Combined whole exome sequencing and chromosomal microarray analysis improve clinical interpretation of genomic variants in patients with intellectual disability
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ABSTRACT:
SUBMITTER: Kashevarova A
PROVIDER: S-EPMC10478954 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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Project description:Despite the current widespread use of chromosomal microarray analysis (CMA) and exome/genome sequencing for the genetic diagnosis of unexplained intellectual disability (ID) in children, gaining improved diagnostic yields and defined guidelines remains a significant challenge. This is a cohort study of children with unexplained ID. We analyzed the diagnostic yield and its correlation to clinical phenotypes in children with ID who underwent concurrent CMA and clinical exome sequencing (CES). A total of 154 children were included (110 [71.4%] male; mean [SD] age, 51.9 [23.1] months). The overall diagnosis yield was 26.0-33.8%, with CMA contributing 12.3-14.3% and CES contributing 13.6-19.4%, showing no significant difference. The diagnostic rate was significantly higher when gross motor delay (odds ratio, 6.69; 95% CI, 3.20-14.00; P < 0.001), facial dysmorphism (odds ratio, 9.34; 95% CI 4.29-20.30; P < 0.001), congenital structural anomaly (odds ratio 3.62; 95% CI 1.63-8.04; P = 0.001), and microcephaly or macrocephaly (odds ratio 4.87; 95% CI 2.05-11.60; P < 0.001) were presented. Patients with only ID without any other concomitant phenotype (63/154, 40.9%) exhibited a 6.3-11.1% diagnostic rate.
| S-EPMC10739828 | biostudies-literature
Project description:Chromosomal 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.
| S-EPMC6375720 | biostudies-literature
Project description:BackgroundIntellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV).MethodsTo identify an appropriate clinical detection scheme for ID in Han Chinese patients, whole genome low-coverage sequencing was performed as the first-tier diagnostic test, and medical exome sequencing (MES) as the second-tier diagnostic test for patients with negative results of CNVs.ResultsA total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 10 pathogenic single-nucleotide variations (SNVs), including 6 novel mutations in 8/95(8.42%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of CNVs in ID with multiple congenital anomalies (MCA) subgroup was significantly higher than ID with autism spectrum disorders and other IDs subgroups. And the single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup.ConclusionsThere were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme in different ID subgroups based on statistically significant differences among the three ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and MES as the first-tier diagnostic test for other ID subgroup was considered as an efficient clinical detection scheme.
| S-EPMC7236547 | biostudies-literature
Project description:BACKGROUND:Developmental delay (DD) and intellectual disability (ID) are frequently associated with a broad spectrum of additional phenotypes. Chromosomal microarray analysis (CMA) has been recommended as a first-tier test for DD/ID in general, whereas the diagnostic yield differs significantly among DD/ID patients with different comorbid conditions. METHODS:To investigate the genotype-phenotype correlation, we examined the characteristics of identified pathogenic copy number variations (pCNVs) and compared the diagnostic yields among patient subgroups with different co-occurring conditions. RESULTS:This study is a retrospective review of CMA results generated from a mixed cohort of 710 Chinese patients with DD/ID. A total of 247 pCNVs were identified in 201 patients (28%). A large portion of these pCNVs were copy number losses, and the size of copy number losses was generally smaller than gains. The diagnostic yields were significantly higher in subgroups with co-occurring congenital heart defects (55%), facial dysmorphism (39%), microcephaly (34%) or hypotonia (35%), whereas co-occurring conditions of skeletal malformation (26%), brain malformation (24%) or epilepsy (24%) did not alter the yield. In addition, the diagnostic yield nominally correlated with ID severity. CONCLUSION:Varied yields exist in DD/ID patients with different phenotypic presentation. The presence of comorbid conditions can be among factors to consider when planning CMA.
| S-EPMC5968608 | biostudies-literature
Project description:Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1-3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent-offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.
| S-EPMC8707363 | biostudies-literature
Project description:Chromosomal copy-number variations (CNVs) are a class of genetic variants highly implicated in the aetiology of neurodevelopmental disorders, including intellectual disabilities (ID), schizophrenia and autism spectrum disorders (ASD). Yet the majority of adults with idiopathic ID presenting to psychiatric services have not been tested for CNVs. We undertook genome-wide chromosomal microarray analysis (CMA) of 202 adults with idiopathic ID recruited from community and in-patient ID psychiatry services across England. CNV pathogenicity was assessed using standard clinical diagnostic methods and participants underwent comprehensive medical and psychiatric phenotyping. We found an 11% yield of likely pathogenic CNVs (22/202). CNVs at recurrent loci, including the 15q11-q13 and 16p11.2-p13.11 regions were most frequently observed. We observed an increased frequency of 16p11.2 duplications compared with those reported in single-disorder cohorts. CNVs were also identified in genes known to effect neurodevelopment, namely NRXN1 and GRIN2B. Furthermore deletions at 2q13, 12q21.2-21.31 and 19q13.32, and duplications at 4p16.3, 13q32.3-33.3 and Xq24-25 were observed. Routine CMA in ID psychiatry could uncover ~11% new genetic diagnoses with potential implications for patient management. We advocate greater consideration of CMA in the assessment of adults with idiopathic ID presenting to psychiatry services.
| S-EPMC5159755 | biostudies-literature
Project description:Intellectual disability affects about 3% of individuals globally, with∼50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copy-number variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis.
| S-EPMC4023222 | biostudies-literature
Project description:BackgroundChromosomal microarray (CMA) testing is a first-tier test for patients with developmental delay, autism, or congenital anomalies. It increases diagnostic yield for patients with developmental delay or intellectual disability. In some countries, including Korea, CMA testing is not yet implemented in clinical practice. We assessed the diagnostic utility of CMA testing in a large cohort of patients with developmental delay or intellectual disability in Korea.MethodsWe conducted a genome-wide microarray analysis of 649 consecutive patients with developmental delay or intellectual disability at the Seoul National University Children's Hospital. Medical records were reviewed retrospectively. Pathogenicity of detected copy number variations (CNVs) was evaluated by referencing previous reports or parental testing using FISH or quantitative PCR.ResultsWe found 110 patients to have pathogenic CNVs, which included 100 deletions and 31 duplications of 270 kb to 30 Mb. The diagnostic yield was 16.9%, demonstrating the diagnostic utility of CMA testing in clinic. Parental testing was performed in 66 patients, 86.4% of which carried de novo CNVs. In eight patients, pathogenic CNVs were inherited from healthy parents with a balanced translocation, and genetic counseling was provided to these families. We verified five rarely reported deletions on 2p21p16.3, 3p21.31, 10p11.22, 14q24.2, and 21q22.13.ConclusionsThis study demonstrated the clinical utility of CMA testing in the genetic diagnosis of patients with developmental delay or intellectual disability. CMA testing should be included as a clinical diagnostic test for all children with developmental delay or intellectual disability.
| S-EPMC5973923 | biostudies-literature
Project description: Not available
| S-EPMC10479214 | biostudies-literature
Project description:BackgroundAutism spectrum disorder (ASD) is defined as a group of genetically and clinically heterogeneous neurodevelopmental disorders. Interplay between de novo and inherited rare variants has been suspected in the development of ASD.MethodsHere, we applied 750K oligonucleotide microarray analysis and whole-exome sequencing (WES) to five trios from Taiwanese families with ASD.ResultsThe chromosomal microarray analysis revealed three representative known diagnostic copy number variants that contributed to the clinical presentation: the chromosome locations 2q13, 1q21.1q21.2, and 9q33.1. WES detected 22 rare variants in all trios, including four that were newly discovered, one of which is a de novo variant. Sequencing variants of JMJD1C, TCF12, BIRC6, and NHS have not been previously reported. A novel de novo variant was identified in NHS (p.I7T). Additionally, seven pathogenic variants, including SMPD1, FUT2, BCHE, MYBPC3, DUOX2, EYS, and FLG, were detected in four probands. One of the involved genes, SMPD1, had previously been reported to be mutated in patients with Parkinson's disease.ConclusionsThese findings suggest that de novo or inherited rare variants and copy number variants may be double or multiple hits of the probands that lead to ASD. WES could be useful in identifying possible causative ASD variants.
| S-EPMC6900387 | biostudies-literature