Indications for Testing
Laboratory evaluation of suspected DD, ID, or ASD should be considered for individuals with any of the following presentations :
- Failure to meet developmental milestones
- IQ <70 and difficulty performing daily living activities
- Comorbidities (eg, dysmorphic features, congenital anomalies) that may guide testing
Determining Diagnosis for Care Planning
Clinical evaluation of DD/ID and ASD will guide the laboratory testing strategy and should include :
- Medical history, including prenatal and birth histories
- Family history with at least a three-generation pedigree
- Physical and neurologic exam with particular attention to dysmorphology (minor anomalies)
- Examination of behavior and neurologic symptoms
Following the clinical evaluation, the judicious use of laboratory testing, imaging, and other techniques is recommended. If a specific condition is suspected, consider targeted testing. If the etiology of DD/ID/ASD is unknown, proceed with tiered testing based on highest diagnostic yield in the patient population.
The American College of Medical Genetics and Genomics (ACMG) developed a tiered evaluation system to assist clinicians in the clinical genetic diagnostic evaluation of ASD. The logic behind the tiered approach is that tests performed in higher (or earlier) tiers have a greater expected diagnostic yield, are less invasive, and provide better potential for intervention. The tiered approach also allows for customization to the clinical situation at hand.
The American Academy of Pediatrics (AAP) recommends a similar stepwise approach in the evaluation of children with ID or global DD. The American Academy of Neurology (AAN) also supports laboratory testing in the evaluation of patients with global DD/ID.
The first-tier evaluation for DD/ID includes a detailed clinical evaluation, as described in Determining Diagnosis for Care Planning (above). If a specific disorder is suspected, targeted testing should be performed with appropriate follow-up. If no specific etiology is suggested, testing should proceed with CMA (and/or chromosome analysis in limited circumstances) and fragile X testing. Especially for global DD/ID, consider testing for IEMs, which has a low yield but high benefit for diagnosed patients.
As with DD/ID, the first-tier evaluation for ASD includes a detailed clinical evaluation and should include an audiogram. Certain disorders that have firmly established associations with ASD (eg, Angelman syndrome and Prader-Willi syndrome) may be identified through disorder-specific testing. If such a diagnosis is made, no further testing to identify the etiology of ASD is required. Otherwise, proceed with tiered testing and/or consider referral for medical genetics evaluation.
CMA is the preferred first-tier test for DD/ID, ASD, and MCAs in patients for whom the causal diagnosis is unknown. CMA offers a higher diagnostic yield (~15-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCAs than does chromosome analysis (~3%; excluding Down syndrome and other recognizable chromosomal syndromes). CMA detects syndrome-associated microdeletions and microduplications that are below the resolution of karyotype analysis. Cryptic copy number variations (CNVs) that indicate unbalanced translocations may be identified. Compared to chromosome analysis, CMA provides far superior detail that facilitates the interpretation of results.
If CMA results are normal, review of other first-tier test results and consideration of second-tier testing and/or referral to medical genetics is recommended. If CMA results are abnormal, genetic counseling is recommended.
FMR1 Testing for Fragile X Syndrome
FXS is the most common form of heritable ID. This X-linked condition presents as severe DD in males and as mild ID in females. Apparently spontaneous cases with negative family history arise due to the expansion of premutations in female carriers. The AAP recommends that all children who present with global DD/ID of unknown etiology be tested for FXS. The AAN evidence report also supports testing patients of both sexes with unexplained DD/ID. The ACMG recommends FMR1 analysis for boys with ASD and for girls with a consistent family history and phenotype. The AAN finds that FMR1 testing has a combined yield of at least 2% in male and female patients who have mild DD/ID. Timely diagnosis supports access to early intervention and timely reproductive risk counseling.
Chromosome Analysis (Karyotyping)
G-banded chromosome analysis is no longer recommended unless aneuploidy is suspected. Chromosome analysis has a lower diagnostic yield than CMA because it typically only detects genomic imbalances greater than 5-10 Mb. It is only cost-effective in patients whose symptoms are consistent with a specific chromosome abnormality such as Down syndrome, trisomy 13, or trisomy 18, or in certain other special cases (eg, family history of multiple miscarriages).
Metabolic and/or Mitochondrial Disorders Testing
Metabolic and/or mitochondrial disorder testing may be considered after reviewing newborn screening (NBS) results and assessing for clinical indicators that may suggest a metabolic disorder (eg, failure to thrive, unusual odors, hearing loss, and episodic symptoms). The AAP, AAN, and ACMG support the consideration of screening for metabolic conditions in children who present with DD/ID/ASD. Many metabolic tests are available at a relatively low cost, and, despite the low prevalence of inherited metabolic conditions, the potential for improved outcomes after diagnosis and treatment is high.
If no etiology is found for ASD, second-tier testing includes MECP2 sequencing (for Rett syndrome) in all females and MECP2 duplication testing in males with suggestive phenotypes.
Second-tier testing for DD/ID includes MECP2 full gene analysis in females. The AAN suggests MECP2 testing in girls with severe global DD/ID, and the AAP emphasizes complete MECP2 testing for females with global DD/ID. Both groups emphasize that MECP2 testing in these patients is indicated even in the absence of classic Rett syndrome features.
Patients of both sexes who have head circumferences >2.5 standard deviations above the mean should have PTEN gene analysis if ASD etiology is still unknown after initial evaluations.
The AAP, ACMG, and AAN recommend considering testing for X-linked ID in males with a suggestive family history.
Brain magnetic resonance imaging (MRI) is recommended for patients with microcephaly, macrocephaly, or abnormal neurologic exams.
Development of a plan for follow-up, including potential reevaluation, is recommended.
Refer to the Testing for Genetic Syndromes Related to Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder Algorithm for suggested testing strategies.
Diagnostic Yields of Genetic Testing
The following approximate diagnostic yields are expected in the genetic evaluation of ASDs and global DD/ID:
||Approximate Diagnostic Yield (Global DD/ID)
||Approximate Diagnostic Yield (ASD)a
||>2% (mild-moderate DD/ID)c
||1.5% (females with moderate-severe DD/ID)c
||5% (of those tested with head circumferences >2.5 SDs)
||3-4%b,c (excluding Down syndrome)
|Other (eg, IEM, X-linked disorders)
||Up to 10%c
bMiller, 2010 ; average of 33 studies
SD, standard deviations