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
            • 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 (fragile X) analysis  
        • MECP2 analysis (Rett syndrome
        • CDKL5 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
        • Plasma amino acids
        • Urine organic acids
        • Plasma acyl carnitines
        • Carnitine profile
        • aCGH may also be useful – especially if there are other abnormalities such as ID or dysmorphic features
  • Other testing based on results of the above
  • Once etiology of DD/ID 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 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
    • Approximately 25-50% have a genetic basis
  • Age – diagnosis generally <5 years
  • Sex – M:F, equal except in 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

  • Neurocognitive impairment in addition to delays in ≥2 of the following
    • Social skills
    • Community living
    • Communication
    • Home living
    • Health
    • Self-direction
    • Work
    • Leisure
  • Mild dysmorphic features
  • 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), or imbalances of the mitochondrial genome

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

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

First-tier test for developmental delay (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), or imbalances of the mitochondrial genome

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

 
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, or imbalances of the mitochondrial genome

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

 
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

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

Diagnose fragile X syndrome

Screen for carrier status

May also be used as newborn screening

If an intermediate to expanded allele (CGG repeats) is detected by PCR and capillary electrophoresis; methylation analysis will be added to determine the size of the expanded CGG repeat

Clinical and analytic sensitivity/specificity 99%

Diagnostic errors can occur due to rare sequence variations  
Rett Syndrome (MECP2), Full Gene Sequencing 0051378
Method: Polymerase Chain Reaction/Sequencing

Because of the complexity of MECP2-related disorders, a gender-specific approach to MECP2 gene testing is recommended

Consultation with a genetic counselor is highly recommended

Deep intronic mutations and large deletions/duplications will not be identified; analytical sensitivity may be compromised by rare primer site mutations

Sequencing testing limited to females; males do not survive mutations or deletions

Males are candidates for duplication analysis by multiplex ligation probe amplification

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

Because of the complexity of MECP2-related disorders, a gender-specific approach to MECP2 gene testing is recommended

Consultation with a genetic counselor is highly recommended

Detects 95% of MECP2 pathogenic mutations

Breakpoints of large deletions/duplications will not be determined; deep intronic mutations will not be detected; analytical sensitivity may be compromised by rare primer site mutations  
X Chromosome Ultra-High Density Microarray 2004434
Method: Exonic Oligonucleotide-based CGH Microarray

Detect loss or gain of DNA on the X chromosome in patients with unexplained disability, autism, and other X-linked genetic conditions

Does not detect numerical X-chromosome changes, such as Klinefelter, Turner, or triple-X syndromes

Balanced rearrangements and base-pair changes will not be detected; copy-number imbalances for areas of high-sequence similarity may not be detected

Negative result does not exclude diagnosis of disorders represented on the microarray

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

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

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 pattern of X-chromosome inactivation in female carrier

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

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

Aid in determining etiology of DD/ID in patients with additional findings associated with Angelman syndrome (AS) (microcephaly, seizures, ataxia) or Prader-Willi syndrome (feeding problems, hypotonia, hypogonadism, and growth failure in infancy; hyperphagia and rapid weight gain in early childhood)

>99% analytic sensitivity

Mutations or mechanisms not affecting methylation patterns will not be detected  
Angelman Syndrome (UBE3A) Sequencing 2005564
Method: Polymerase Chain Reaction/Sequencing

Confirm diagnosis of Angelman syndrome (AS) in individuals with normal DNA methylation test and symptoms of AS

UBE3A sequencing identifies ~11% of individuals with AS

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

May be useful for individuals with early onset seizures and intellectual disability when MEPC2 full gene analysis fails to detect a pathogenic mutation

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Rett Syndrome (MECP2), Deletion and Duplication 0051618
Method: Multiplex Ligation-dependent Probe Amplification

Because of the complexity of MECP2-related disorders, a gender-specific approach to MECP2 gene testing is recommended

Consultation with a genetic counselor is highly recommended

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

Test for Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome

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

Noonan Syndrome (PTPN11) Sequencing with Reflex to (SOS1) Sequencing 2004189
Method: Polymerase Chain Reaction/Sequencing
Noonan Syndrome (SOS1) Sequencing 2004195
Method: Polymerase Chain Reaction/Sequencing
CDKL5-Related Disorders (CDKL5) Deletion/Duplication 2004927
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Order to confirm the clinical diagnosis of a CDKL5 mutation-related disorder

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

Order to confirm the clinical diagnosis of a CDKL5 mutation-related disorder

Amino Acids Quantitative by LC-MS/MS, Plasma 2009389
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry
Organic Acids, Urine (Temporary Referral as of 04/15/14) 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