Genetic Testing for Developmental Disabilities, Intellectual Disability, and Autism Spectrum Disorder

Project Summary Title and Description

Genetic Testing for Developmental Disabilities, Intellectual Disability, and Autism Spectrum Disorder
Background: Genetics research in recent decades has discovered numerous genetic variants that help explain the etiology of developmental disabilities (DDs). Genetic tests (e.g., array comparative genomic hybridization, sequencing) are rapidly diffusing into clinical practice for diagnosing DDs or, more often, for determining their genetic etiology. An urgent need exists for a better understanding of these tests and their clinical utility. Purpose: This Technical Brief collects and summarizes information on genetic tests that are clinically available in the United States to detect genetic markers that predispose to DDs. It also identifies, but does not systematically review, existing evidence addressing the tests’ clinical utility. This Brief primarily focuses on patients with idiopathic or unexplained DDs, particularly intellectual disability, global developmental delay, and autism spectrum disorder. Several better-defined DD syndromes, including Angelman syndrome, fragile X syndrome, Prader-Willi syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Smith-Magenis syndrome, velocardiofacial syndrome, and Williams syndrome are also included. Patient-centered health outcomes (e.g., functional or symptomatic improvement) and intermediate outcomes (e.g., changes in clinical decisions or family reproductive decisions, the tests’ diagnostic accuracy and analytic validity) are examined. Methods: We sought input from nine Key Informants to identify important clinical, technology, and policy issues from different perspectives. We searched the National Center for Biotechnology Information’s Genetic Testing Registry (GTR) to identify genetic tests. A structured search of studies published since 2000 was performed to identify available evidence that addresses genetic tests’ clinical utility. Findings: Our search of the GTR database identified 672 laboratory-developed tests offered by 63 providers in 29 States. We also identified one test cleared by the U.S. Food and Drug Administration. Common genetic testing methods used include array comparative genomic hybridization, microarray, DNA sequencing (the Sanger method or next-generation sequencing), and polymerase chain reaction. We did not identify any studies that directly assessed the impact of genetic testing on health outcomes. Most of the clinical studies identified for indirect assessment of clinical utility are case series reporting on a test’s diagnostic yield.
Authors of Report
Methodology description
This is an EPC Technical Brief, not a systematic review. The web address of the report posted in the AHRQ website is: The report's PubMed ID is 26158183. Data was entered into this project retrospectively. Data on relevant genetic tests were uploaded using the Manage Reports tool and can be found in the PDF file (Appendix D.pdf). Data relevant to the state of evidence were imported from Excel and can be found in the extraction form (the Design tab) in the project.
Funding Source

Key Questions

1. What genetic tests for diagnosing or determining the etiology of DDs are available for clinical practice in the United States? What genetic techniques or analysis methods are used in these tests? What is the regulatory status (i.e., FDA clearance or approval status, CLIA certification of the test provider) of the tests?
2. State of the evidence on genetic tests for diagnosing or determining the etiology of DDs a. What are the DD conditions addressed in studies of these tests? b. What are the study designs used? c. What outcomes are reported?

Associated Extraction Forms

Associated Studies (each link opens a new tab)

Clinical whole exome sequencing in child neurology practice.2014
Are there cultural differences in parental interest in early diagnosis and genetic risk assessment for autism spectrum disorder?
Clinical utility of chromosomal microarray analysis.2012
The usefulness of whole-exome sequencing in routine clinical practice.2014
Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome.2012
Solving the puzzle: case examples of array comparative genomic hybridization as a tool to end the diagnostic odyssey.2012
Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice.2009
Parental perceived value of a diagnosis for intellectual disability (ID): a qualitative comparison of families with and without a diagnosis for their child's ID.2009
How physicians use array comparative genomic hybridization results to guide patient management in children with developmental delay.2008
Development of a genomic DNA reference material panel for Rett syndrome (MECP2-related disorders) genetic testing.2014
Early detection of fragile X syndrome: applications of a novel approach for improved quantitative methylation analysis in venous blood and newborn blood spots.2014
Diagnosis of copy number variation by Illumina next generation sequencing is comparable in performance to oligonucleotide array comparative genomic hybridisation.2013
Rapid and inexpensive screening of genomic copy number variations using a novel quantitative fluorescent PCR method.2013
Simple, rapid and inexpensive quantitative fluorescent PCR method for detection of microdeletion and microduplication syndromes.
Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder.
Fragile X screening by quantification of FMRP in dried blood spots by a Luminex immunoassay.2013
Comparison between the polymerase chain reaction-based screening and the Southern blot methods for identification of fragile X syndrome.2012
Performance evaluation of two methods using commercially available reagents for PCR-based detection of FMR1 mutation.2012
Quantitative measurement of FMRP in blood platelets as a new screening test for fragile X syndrome.2012
High-resolution SNP arrays in mental retardation diagnostics: how much do we gain?2010
An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis.2010
A novel FMR1 PCR method for the routine detection of low abundance expanded alleles and full mutations in fragile X syndrome.2010
Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA.2009
Mutation screening in 86 known X-linked mental retardation genes by droplet-based multiplex PCR and massive parallel sequencing.2009
Detection and discrimination between deletional and non-deletional Prader-Willi and Angelman syndromes by methylation-specific PCR and quantitative melting curve analysis.2009
Diagnosing Smith-Magenis syndrome and duplication 17p11.2 syndrome by RAI1 gene copy number variation using quantitative real-time PCR.2008
The clinical utility of enhanced subtelomeric coverage in array CGH.2007
Development of a focused oligonucleotide-array comparative genomic hybridization chip for clinical diagnosis of genomic imbalance.2007
A rapid microarray based whole genome analysis for detection of uniparental disomy.2005
Clinical exome sequencing for genetic identification of rare Mendelian disorders.
Molecular findings among patients referred for clinical whole-exome sequencing.2014
Screening for intellectual disability using high-resolution CMA technology in a retrospective cohort from Central Brazil.2014
The clinical impact of chromosomal microarray on paediatric care in Hong Kong.2014
Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.2014
Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability.2014
Clinical utility of multiplex ligation-dependent probe amplification technique in identification of aetiology of unexplained mental retardation: a study in 203 Indian patients.2014
Application of array-based comparative genomic hybridization to pediatric neurologic diseases.2014
Molecular diagnosis of fragile X syndrome using methylation sensitive techniques in a cohort of patients with intellectual disability.2014
Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome.2014
Performance of chromosomal microarray for patients with intellectual disabilities/developmental delay, autism, and multiple congenital anomalies in a Chinese cohort.2014
Array-CGH in children with mild intellectual disability: a population-based study.2015
Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions.2014
Frequency of FMR1 gene mutation and CGG repeat polymorphism in intellectually disabled children in Pakistan.2014
Genome sequencing identifies major causes of severe intellectual disability.2014
Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing.2015
Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
Clinical and mutational spectrum in Korean patients with Rubinstein-Taybi syndrome: the spectrum of brain MRI abnormalities.2015
Multiplex ligation-dependent probe amplification to subtelomeric rearrangements in idiopathic intellectual disability in Colombia.2014
Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.2014
Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability.2014
Diagnostic yield of array comparative genomic hybridization in adults with autism spectrum disorders.2014
Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes.2014
Prevalence of Prader-Willi syndrome among infants with hypotonia.2014
Etiological yield of SNP microarrays in idiopathic intellectual disability.2014
Array-CGH analysis in Rwandan patients presenting development delay/intellectual disability with multiple congenital anomalies.2014
Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations.2014
Making headway with genetic diagnostics of intellectual disabilities.2014
Combined array CGH plus SNP genome analyses in a single assay for optimized clinical testing.2014
Array CGH as a first line diagnostic test in place of karyotyping for postnatal referrals - results from four years' clinical application for over 8,700 patients.
Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features.2013
Identification of Chromosome Abnormalities in Subtelomeric Regions Using Multiplex Ligation Dependent Probe Amplification (MLPA) Technique in 100 Iranian Patients With Idiopathic Mental Retardation.2013
Genomic characterization of some Iranian children with idiopathic mental retardation using array comparative genomic hybridization.2013
Clinical findings in 32 patients with 22qll.2 microdeletion attended in the city of Córdoba, Argentina.2013
Developmental delay referrals and the roles of Fragile X testing and molecular karyotyping: a New Zealand perspective.2013
A 15-year case-mix experience for fragile X syndrome molecular diagnosis and comparison between conventional and alternative techniques leading to a novel diagnostic procedure.2013
Diagnostic, carrier and prenatal genetic testing for fragile X syndrome and other FMR-1-related disorders in Johannesburg, South Africa: a 20-year review.2013
Frequent detection of parental consanguinity in children with developmental disorders by a combined CGH and SNP microarray.
Fluorescence in situ hybridization (FISH) using non-commercial probes in the diagnosis of clinically suspected microdeletion syndromes.2013
Intellectual disability in Indian children: experience with a stratified approach for etiological diagnosis.2013
Development and validation of a multiplex-PCR assay for X-linked intellectual disability.2013
Clinical and genetic analysis of idiopathic intellectual disability based on array comparative genomic hybridization.2013
Array-based comparative genomic hybridization in 190 Korean patients with developmental delay and/or intellectual disability: a single tertiary care university center study.2013
Subtelomeric chromosomal rearrangements in a large cohort of unexplained intellectually disabled individuals in Indonesia: A clinical and molecular study.2013
Epilepsy with cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.2013
Multiplex ligation-dependent probe amplification workflow for the detection of submicroscopic chromosomal abnormalities in patients with developmental delay/intellectual disability.2013
Genotyping FOXG1 Mutations in Patients with Clinical Evidence of the FOXG1 Syndrome.2013
Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability.2013
A parallel study of different array-CGH platforms in a set of Spanish patients with developmental delay and intellectual disability.2013
Clinical and neuropsychiatric status in children with Williams-Beuren Syndrome in Upper Egypt.2013
Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?2013
Copy number variation findings among 50 children and adolescents with autism spectrum disorder.2013
Subtelomeric fish findings in Turkish patients with idiopathic mental retardation.2013
Customized high resolution CGH-array for clinical diagnosis reveals additional genomic imbalances in previous well-defined pathological samples.2013
Genomic abnormalities in children with mental retardation and autism: the use of comparative genomic hybridization in situ (HRCGH) and molecular karyotyping with DNA-microchips (array CGH).2013
Fragile X syndrome: clinical, cytogenetic and molecular screening among autism spectrum disorder children in Indonesia.2013
Clinical utility of the X-chromosome array.2013
Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders.2012
Absence of subtelomeric rearrangements in selected patients with mental retardation as assessed by multiprobe T FISH.2012
Discovery of variants unmasked by hemizygous deletions.2012
Molecular karyotyping by array CGH in a Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies.
Diagnostic yield of chromosomal microarray analysis in an autism primary care practice: which guidelines to implement?2012
"Familial" versus "Sporadic" intellectual disability: contribution of common microdeletion and microduplication syndromes.
"Familial" versus "sporadic" intellectual disability: contribution of subtelomeric rearrangements.2012
Structural chromosomal abnormalities in patients with mental retardation and/or multiple congenital anomalies: a new series of 24 patients.2012
The clinical utility of molecular karyotyping using high-resolution array-comparative genomic hybridization.2012
Searching for Copy Number Changes in Nonsyndromic X-Linked Intellectual Disability.2012
Copy number variation characteristics in subpopulations of patients with autism spectrum disorders.2011
Pathogenic aberrations revealed exclusively by single nucleotide polymorphism (SNP) genotyping data in 5000 samples tested by molecular karyotyping.2011
Chromosomal microarray testing influences medical management.2011
Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome.2011
Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies.2011
Diagnostic yield of genetic testing in children diagnosed with autism spectrum disorders at a regional referral center.2011
Array-based MLPA to detect recurrent copy number variations in patients with idiopathic mental retardation.2011
High-resolution molecular karyotyping in patients with developmental delay and/or multiple congenital anomalies in a clinical setting.2011
Microarray analysis in children with developmental disorder or epilepsy.2010
High frequency of copy number imbalances in Rubinstein-Taybi patients negative to CREBBP mutational analysis.2010
The use of array-CGH in a cohort of Greek children with developmental delay.2010
Candidate gene study of HOXB1 in autism spectrum disorder.2010
Array comparative genomic hybridization findings in a cohort referred for an autism evaluation.2010
Clinical genetic testing for patients with autism spectrum disorders.2010
Array CGH in molecular diagnosis of mental retardation - A study of 150 Finnish patients.2010
Genome-wide oligonucleotide array comparative genomic hybridization for etiological diagnosis of mental retardation: a multicenter experience of 1499 clinical cases.2010
Identification of subtelomeric genomic imbalances and breakpoint mapping with quantitative PCR in 296 individuals with congenital defects and/or mental retardation.2009
A multiplexed ARMS-PCR approach for the detection of common MECP2 mutations.2009
Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.2009
Comparing two diagnostic laboratory tests for several microdeletions causing mental retardation syndromes: multiplex ligation-dependent amplification vs fluorescent in situ hybridization.2009
Autism-specific copy number variants further implicate the phosphatidylinositol signaling pathway and the glutamatergic synapse in the etiology of the disorder.2009
Screening of rural children in West Bengal for fragile-X syndrome.2009
Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization.2009
A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first.2009
Complex segmental duplications mediate a recurrent dup(X)(p11.22-p11.23) associated with mental retardation, speech delay, and EEG anomalies in males and females.2009
Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands.-- Not Found --
Genomic microarrays in mental retardation: a practical workflow for diagnostic applications.2009
Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: a multicenter study.2009
Diagnostic outcome following routine genetics clinic referral for the assessment of global developmental delay.2009
Subtelomeric rearrangements in mental retardation: Hacettepe University experience in 130 patients.-- Not Found --
Use of Multiplex Ligation-Dependent Probe Amplification (MLPA) in screening of subtelomeric regions in children with idiopathic mental retardation.2009
Diagnostic utility of array-based comparative genomic hybridization in a clinical setting.2007
Array comparative genomic hybridization for diagnosis of developmental delay: an exploratory cost-consequences analysis.2007
Comparing two diagnostic laboratory tests for Williams syndrome: fluorescent in situ hybridization versus multiplex ligation-dependent probe amplification.2007
Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation.2006
Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR.2004
MECP2 analysis in mentally retarded patients: implications for routine DNA diagnostics.2004
Flourescence in situ hybridization (FISH) screening for the 22q11.2 deletion in patients with clinical features of velocardiofacial syndrome but without cardiac anomalies2007
Fluorescent in situ hybridization (FISH) as a diagnostic tool for Williams-Beuren syndrome2007
Screening for Fragile X Syndrome among neurobehavioural patients from Kolkata, Eastern India2009
A PCR-based screening method for rapid detection and genetic counseling in Fragile-X syndrome2010
Screening for subtle chromosomal rearrangements in an Egyptian sample of children with unexplained mental retardation2011
To determine the frequency of subtelomeric abnormalities in children with idiopathic mental retardation2011
Centro de estudos do genoma humano: Our six-year experience on the molecular diagnosis of rett syndrome2012
Risk assessment models in genetics clinic for array comparative genomic hybridization: clinical information can be used to predict the likelihood of an abnormal result in patients2013

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