 40 and 70%. Array-based comparative genomic hybridization (array-CGH) can detect CNVs in the whole genome at a higher resolution than conventional cytogenetic methods. Array-CGH is currently recommended as the first-tier genetic test for ID cases worldwide. In the present study, we aimed to evaluate clinical, radiological, and genetic analyses of a 12-year and 4-month-old girl with microcephaly, ID, and obesity. In the array-CGH analysis, a 3.1-Mb deletion, arr[GRGh37] 10q23.31g23.33 (92745793_95937944)×1 was detected, and this alteration was evaluated to be pathogenic. We consider that haploinsufficiency of the candidate genes (GPR120, KIF11, EXOC6, CYP26A1, CYP26C1, and LGI1) in the deletion region may explain microcephaly, ID, obesity, seizures, and ophthalmological findings in our patient. The investigation of 10q23.31q23.33 microdeletion in cases with syndromic obesity may contribute to molecular genetic diagnosis.

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Findings from ACGH in patient with psychomotor delay-case report

Genetics & Applications ◽

10.31383/ga.vol3iss3pp38-41 ◽

2019 ◽

Vol 3 (3) ◽

pp. 38

Author(s):

Vanja Vidović ◽

Nela Maksimović ◽

Tatjana Damnjanović ◽

Biljana Jekić ◽

Irina Milovac ◽

...

Keyword(s):

Case Report ◽

Array Cgh ◽

Karyotype Analysis ◽

Comparative Genomic ◽

Fish Analysis ◽

Mild Mental Retardation ◽

Psychomotor Delay ◽

Left Hand ◽

Highly Sensitive ◽

Clinically Significant

Initial testing of children with psychomotor delays considers karyotype analysis and metabolic tests. However, introduction of Array Comparative Genomic Hybridization (ACGH) has become the standard method of diagnostics worldwide. ACGH is a highly sensitive method which enables detection of unbalanced chromosomal aberrations and aneuploidies. In this case report, a patient is a sixteen year old girl born to unrelated parents with mild mental retardation and psychomotor delay, hyperacusis, epilepsy, silent nasal speech, clinodactyly of the V finger on left hand, as well as low set ears. Patient had a karyotype interpreted as normal using GTG band analysis. Array CGH was performed using Agilent SurePrint G3 custom CGH+SNP Microarray 8x60K (UCSC, hg19, NCBI Build 37, February,2009). Results were analyzed by CytoGenomics 3.0 Agilent software. Results of aCGH revealed clinically significant duplication of 17q25.1-q25.3 region with the size of~7.96Mb. Within the duplicated region 217 genes are present, of which 36 are described as OMIM morbid. Duplications of similar size are described in DECIPHER date base in patients with psychomotor delay, hyperactivity and neoplasm of CNS. Besides duplication, a ~755kb clinically significant deletion was detected in the 17q25.3 region. Deletion involves 18 genes of which 2 are described as OMIM morbid: TBCD (MIM604649) and ZNF750 (MIM610226). Patient with similar deletion was described in DECIPHER date base with notable psychomotor delay. Based on these results FISH analysis is recommended for both parents in order to determine the possible carrier of inversion in the region of 17qter.

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Genetic Diagnosis of Chromosomal Congenital Anomalies in Albanian Pediatric Patients by Array CGH

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2017.147 ◽

2017 ◽

Vol 5 (5) ◽

pp. 587-591

Author(s):

Anila Babameto-Laku ◽

Dorina Roko ◽

Gentian Vyshka

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Congenital Anomalies ◽

Array Cgh ◽

International System ◽

Genetic Diagnosis ◽

Case Series ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Chromosomal Anomalies

AIM: The aim of our study was to identify chromosomal imbalances by whole-genome microarray-based comparative genomic hybridization (array CGH) in DNA samples of children in which karyotype results cannot be obtained. The present paper describes the first Albanian experience of an array CGH application.MATERIAL AND METHODS: The cohort included seven children with developmental delay or intellectual disability, facial dysmorphism and congenital anomalies according to clinical criteria, suggestive of chromosomal anomalies. The age range was from newborn to five years old. The cytogenetic analysis determined by a standard method of G-banding according to the International System for Human Cytogenetic Nomenclature (ISCN 2005) was performed for all our patients, while array CGH was performed on genomic DNA isolated from the blood of 7 cases.RESULTS: Among the seven patients analysed with array CGH, three patients resulted in duplication and one deletion, one patient with a microdeletion and three patients with duplication. Array CGH facilitated the recognition of submicroscopic deletions and duplications as risk factors for genetic diagnosis in all our patients.CONCLUSIONS: Our case series with congenital chromosomal anomalies confirms the high diagnostic value of the method, as suggested by previous studies. The technique must be available also in less developed countries, to significantly improve the genetic diagnosis of paediatric patients with developmental delay or intellectual disability, congenital anomalies and dysmorphic features. The identification of chromosomal abnormalities in these patients and the genetic counselling will provide family members with an explanation for their child’s developmental disability or birth defect, allowing better information about recurrence risks, and permit the anticipation of certain medical problems that require intervention.

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16p11.2 Duplication Syndrome - a Case Report

Folia Medica ◽

10.3897/folmed.63.e52763 ◽

2021 ◽

Vol 63 (1) ◽

pp. 138-141

Author(s):

Mariya Levkova ◽

Milena Stoyanova ◽

Rada Staneva ◽

Mari Hachmeriyan ◽

Lyudmila Angelova

Keyword(s):

Intellectual Disability ◽

Intellectual Development ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Comparative Genomic Hybridization Analysis ◽

Genetic Condition ◽

Autistic Behavior ◽

Hyperactivity Disorder ◽

Whole Exome ◽

Duplication Syndrome

16p11.2 duplication syndrome is a rare disorder, often associated with intellectual disability, attention deficit, hyperactivity disorder, and a predisposition to epilepsy and schizophrenia. There are no specific dysmorphic features for this genetic condition, but micro-cephaly, micrognathia and hypertelorism could be present. We report a case of 16p11.2 duplication syndrome which has the typical clinical presentation – slight facial dysmorphism, impaired intellectual development, and autistic behavior. Whole-exome sequencing was performed, but no pathogenic or likely pathogenic mutations were identified. Array comparative genomic hybridization analysis established the diagnosis of 16p11.2 duplication syndrome, which illustrates the importance of this method when diagnosing children with unexplained intellectual disability. 

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6q13q14.3 Microdeletion Syndrome with Severe Hypotonia and Facial Dysmorphism: Genotype–Phenotype Correlation

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721739 ◽

2021 ◽

Author(s):

Manisha Goyal ◽

Mohammed Faruq ◽

Ashok Gupta ◽

Divya Shrivastava ◽

Uzma Shamim

Keyword(s):

Array Cgh ◽

Chromosomal Abnormalities ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Genetic Syndromes ◽

Phenotype Correlation ◽

Microdeletion Syndrome ◽

Genetic Syndrome ◽

Severe Hypotonia ◽

Diagnostic Technologies

AbstractHypotonia is a symptom of diminished tone of skeletal muscle and can be nongenetic or a part of genetic syndrome. Hypotonia, developmental delay, and facial dysmorphism are nonspecific findings observed in many genetic syndromes mostly in chromosomal microdeletion and duplication. Here we report a case with severe hypotonia and facial dysmorphism, diagnosed with deletion at 6q13q14.3 by array comparative genomic hybridization (CGH) at very early age. Recent genetic diagnostic technologies such as array CGH may enable clinicians to diagnose chromosomal abnormalities earlier and provide appropriate medical management

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Cytogenomic Evaluation of Subjects with Syndromic and Nonsyndromic Conotruncal Heart Defects

BioMed Research International ◽

10.1155/2015/401941 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Karen Regina de Souza ◽

Rafaella Mergener ◽

Janaina Huber ◽

Lucia Campos Pellanda ◽

Mariluce Riegel

Keyword(s):

Array Cgh ◽

Heart Defects ◽

Copy Number Variations ◽

Comparative Genomic ◽

Data Sets ◽

Comparative Genomic Hybridization Array ◽

Genomic Databases ◽

Genomic Imbalances ◽

Genome Wide ◽

Line Test

Despite considerable advances in the detection of genomic abnormalities in congenital heart disease (CHD), the etiology of CHD remains largely unknown. CHD is the most common birth defect and is a major cause of infant morbidity and mortality, and conotruncal defects constitute 20% of all CHD cases. We used array comparative genomic hybridization (array-CGH) to retrospectively study 60 subjects with conotruncal defects and identify genomic imbalances. The DNA copy number variations (CNVs) detected were matched with data from genomic databases, and their clinical significance was evaluated. We found that 38.3% (23/60) of CHD cases possessed genomic imbalances. In 8.3% (5/60) of these cases, the imbalances were causal or potentially causal CNVs; in 8.3% (5/60), unclassified CNVs were identified; and in 21.6% (13/60), common variants were detected. Although the interpretation of the results must be refined and there is not yet a consensus regarding the types of CHD cases in which array-CGH should be used as a first-line test, the identification of these CNVs can assist in the evaluation and management of CHD. The results of such studies emphasize the growing importance of the use of genome-wide assays in subjects with CHD to increase the number of genomic data sets associated with this condition.

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Identification of de novo mutations for ARID1B haploinsufficiency associated with Coffin–Siris syndrome 1 in three Chinese families via array-CGH and whole exome sequencing

BMC Medical Genomics ◽

10.1186/s12920-021-01119-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Guanting Lu ◽

Qiongling Peng ◽

Lianying Wu ◽

Jian Zhang ◽

Liya Ma

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Array Cgh ◽

De Novo ◽

Current Knowledge ◽

Comparative Genomic ◽

De Novo Mutations ◽

Single Nucleotide Variants ◽

Whole Exome

Abstract Background Coffin–Siris syndrome (CSS) is a multiple malformation syndrome characterized by intellectual disability associated with coarse facial features, hirsutism, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. CSS represents a small group of intellectual disability, and could be caused by at least twelve genes. The genetic background is quite heterogenous, making it difficult for clinicians and genetic consultors to pinpoint the exact disease types. Methods Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for three trios affected with intellectual disability and clinical features similar with those of Coffin–Siris syndrome. Sanger sequencing was used to verify the detected single-nucleotide variants (SNVs). Results All of the three cases were female with normal karyotypes of 46, XX, born of healthy, non-consanguineous parents. A 6q25 microdeletion (arr[hg19]6q25.3(155,966,487–158,803,979) × 1) (2.84 Mb) (case 1) and two loss-of-function (LoF) mutations of ARID1B [c.2332 + 1G > A in case 2 and c.4741C > T (p.Q1581X) in case 3] were identified. All of the three pathogenic abnormalities were de novo, not inherited from their parents. After comparison of publicly available microdeletions containing ARID1B, four types of microdeletions leading to insufficient production of ARID1B were identified, namely deletions covering the whole region of ARID1B, deletions covering the promoter region, deletions covering the termination region or deletions covering enhancer regions. Conclusion Here we identified de novo ARID1B mutations in three Chinese trios. Four types of microdeletions covering ARID1B were identified. This study broadens current knowledge of ARID1B mutations for clinicians and genetic consultors.

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An Indian infant with de novo duplication of 16p chromosome: A rare genetic syndrome

Indian Journal of Medical Sciences ◽

10.25259/ijms_278_2020 ◽

2020 ◽

Vol 0 ◽

pp. 1-3

Author(s):

Manisha Goyal ◽

Ashok Gupta ◽

Mohammed Faruq ◽

Divya Shrivastava

Keyword(s):

Array Cgh ◽

De Novo ◽

Chromosomal Abnormalities ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Genetic Syndromes ◽

Genetic Syndrome ◽

Diagnostic Technology ◽

Chromosome 16P13.3 ◽

Indian Infant

Facial dysmorphism along with multiple congenital anomalies is observed in many genetic syndromes mostly in chromosomal microdeletion or duplication, which cannot be detected by conventional karyotype. Here, we report a case with facial dysmorphism, cleft palate, congenital heart defect, and umbilical hernia, diagnosed with duplication at chromosome 16p13.3 by array comparative genomic hybridization (CGH) at very early age. Array CGH is the advanced diagnostic technology; enable to diagnose chromosomal abnormalities earlier thus can provide appropriate medical management and prognostication.

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Bilateral Phyllodes Giant Tumor. A Case Report Analyzed by Array-CGH

Diagnostics ◽

10.3390/diagnostics10100825 ◽

2020 ◽

Vol 10 (10) ◽

pp. 825

Author(s):

Francesco Fortarezza ◽

Federica Pezzuto ◽

Gerardo Cazzato ◽

Clelia Punzo ◽

Antonio d’Amati ◽

...

Keyword(s):

Array Cgh ◽

Phyllodes Tumor ◽

Molecular Classification ◽

Left Breast ◽

Comparative Genomic ◽

Fish Analysis ◽

Molecular Tests ◽

Giant Tumor ◽

Metastatic Risk ◽

The Right

The breast phyllodes tumor is a biphasic tumor that accounts for less than of 1% of all breast neoplasms. It is classified as benign, borderline, or malignant, and can mimic benign masses. Some recurrent alterations have been identified. However, a precise molecular classification of these tumors has not yet been established. Herein, we describe a case of a 43-year-old woman that was admitted to the emergency room for a significant bleeding from the breast skin. A voluminous ulcerative mass of the left breast and multiple nodules with micro-calcifications on the right side were detected at a physical examination. A left total mastectomy and a nodulectomy of the right breast was performed. The histological diagnosis of the surgical specimens reported a bilateral giant phyllodes tumor, showing malignant features on the left and borderline characteristics associated with a fibroadenoma on the right. A further molecular analysis was carried out by an array-Comparative Genomic Hybridization (CGH) to characterize copy-number alterations. Many losses were detected in the malignant mass, involving several tumor suppressor genes. These findings could explain the malignant growth and the metastatic risk. In our study, genomic profiling by an array-CGH revealed a greater chromosomal instability in the borderline mass (40 total defects) than in the malignant (19 total defects) giant phyllodes tumor, reflecting the tumor heterogeneity. Should our results be confirmed with more sensitive and specific molecular tests (DNA sequencing and FISH analysis), they could allow a better selection of patients with adverse pathological features, thus optimizing and improving patient’s management.

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