Developmental Delay (DD) or Intellectual Disability (ID) Testing - Neurocognitive Impairments

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Intellectual disability (ID)
  • Dysmorphic features
  • Congenital abnormalities
  • Unexplained seizures
  • Delay in attaining milestones or loss of milestones
  • Hypotonia
  • Abnormal growth
  • Autism spectrum disorder (ASD)

Laboratory Testing

  • In all patients, consider basic screening
  • Consider genetics consultation prior to extensive genetic testing
  • Sequential testing based on physical exam and history – consider specific tests depending on the patient’s phenotype
    • Dysmorphic features with developmental delay (DD)/ID
      • Array comparative genomic hybridization (aCGH) testing – identifies a suspected but unspecified chromosome imbalance
        • First-tier test for identification of DD/ID, dysmorphic features, congenital anomalies, and autism
        • Several array platforms are available
          • Single nucleotide polymorphism (SNP)-based array – high-density platform testing for genomic imbalance and long stretches of homozygosity
            • Can be performed on blood or buccal specimens
          • Oligonucleotide-based array – usually lower-density platform testing for genomic imbalance
          • Single chromosome platforms – usually oligo based
            • Focus all probes on a single chromosome for identification of very small (usually exonic) deletions and duplications
      • Karyotype and/or FISH analysis to confirm a recognizable diagnosis
    • Autism/ASD with DD/ID – consider the following testing
      • aCGH
      • FMR1 gene analysis (fragile X syndrome)
      • MECP2 gene analysis (Rett syndrome)
      • CDKL5 gene analysis (Rett syndrome)
      • PTEN-related disorders
      • X-linked pattern of inheritance
        • X-chromosome ultrahigh density microarray
        • X-linked ID panel
    • Seizures or hypotonia – metabolic consultation recommended, but tests ordered may include the following (Moeschler, 2014)
      • Plasma amino acids
      • Urine organic acids
      • Plasma acylcarnitines
      • Glycosaminoglycans
      • Carnitine profile
      • Oligosaccharides
      • Purines
      • Pyrimidines
      • GAA/creatinine metabolites
      • aCGH may also be useful – especially if other abnormalities such as ID or dysmorphic features are present
  • Other testing based on results of the above
  • Once etiology of DD/ID has been identified in a family, carrier testing of unaffected family members and prenatal testing of at-risk fetuses may be advisable

Imaging Studies

  • CT/MRI with/without spectroscopy – consider ordering if there are focal neurologic findings, microcephaly, seizures, macrocephaly, or hypotonia

Differential Diagnosis

Developmental delay (DD) is any significant lag in a child's physical, cognitive, emotional, or social maturity when compared to established norms. Intellectual disability (ID) is defined as neurocognitive impairments (IQ <70) as well as significant limitations in adaptive living skills (social, communication, work, leisure, daily living).

Epidemiology

  • Prevalence – 1-3% in the general population (Moescher, 2014)
    • Approximately 25-50% have a genetic basis
  • Age – diagnosis generally <5 years
  • Sex – M>F, due to X-linked disorders

Risk Factors

  • Family history of genetic disorders/ID
  • Neurocognitive dysfunction
  • Cerebral palsy and static encephalopathy
  • Hypotonia
  • Seizure disorder
  • Birth defects (eg, cardiac defect, cleft palate, club feet)
  • Growth abnormalities
  • Nonfamilial dysmorphic features
  • Family history of recurrent miscarriages

Clinical Presentation

  • Global developmental delay in 2 or more domains
    • Gross or fine motor skills
    • Speech/language
    • Cognitive
    • Social/personal
    • Activities of daily living
  • Mild dysmorphic features may be present
  • Abnormal neurologic exam – hypotonia, spasticity, apraxia, microcephaly, macrocephaly

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Cytogenomic SNP Microarray 2003414
Method: Genomic Microarray (Oligo-SNP Array)

Limitations

Does not detect base pair mutations; very small deletions/duplications; balanced rearrangements (translocations, inversions, and balanced insertions); imbalances of the mitochondrial genome

Low-level mosaicism (<25%) may not be detected

May not be investigated or reported – CNVs devoid of relevant gene content or reported as common findings in the general population; duplications <400 kb and deletions <50 kb, depending on genomic content of the imbalance; LCSH <8 Mb (telomeric) or <15 Mb (interstitial) on imprinted chromosomes; LCSH <10 Mb (telomeric) or <15 Mb (interstitial) on non-imprinted chromosomes; LCSH <3% of the autosomal genome

Cytogenomic SNP Microarray Buccal Swab 2006267
Method: Genomic Microarray (Oligo-SNP Array)

Limitations

Does not detect base pair mutations; very small deletions/duplications; balanced rearrangements (translocations, inversions, and balanced insertions); imbalances of the mitochondrial genome

Low-level mosaicism (<25%) may not be detected

May not be investigated or reported – CNVs devoid of relevant gene content or reported as common findings in the general population; duplications <400 kb and deletions <50 kb, depending on genomic content of the imbalance; LCSH <8 Mb (telomeric) or <15 Mb (interstitial) on imprinted chromosomes; LCSH <10 Mb (telomeric) or <15 Mb (interstitial) on non-imprinted chromosomes; LCSH <3% of the autosomal genome

Cytogenomic SNP Microarray with Five-Cell Chromosome Study, Peripheral Blood 2009353
Method: Genomic Microarray (Oligo-SNP Array)/Giemsa band

Limitations

Does not detect base pair mutations; very small deletions/duplications; balanced rearrangements (translocations, inversions, and balanced insertions); imbalances of the mitochondrial genome

Low-level mosaicism (<25%) may not be detected

May not be investigated or reported – CNVs devoid of relevant gene content or reported as common findings in the general population; duplications <400 kb and deletions <50 kb, depending on genomic content of the imbalance; LCSH <8 Mb (telomeric) or <15 Mb (interstitial) on imprinted chromosomes; LCSH <10 Mb (telomeric) or <15 Mb (interstitial) on non-imprinted chromosomes; LCSH <3% of the autosomal genome

Chromosome Analysis, Peripheral Blood, with Reflex to Genomic Microarray 2005763
Method: Giemsa Band/Genomic Microarray (Oligo-SNP Array)

Chromosome FISH, Metaphase 2002299
Method: Fluorescence in situ Hybridization

Limitations

Detects deletions/duplications of the genome at specific, targeted loci

May not detect partial imbalances of the targeted regions

Fragile X (FMR1) with Reflex to Methylation Analysis 2009033
Method: Polymerase Chain Reaction/Capillary Electrophoresis

Limitations

Estimated size is not provided for full mutations with >200 repeats

Methylation patterns are not fully established at the time of chorionic villus sampling for fetal testing

Amniocytes are recommended to distinguish a small, full mutation from a large premutation

Rare mutations in FMR1 unrelated to trinucleotide expansion will not be detected

Diagnostic errors can occur due to rare sequence variations

Rett Syndrome (MECP2), Full Gene Sequencing 0051378
Method: Polymerase Chain Reaction/Sequencing

Limitations

Diagnostic errors can occur due to rare sequence variations

Not detected – breakpoints of large deletions/duplications; regulatory region mutations; deep intronic mutations

Rett Syndrome (MECP2), Sequencing and Deletion/Duplication 0051614
Method: Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations

Diagnostic errors can occur due to rare sequence variations

Not detected – breakpoints of large deletions/duplications; regulatory region mutations; deep intronic mutations

X Chromosome Ultra-High Density Microarray 2004434
Method: Exonic Oligonucleotide-based CGH Microarray

Limitations

Does not exclude the diagnosis of any disorders represented on the microarray

Will not detect numerical X chromosome changes ( eg, Klinefelter, Turner, or XXX syndromes); balanced rearrangements; base-pair changes within genes; genomic imbalances smaller than the resolution of the array; gains or losses within regions of the genome not represented on the array

May not detect copy number imbalances for areas of high-sequence similarity; mosaic gains or losses

X-Linked Intellectual Disability Panel, Sequencing, 76 Genes 2010225
Method: Massively Parallel Sequencing

Limitations

Not analyzed – mutations in genes not included on the panel, deep intronic and regulatory region mutations, and large deletions/duplications

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of hereditary XLID

X-Chromosome Inactivation Analysis 2006352
Method: Restriction Enzyme Digestion/Polymerase Chain Reaction/Fragment Analysis

Limitations

Testing limited to XX females only

Test will be uninformative if there is homozygosity at the analyzed AR locus

XCI patterns may differ among tissues

Will not determine whether the X inactivation pattern is associated with rearrangements of the X chromosome, gene mutations in X-linked genes, or neoplastic disease

Not recommended for prenatal diagnosis

Parent origin of the active X chromosome cannot be determined without parental samples in cases of nonrandom XCI

Should not be used to predict prognosis for female carriers of X-linked disorders

Does not detect clonality

Angelman Syndrome and Prader-Willi Syndrome by Methylation 2005077
Method: Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Specific molecular mechanism responsible for abnormal methylation results cannot be determined

AS resulting from molecular mechanisms that do not affect methylation patterns will not be identified

Diagnostic errors can occur due to rare sequence variations

CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication 2004935
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations

Diagnostic errors can occur due to rare sequence variations

Not determined or evaluated – deep intronic mutations, regulatory region mutations, breakpoints of large deletions/duplications

Additional Tests Available

Angelman Syndrome (UBE3A) Sequencing 2005564
Method: Polymerase Chain Reaction/Sequencing

Comments

Second-tier test for diagnosis of AS

Order if suspicion for Angelman syndrome remains after normal methylation analysis

UBE3A sequencing identifies ~11% of individuals with AS

Angelman Syndrome and Prader-Willi Syndrome by Methylation, Fetal 2012232
Method: Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring

Comments

Prenatal testing for Angelman syndrome or Prader-Willi syndrome

Identifies cases resulting from molecular mechanisms that produce abnormal methylation patterns

Rett Syndrome (MECP2), Deletion and Duplication 0051618
Method: Multiplex Ligation-dependent Probe Amplification

Comments

Second-tier diagnostic test for Rett syndrome

Consultation with a genetic counselor is recommended to plan the optimal MECP2 genetic testing sequence

PTEN-Related Disorders (PTEN) Sequencing and Deletion/Duplication 2002470
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Comments

Preferred initial test

Confirm clinical diagnosis of PTEN hamartoma tumor syndrome (PHTS)

Determine if at-risk family members have a PTEN mutation when a familial mutation is unknown and affected relatives are not available for testing

Chromosome Analysis, Peripheral Blood 2002289
Method: Giemsa Band

Comments

Confirm diagnosis of a known aneuploid syndrome or detect a chromosome translocation

Refer to cytogenomic SNP microarray for the preferred first-tier test for intellectual disability, multiple anomalies, and ASD

Noonan Spectrum Disorders Panel, Sequencing, 15 Genes 2010772
Method: Massively Parallel Sequencing

Comments

Preferred test for individuals with clinical phenotype of Noonan syndrome (NS); cardiofaciocutaneous syndrome (CFCS); Costello syndrome (CS); Legius syndrome (LS); LEOPARD (lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, deafness) syndrome; or Noonan-like syndrome

Noonan Spectrum Disorders Panel, Sequencing, 15 Genes, Fetal 2010769
Method: Massively Parallel Sequencing

Comments

Prenatal testing for fetus with ultrasound findings suggestive of NS

  • Cystic hygroma
  • Increased nuchal translucency
  • Polyhydramnios
  • Hydronephrosis
  • Pleural and/or pericardial effusion
  • Edema
  • Cardiac defects
  • Distended jugular lymphatic sacs
  • Ascites
  • Hydrops fetalis

Noonan Syndrome (PTPN11) Sequencing with Reflex to (SOS1) Sequencing 2004189
Method: Polymerase Chain Reaction/Sequencing

Comments

Acceptable initial test to confirm a clinical diagnosis of NS or LEOPARD syndrome

Clinical sensitivity – ~70% for NS and 90% for LEOPARD syndrome

Noonan Syndrome (SOS1) Sequencing 2004195
Method: Polymerase Chain Reaction/Sequencing

Comments

Acceptable secondary test if no pathogenic mutations are detected with PTPN11 testing

Clinical sensitivity – ~10% for NS

Noonan Syndrome (PTPN11) Sequencing 0051805
Method: Polymerase Chain Reaction/Sequencing

Comments

Acceptable initial test to confirm a clinical diagnosis of NS or LEOPARD syndrome

Clinical sensitivity – ~50-60% for NS and 90% for LEOPARD syndrome

CDKL5-Related Disorders (CDKL5) Deletion/Duplication 2004927
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Comments

Use if mutation not detected with sequencing in cases of suspected CDKL5-related disorders

CDKL5-Related Disorders (CDKL5) Sequencing 2004931
Method: Polymerase Chain Reaction/Sequencing

Comments

Acceptable initial test

Amino Acids Quantitative by LC-MS/MS, Plasma 2009389
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Organic Acids, Urine 0098389
Method: Gas Chromatography/Mass Spectrometry

Carnitine Panel 0081110
Method: Tandem Mass Spectrometry

Lead, Blood (Capillary) 0020745
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Comments

Detect exposure to lead

Elevated results may be due to skin or collection-related contamination, including use of a noncertified lead-free tube

Elevated levels of blood lead should be confirmed with a second specimen collected in a lead-free tube

Repeat testing is recommended prior to initiating chelation therapy or conducting environmental investigations of potential lead sources

Guidelines

Curry C, Stevenson R, Aughton D, Byrne J, Carey J, Cassidy S, Cunniff C, Graham J, Jones M, Kaback M, Moeschler J, Schaefer G, Schwartz S, Tarleton J, Opitz J. Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics. Am J Med Genet. 1997; 72(4): 468-77. PubMed

Filipek P, Accardo P, Ashwal S, Baranek G, Cook E, Dawson G, Gordon B, Gravel J, Johnson C, Kallen R, Levy S, Minshew N, Ozonoff S, Prizant B, Rapin I, Rogers S, Stone W, Teplin S, Tuchman R, Volkmar F. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology. 2000; 55(4): 468-79. PubMed

Manning M, Hudgins L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010; 12(11): 742-5. PubMed

Michelson D, Shevell M, Sherr E, Moeschler J, Gropman A, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011; 77(17): 1629-35. PubMed

Miller D, Adam M, Aradhya S, Biesecker L, Brothman A, Carter N, Church D, Crolla J, Eichler E, Epstein C, Faucett A, Feuk L, Friedman J, Hamosh A, Jackson L, Kaminsky E, Kok K, Krantz I, Kuhn R, Lee C, Ostell J, Rosenberg C, Scherer S, Spinner N, Stavropoulos D, Tepperberg J, Thorland E, Vermeesch J, Waggoner D, Watson M, Martin C, Ledbetter D. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010; 86(5): 749-64. PubMed

Moeschler J, Shevell M, Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014; 134(3): e903-18. PubMed

Schaefer B, Mendelsohn N, Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013; 15(5): 399-407. PubMed

Shaffer L, American College of Medical Genetics Professional Practice and Guidelines Committee. American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation. Genet Med. 2005; 7(9): 650-4. PubMed

Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, Majnemer A, Noetzel M, Sheth R, Quality Standards Subcommittee of the American Academy of Neurology, Practice Committee of the Child Neurology Society. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology. 2003; 60(3): 367-80. PubMed

General References

Mackrides P, Ryherd S. Screening for developmental delay. Am Fam Physician. 2011; 84(5): 544-9. PubMed

Shaffer L, Beaudet A, Brothman A, Hirsch B, Levy B, Martin C, Mascarello J, Rao K, Working Group of the Laboratory Quality Assurance Committee of the American College of Medical Genetics. Microarray analysis for constitutional cytogenetic abnormalities. Genet Med. 2007; 9(9): 654-62. PubMed

Shevell M. Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation, and etiology. Pediatr Clin North Am. 2008; 55(5): 1071-84, xi. PubMed

Silove N, Collins F, Ellaway C. Update on the investigation of children with delayed development. J Paediatr Child Health. 2013; 49(7): 519-25. PubMed

Srour M, Mazer B, Shevell M. Analysis of clinical features predicting etiologic yield in the assessment of global developmental delay. Pediatrics. 2006; 118(1): 139-45. PubMed

Toriello H. Role of the dysmorphologic evaluation in the child with developmental delay. Pediatr Clin North Am. 2008; 55(5): 1085-98, xi. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Andersen E, Baldwin E, Ellingwood S, Smith R, Lamb A. Xq28 duplication overlapping the int22h-1/int22h-2 region and including RAB39B and CLIC2 in a family with intellectual and developmental disability. Am J Med Genet A. 2014; 164A(7): 1795-801. PubMed

Barber J, Rosenfeld J, Foulds N, Laird S, Bateman M, Thomas S, Baker S, Maloney V, Anilkumar A, Smith W, Banks V, Ellingwood S, Kharbutli Y, Mehta L, Eddleman K, Marble M, Zambrano R, Crolla J, Lamb A. 8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients. Am J Med Genet A. 2013; 161A(3): 487-500. PubMed

Barker S, Bale S, Booker J, Buller A, Das S, Friedman K, Godwin A, Grody W, Highsmith E, Kant J, Lyon E, Mao R, Monaghan K, Payne D, Pratt V, Schrijver I, Shrimpton A, Spector E, Telatar M, Toji L, Weck K, Zehnbauer B, Kalman L. Development and characterization of reference materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 genetic testing. J Mol Diagn. 2009; 11(6): 553-61. PubMed

Curry C, Mao R, Aston E, Mongia S, Treisman T, Procter M, Chou B, Whitby H, South S, Brothman A. Homozygous deletions of a copy number change detected by array CGH: a new cause for mental retardation? Am J Med Genet A. 2008; 146A(15): 1903-10. PubMed

Millson A, Lagrave D, Willis M, Rowe L, Lyon E, South S. Chromosomal loss of 3q26.3-3q26.32, involving a partial neuroligin 1 deletion, identified by genomic microarray in a child with microcephaly, seizure disorder, and severe intellectual disability. Am J Med Genet A. 2012; 158A(1): 159-65. PubMed

Pasquali M, Longo N. Response to chen et Al.: carnitine uptake defect (primary carnitine deficiency): risk in genotype-phenotype correlation. Hum Mutat. 2013; 34(4): 656. PubMed

Saam J, Gudgeon J, Aston E, Brothman A. How physicians use array comparative genomic hybridization results to guide patient management in children with developmental delay. Genet Med. 2008; 10(3): 181-6. PubMed

van de Kamp J, Betsalel O, Mercimek-Mahmutoglu S, Abulhoul L, Grünewald S, Anselm I, Azzouz H, Bratkovic D, de Brouwer A, Hamel B, Kleefstra T, Yntema H, Campistol J, Vilaseca M, Cheillan D, D'Hooghe M, Diogo L, Garcia P, Valongo C, Fonseca M, Frints S, Wilcken B, von der Haar S, Meijers-Heijboer H, Hofstede F, Johnson D, Kant S, Lion-Francois L, Pitelet G, Longo N, Maat-Kievit J, Monteiro J, Munnich A, Muntau A, Nassogne M, Osaka H, Ounap K, Pinard J, Quijano-Roy S, Poggenburg I, Poplawski N, Abdul-Rahman O, Ribes A, Arias A, Yaplito-Lee J, Schulze A, Schwartz C, Schwenger S, Soares G, Sznajer Y, Valayannopoulos V, Van Esch H, Waltz S, Wamelink M, Pouwels P, Errami A, van der Knaap M, Jakobs C, Mancini G, Salomons G. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet. 2013; 50(7): 463-72. PubMed

Vanzo R, Martin M, Sdano M, South S. Familial KANK1 deletion that does not follow expected imprinting pattern. Eur J Med Genet. 2013; 56(5): 256-9. PubMed

Wilson J, Pratt V, Phansalkar A, Muralidharan K, Highsmith E, Beck J, Bridgeman S, Courtney E, Epp L, Ferreira-Gonzalez A, Hjelm N, Holtegaard L, Jama M, Jakupciak J, Johnson M, Labrousse P, Lyon E, Prior T, Richards S, Richie K, Roa B, Rohlfs E, Sellers T, Sherman S, Siegrist K, Silverman L, Wiszniewska J, Kalman L, Fragile Xperts Working Group of the Association for Molecular Pathology Clinical Practice Committee. Consensus characterization of 16 FMR1 reference materials: a consortium study. J Mol Diagn. 2008; 10(1): 2-12. PubMed

Medical Reviewers

Last Update: December 2015