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

Diagnosis

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 acyl carnitines
      • 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

Clinical Background

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
Test Name and Number Recommended Use Limitations Follow Up
Cytogenomic SNP Microarray 2003414
Method: Genomic Microarray (Oligo-SNP Array)

Preferred first-tier test for developmental delay (DD), multiple anomalies, and ASD

Specimen – peripheral blood

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)

Preferred first-tier test for DD, multiple anomalies, and ASD

Specimen – buccal (requires use of Oracollect collection kit)

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

Cytogenomic SNP Microarray is performed concurrently with a limited five-cell chromosome study

 Useful when chromosome and array tests would otherwise have been ordered concurrently

 May provide information regarding mechanism of gains and losses

 May identify cytogenetically visible rearrangements

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)

Appropriate when there is a significant chance of trisomy

Chromosome studies will identify obvious numerical abnormalities, balanced chromosomal rearrangements, and large deletions/duplications

Reflex pattern – if chromosomes are normal, then testing reflexes to microarray

   
Chromosome FISH, Metaphase 2002299
Method: Fluorescence in situ Hybridization

FISH probes for specific microdeletion/microduplication syndromes must be specified; if no specific syndrome is in question, genomic microarray should be ordered instead of screening multiple loci by FISH

ARUP Constitutional FISH Probes menu

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

Preferred test for fragile X syndrome screening

Preferred test for symptomatic individuals or those with a positive family history

Reflex pattern – repeat lengths of ≥55 will reflex to methylation analysis

Clinical and analytical sensitivity/specificity – 99%

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

Acceptable first-tier test for Rett syndrome

Preferred initial test for females with a phenotype of classic or atypical Rett syndrome

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

Clinical sensitivity

Classic Rett syndrome

  • Sequencing – ~80%
  • Deletions/duplications – ~8-10%

Atypical Rett

  • Sequencing – ~40%
  • Deletions/duplications – ~3%

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

Confirm clinical diagnosis of Rett syndrome or MECP2-related disorder

Determine cause of severe neonatal encephalopathy or intellectual disability in males

Rule out MECP2 mutation in families with X-linked intellectual disability

Rule out MECP2 mutation in individuals with clinical features of Angelman syndrome and who lack a molecular abnormality involving 15q11.2-13

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

Clinical sensitivity

Classic Rett syndrome

  • Sequencing – ~80%
  • Deletions/duplications – ~8-10%

Atypical Rett

  • Sequencing – ~40%
  • Deletions/duplications – ~3%

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

Detects exon-level losses or gains of DNA on the X chromosome in individuals with unexplained intellectual disability, autism, or other X-linked genetic conditions

For whole-genome coverage, refer to cytogenomic SNP microarray test

Clinical sensitivity – varies by condition

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

Preferred test for individuals with suspected X-linked intellectual disability (XLID) when genomic microarray testing has not identified causal variant(s)

Refer to Additional Technical Information document for list of genes tested

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

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

Determine X-chromosome inactivation (XCI) pattern for female carriers of X-linked disorders

Assess pathogenicity of genetic variant in an X-linked gene

Clinical sensitivity – 90%; 10% of women have skewed XCI by chance (increases with age)

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

Preferred initial diagnostic test for Angelman syndrome (AS) or Prader-Willi syndrome

Clinical sensitivity – 78%

Analytic sensitivity – 99%

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

Confirmation of a clinical diagnosis of a CDKL5-related disorder in individuals with infantile seizures; X-linked infantile spasm syndrome (ISSX);  MECPC2-negative atypical Rett syndrome; autism; intellectual disability with seizure disorder

Clinical sensitivity – for sequencing combined with deletion/duplication; dependent on phenotype; 17% for females with early-onset seizures

Deep intronic mutations and some regulatory region mutations are not detected

Diagnostic errors may occur due to rare sequence variations

Large deletions/duplications of exon 3 will not be detected

Breakpoints of large deletions/duplications will not be determined

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Angelman Syndrome (UBE3A) Sequencing 2005564
Method: Polymerase Chain Reaction/Sequencing

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

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

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

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

Microarray Family Study by FISH 2002301
Method: Fluorescence in situ Hybridization

Used to test for the presence or absence of a deletion or duplication previously identified in a family member (contact ARUP genetic counselor before ordering this test)

Chromosome Analysis, Peripheral Blood 2002289
Method: Giemsa Band

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

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

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

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

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

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

Use if mutation not detected by sequencing

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

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

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