Application of chromosomal microarrays in the evaluation of intellectual disability/global developmental delay patients – A study from a tertiary care genetic centre in India

Sharma, Pankaj; Gupta, Neerja; Chowdhury, Madhumita Roy; Sapra, Savita; Ghosh, Manju; Gulati, Sheffali; Kabra, Madhulika

doi:10.1016/j.gene.2016.06.020

Cited by 13 publications

(11 citation statements)

References 60 publications

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“…9,36 This approach, which does not encompass WES, 7 , provides a genetic diagnosis in about one third of cases. By comparison, first-tier WES for children with neurodevelopmental disorders yields a molecular diagnostic rate of 40-60% 5,9,34 to $3,150) per exome trio (based on 34 reporting labs at http://www.scienceexchange.com). Using this information to calculate a simple metric of value (i.e., favorable outcomes per dollar spent), 37 we assign a theoretical genomic evaluation cost of $4,000 per study subject (to comprise costs of targeted allele detection, CMA, and 0-4 additional exomes per proband; Figure 1a) to return actionable information in at least 50% of cases.…”

Section: Discussionmentioning

confidence: 99%

“…Whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) have revolutionized investigation of rare genetic disorders and intellectual disability, [1][2][3][4][5][6] but important diagnostic and service gaps remain. The pretest probability of a genetic lesion is high for individuals who move through contemporary diagnostic algorithms to arrive at CMA or WES, 7-9 yet many remain undiagnosed at the culmination of the process.…”

Section: Introductionmentioning

confidence: 99%

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Genomic diagnostics within a medically underserved population: efficacy and implications

Strauss

Gonzaga‐Jauregui

Brigatti

et al. 2018

Genetics in Medicine

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PurposeWe integrated whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) into a clinical workflow to serve an endogamous, uninsured, agrarian community.MethodsSeventy-nine probands (newborn to 49.8 years) who presented between 1998 and 2015 remained undiagnosed after biochemical and molecular investigations. We generated WES data for probands and family members and vetted variants through rephenotyping, segregation analyses, and population studies.ResultsThe most common presentation was neurological disease (64%). Seven (9%) probands were diagnosed by CMA. Family WES data were informative for 37 (51%) of the 72 remaining individuals, yielding a specific genetic diagnosis (n = 32) or revealing a novel molecular etiology (n = 5). For five (7%) additional subjects, negative WES decreased the likelihood of genetic disease. Compared to trio analysis, "family" WES (average seven exomes per proband) reduced filtered candidate variants from 22 ± 6 to 5 ± 3 per proband. Nineteen (51%) alleles were de novo and 17 (46%) inherited; the latter added to a population-based diagnostic panel. We found actionable secondary variants in 21 (4.2%) of 502 subjects, all of whom opted to be informed.ConclusionCMA and family-based WES streamline and economize diagnosis of rare genetic disorders, accelerate novel gene discovery, and create new opportunities for community-based screening and prevention in underserved populations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic diagnostics within a medically underserved population: efficacy and implications

Strauss

Gonzaga‐Jauregui

Brigatti

et al. 2018

Genetics in Medicine

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“…In conclusion, we report a relatively high diagnostic yield by CGH microarray analyses in a very large cohort of children with DD/ID, with results being confirmed by FISH/qPCR and parental testing in more than half of the cases, compared with other studies in Korea [ 7 9 10 ]. We demonstrate the clinical diagnostic utility of CMA testing for pediatric populations in some countries, including Korea, where CMA testing has not been implemented in routine clinical settings for patients with DD/ID [ 2 3 7 8 ]. CMA testing with appropriate resolution should be conducted for diagnostic use.…”

Section: Discussionmentioning

confidence: 99%

“…Even with its high diagnostic yield and clinical impact on pediatric care [ 2 3 ], CMA testing is not yet widely used for clinical diagnostic purposes in children with DD/ID in some countries, including Korea [ 3 7 8 9 10 ]. We demonstrate the diagnostic utility of CMA testing for DD/ID in the pediatric population, by assessing data from a large cohort of Korean patients with DD/ID.…”

Section: Introductionmentioning

confidence: 99%

Chromosomal Microarray With Clinical Diagnostic Utility in Children With Developmental Delay or Intellectual Disability

Lee

Kim

et al. 2018

Ann Lab Med

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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.

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“…Diagnostic yield of chromosomal microarray analysis in children with developmental delay/intellectual disability has been reported between 7% and 20%101112131415161718). One literature review regarding the use of chromosomal microarray as a diagnostic test for patients with developmental disabilities, autism, or congenital abnormalities reviewed 33 original reports, including 21,698 patients tested by chromosomal microarray, showed that the average detection rate of pathogenic CNVs was 12.2%, whereas the average diagnostic yield of G-banded karyotyping was less than 3% if Down syndrome was excluded5).…”

Section: Discussionmentioning

confidence: 99%

Application of array comparative genomic hybridization in Korean children under 6 years old with global developmental delay

Lee

Shin²

2017

Korean J Pediatr

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PurposeRecent advancements in molecular techniques have greatly contributed to the discovery of genetic causes of unexplained developmental delay. Here, we describe the results of array comparative genomic hybridization (CGH) and the clinical features of 27 patients with global developmental delay.MethodsWe included 27 children who fulfilled the following criteria: Korean children under 6 years with global developmental delay; children who had at least one or more physical or neurological problem other than global developmental delay; and patients in whom both array CGH and G-banded karyotyping tests were performed.ResultsFifteen male and 12 female patients with a mean age of 29.3±17.6 months were included. The most common physical and neurological abnormalities were facial dysmorphism (n=16), epilepsy (n=7), and hypotonia (n=7). Pathogenic copy number variation results were observed in 4 patients (14.8%): 18.73 Mb dup(2)(p24.2p25.3) and 1.62 Mb del(20p13) (patient 1); 22.31 Mb dup(2) (p22.3p25.1) and 4.01 Mb dup(2)(p21p22.1) (patient 2); 12.08 Mb del(4)(q22.1q24) (patient 3); and 1.19 Mb del(1)(q21.1) (patient 4). One patient (3.7%) displayed a variant of uncertain significance. Four patients (14.8%) displayed discordance between G-banded karyotyping and array CGH results. Among patients with normal array CGH results, 4 (16%) revealed brain anomalies such as schizencephaly and hydranencephaly. One patient was diagnosed with Rett syndrome and one with Möbius syndrome.ConclusionAs chromosomal microarray can elucidate the cause of previously unexplained developmental delay, it should be considered as a first-tier cytogenetic diagnostic test for children with unexplained developmental delay.

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Application of chromosomal microarrays in the evaluation of intellectual disability/global developmental delay patients – A study from a tertiary care genetic centre in India

Cited by 13 publications

References 60 publications

Genomic diagnostics within a medically underserved population: efficacy and implications

Genomic diagnostics within a medically underserved population: efficacy and implications

Chromosomal Microarray With Clinical Diagnostic Utility in Children With Developmental Delay or Intellectual Disability

Application of array comparative genomic hybridization in Korean children under 6 years old with global developmental delay

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