scholarly journals Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: a prospective study

2021 ◽  
Author(s):  
Yu Sun ◽  
Jing Peng ◽  
Desheng Liang ◽  
Xiantao Ye ◽  
Na Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Genome Sequencing ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Chromosomal Microarray Analysis ◽  
High Diagnostic Yield ◽  
Wide Range

Genome sequencing(GS) has been applied in the diagnosis of global developmental delay(GDD)/intellectual disability(ID). However, the performance in those with inconclusive results from chromosomal microarray analysis(CMA) and exome sequencing(ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test prior to enrollment. Reanalysis of CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 23%. Seven families could have been solved with reanalysis of ES data. 13 families were missed by previous CMA/ES due to improper method. Three remained unsolved after ES reanalysis due to allele dropout, complex variants missed by ES, and a CNV in untranslated regions. Follow-up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this cohort of undiagnosed GDD/ID patients, detecting a wide range of variant types of different sizes in a single workflow.

Diagnostic and Clinical Utility of Clinical Exome Sequencing in Children With Moderate and Severe Global Developmental Delay / Intellectual Disability

2019 ◽  
Vol 35 (2) ◽  
pp. 116-131 ◽  
Author(s):  
Jelena Ruml Stojanovic ◽  
Aleksandra Miletic ◽  
Borut Peterlin ◽  
Ales Maver ◽  
Marija Mijovic ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Significant Proportion ◽  
Global Developmental Delay ◽  
Clinical Exome Sequencing ◽  
The Impact

Clinical exome sequencing is currently being used in diagnostics of various genetic disorders, but studies supporting its application in clinical setting are scarce. The aim of this study was to establish diagnostic and clinical utility of clinical exome sequencing in patients with moderate and severe global developmental delay/intellectual disability. Clinical diagnosis was made in 49 of 88 investigated patients, with overall diagnostic yield of 55.7%. Molecular findings are characterized in detail, including the impact of newly made diagnosis on clinical management. Several previously unreported genotype-phenotype correlations and 33 novel variants are described. Genetic and clinical data were shared through publicly available database. In conclusion, clinical exome sequencing allows identification of causative variants in a significant proportion of patients in investigated clinical subgroup. Compared to whole exome sequencing, it shows similar diagnostic and clinical utility with reduced costs, which could be of particular importance for institutions with limited resources.

scholarly journals Chromosomal microarray analysis of 410 Han Chinese patients with autism spectrum disorder or unexplained intellectual disability and developmental delay

2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Liu ◽  
Yuqiang Lv ◽  
Mehdi Zarrei ◽  
Rui Dong ◽  
Xiaomeng Yang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Microarray Analysis ◽  
Diagnostic Yield ◽  
Autism Spectrum ◽  
Han Chinese ◽  
Chinese Patients ◽  
European Ancestry ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis

AbstractCopy number variants (CNVs) are recognized as a crucial genetic cause of neurodevelopmental disorders (NDDs). Chromosomal microarray analysis (CMA), the first-tier diagnostic test for individuals with NDDs, has been utilized to detect CNVs in clinical practice, but most reports are still from populations of European ancestry. To contribute more worldwide clinical genomics data, we investigated the genetic etiology of 410 Han Chinese patients with NDDs (151 with autism and 259 with unexplained intellectual disability (ID) and developmental delay (DD)) using CMA (Affymetrix) after G-banding karyotyping. Among all the NDD patients, 109 (26.6%) carried clinically relevant CNVs or uniparental disomies (UPDs), and 8 (2.0%) had aneuploidies (6 with trisomy 21 syndrome, 1 with 47,XXY, 1 with 47,XYY). In total, we found 129 clinically relevant CNVs and UPDs, including 32 CNVs in 30 ASD patients, and 92 CNVs and 5 UPDs in 79 ID/DD cases. When excluding the eight patients with aneuploidies, the diagnostic yield of pathogenic and likely pathogenic CNVs and UPDs was 20.9% for all NDDs (84/402), 3.3% in ASD (5/151), and 31.5% in ID/DD (79/251). When aneuploidies were included, the diagnostic yield increased to 22.4% for all NDDs (92/410), and 33.6% for ID/DD (87/259). We identified a de novo CNV in 14.9% (60/402) of subjects with NDDs. Interestingly, a higher diagnostic yield was observed in females (31.3%, 40/128) compared to males (16.1%, 44/274) for all NDDs (P = 4.8 × 10−4), suggesting that a female protective mechanism exists for deleterious CNVs and UPDs.

scholarly journals Chromosomal Microarray Analysis in Children with Unexplained Developmental Delay/Intellectual Disability

2018 ◽  
Vol 08 (01) ◽  
pp. 001-009
Author(s):  
Pinar Arican ◽  
Berk Ozyilmaz ◽  
Dilek Cavusoglu ◽  
Pinar Gencpinar ◽  
Kadri Erdogan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
De Novo ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Genetic Syndromes ◽  
Pathogenic Cnvs ◽  
Spectrum Disorders

AbstractChromosomal microarray (CMA) analysis for discovery of copy number variants (CNVs) is now recommended as a first-line diagnostic tool in patients with unexplained developmental delay/intellectual disability (DD/ID) and autism spectrum disorders. In this study, we present the results of CMA analysis in patients with DD/ID. Of 210 patients, pathogenic CNVs were detected in 26 (12%) and variants of uncertain clinical significance in 36 (17%) children. The diagnosis of well-recognized genetic syndromes was achieved in 12 patients. CMA analysis revealed pathogenic de novo CNVs, such as 11p13 duplication with new clinical features. Our results support the utility of CMA as a routine diagnostic test for unexplained DD/ID.

scholarly journals From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Lindstrand ◽  
Jesper Eisfeldt ◽  
Maria Pettersson ◽  
Claudia M. B. Carvalho ◽  
Malin Kvarnung ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Uniparental Disomy ◽  
Patient Specific ◽  
Chromosomal Microarray Analysis ◽  
Whole Genome ◽  
First Line ◽  
Human Phenotype ◽  
Wide Range

Abstract Background Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test. Methods We analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n = 68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n = 156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure. Results First, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850 kb (min 500 bp, max 155 Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (> 10 kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data. Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively. Conclusion The overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.

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