Identification of microdeletion and microduplication syndromes by chromosomal microarray in patients with intellectual disability with dysmorphism

Trisomy 18p is a rarely observed chromosomal aberration. Only 31 cases have previously been described in the literature. Trisomy 18p is associated with mild to moderate phenotypic anomalies and intellectual disability. Here, we report on a pregnant woman in whom noninvasive prenatal testing indicated a high risk of fetal trisomy 18. Prenatal diagnosis and karyotyping of the parents were performed and demonstrated that both the mother and the fetus had a derivative chromosome 15 with a segment of unknown origin. Chromosomal microarray analysis and FISH revealed a 14.9-Mb duplication of 18p and detected 3 centromeres of chromosome 18. To our knowledge, this is the first study reporting trisomy 18p due to an unbalanced translocation of 18p onto chromosome 15q showing 2-generation transmission. The results suggest that trisomy 18p can be considered a euchromatic variant.

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Duplication of 19p13.3 in 11-Year-Old Male Patient with Dysmorphic Features and Intellectual Disability: A Review

Journal of Pediatric Genetics ◽

10.1055/s-0037-1603650 ◽

2017 ◽

Vol 06 (04) ◽

pp. 227-233 ◽

Cited By ~ 2

Author(s):

Irina Novikova ◽

Paushpala Sen ◽

Ann Manzardo ◽

Merlin Butler

Keyword(s):

Intellectual Disability ◽

Male Patient ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Clinical Report ◽

Intrauterine Growth ◽

Interstitial Duplication ◽

Craniofacial Features ◽

Sparse Hair ◽

Small Mouth

AbstractWe present a clinical report of an 11-year-old male patient with an interstitial duplication of 19p13.3 (829 kb in size) at genomic coordinates 3,804,495–4,033,722 bp (hg19) identified by chromosomal microarray analysis and review the literature from nine published reports adding knowledge regarding this chromosomal anomaly and clinical outcomes. The size of the duplication ranged from 0.83 to 8.9 Mb in the nine individuals. The young boy in our report was dysmorphic with microcephaly, abnormal craniofacial features, intellectual disability, aggression, and a heart murmur. All patients were found to have a psychomotor developmental delay and/or intellectual disability with the majority having microcephaly, intrauterine growth retardation, and hypotonia. Common craniofacial findings included a tall, prominent forehead, an elongated face, epicanthal folds, hypertelorism, prominent low-set ears, philtrum anomaly, and a small mouth. Other less common features included abnormal digits, sparse hair, and cardiac defects. Clinical features, chromosome duplication sizes, locations, and the number of genes will be summarized in a tabular form.

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Genomic study via chromosomal microarray analysis in a group of Romanian patients with obesity and developmental disability/intellectual disability

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0439 ◽

2019 ◽

Vol 32 (7) ◽

pp. 667-674 ◽

Cited By ~ 1

Author(s):

Diana Micleaa ◽

Camelia Al-Khzouza ◽

Sergiu Osan ◽

Simona Bucerzan ◽

Victoria Cret ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Disability ◽

Snp Array ◽

Uniparental Disomy ◽

Genomic Analysis ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Syndromic Obesity ◽

Genomic Study ◽

Array Technology

Abstract Background Obesity with developmental disability/intellectual disability (DD/ID) is the most common association in syndromic obesity. Genomic analysis studies have allowed the decipherment of disease aetiology, both in cases of syndromic obesity as well as in cases of isolated or syndromic DD/ID. However, more data are needed to further elucidate the link between the two. The aim of this pangenomic study was to use single nucleotide polymorphism (SNP) array technology to determine the copy number variant (CNV) type and frequency associated with both obesity and DD/ID. Methods Thirty-six patients were recruited from the Clinical Emergency Hospital for Children, in Cluj-Napoca, Romania during the period 2015–2017. The main inclusion criterion was a diagnosis that included both obesity and DD/ID. Genomic analysis via SNP array technology was performed. Results Out of the 36 patients, 12 (33%) presented CNVs with a higher degree of pathogenicity (A group) and 24 (66%) presented benign CNVs (B group). The SNP array results for the A group were as follows: pathogenic CNVs in 8/12 patients (67%); variants of unknown significance (VOUS) in 2/12 patients (16%); and uniparental disomy (UPD) in 2/12 patients (16%). Conclusions Some of these CNVs have already been observed in patients with both obesity and DD/ID, but the others were noticed only in DD/ID patients and have not been described until now in association with obesity.

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The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals

Genetics in Medicine ◽

10.1038/s41436-021-01153-6 ◽

2021 ◽

Author(s):

Pia Zacher ◽

Thomas Mayer ◽

Frank Brandhoff ◽

Tobias Bartolomaeus ◽

Diana Le Duc ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Diagnostic Yield ◽

Fragile X ◽

Genetic Diagnostics ◽

High Yield ◽

Chromosomal Microarray ◽

Limited Information ◽

Single Nucleotide Variants ◽

Elderly Individuals

Abstract Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

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Cost Effectiveness of Karyotyping, Chromosomal Microarray Analysis, and Targeted Next-Generation Sequencing of Patients with Unexplained Global Developmental Delay or Intellectual Disability

Molecular Diagnosis & Therapy ◽

10.1007/s40291-017-0309-5 ◽

2017 ◽

Vol 22 (1) ◽

pp. 129-138 ◽

Cited By ~ 6

Author(s):

Yonghong Li ◽

Lori A. Anderson ◽

Edward I. Ginns ◽

James J. Devlin

Keyword(s):

Intellectual Disability ◽

Cost Effectiveness ◽

Next Generation Sequencing ◽

Developmental Delay ◽

Microarray Analysis ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Chromosomal Microarray Analysis ◽

Targeted Next Generation Sequencing ◽

Generation Sequencing

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A non-syndromic intellectual disability associated with a de novo microdeletion at 7q and 18p, microduplication at Xp, and 18q partial trisomy detected using chromosomal microarray analysis approach

Molecular Cytogenetics ◽

10.1186/1755-8166-7-44 ◽

2014 ◽

Vol 7 (1) ◽

pp. 44 ◽

Cited By ~ 6

Author(s):

Irene Pinto ◽

Lysa Minasi ◽

Alex da Cruz ◽

Aldaires de Melo ◽

Damiana da Cruz e Cunha ◽

...

Keyword(s):

Intellectual Disability ◽

Microarray Analysis ◽

De Novo ◽

Partial Trisomy ◽

Analysis Approach ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis

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A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect

Cytogenetic and Genome Research ◽

10.1159/000486947 ◽

2018 ◽

Vol 154 (1) ◽

pp. 6-11 ◽

Cited By ~ 3

Author(s):

Beata Aleksiūnienė ◽

Egle Preiksaitiene ◽

Aušra Morkūnienė ◽

Laima Ambrozaitytė ◽

Algirdas Utkus

Keyword(s):

Intellectual Disability ◽

Congenital Heart Defect ◽

Congenital Heart ◽

De Novo ◽

Molecular Karyotyping ◽

Pcr Analysis ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Protein Coding ◽

Heart Defect

Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4-5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23.1 region, arr[GRCh37] 1q22q23.1(155630752_157193893)×1. Real-time PCR analysis confirmed its de novo origin. The deleted region encompasses 50 protein-coding genes, including the morbid genes APOA1BP, ARHGEF2, LAMTOR2, LMNA, NTRK1, PRCC, RIT1, SEMA4A, and YY1AP1. Although the unique phenotype observed in our patient can arise from the haploinsufficiency of the dosage-sensitive LMNA gene, the dosage imbalance of other genes implicated in the rearrangement could also contribute to the phenotype. Further studies are required for the delineation of the phenotype associated with this rare chromosomal alteration and elucidation of the critical genes for manifestation of the specific clinical features.

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Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106470 ◽

2020 ◽

Vol 57 (10) ◽

pp. 717-724

Author(s):

Jorge Luis Granadillo ◽

Alexander P.A. Stegmann ◽

Hui Guo ◽

Kun Xia ◽

Brad Angle ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Genetic Disorder ◽

Retrospective Chart Review ◽

Autistic Traits ◽

Clinical Findings ◽

Fine Motor ◽

Chromosomal Microarray ◽

Motor Delay ◽

Phenotypic Characterisation

BackgroundRare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described.MethodsClinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation.ResultsClinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1).ConclusionsVariants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

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