The yield of different genetic tests in the evaluation of unexplained intellectual disability in children

Population tested	Diagnostic yield (percent of patients with positive results)	Comments
Chromosomal microarray analysis (CMA; also called array-based comparative genomic hybridization)
Unexplained GDD/ID	15 to 20%	Among the preferred first-tier tests for unexplained ID Does not detect point mutations (sequence variants) responsible for single-gene disorders Does not detect triplet repeat disorders (eg, fragile X)
Whole exome or sequencing (WES)
Unexplained GDD/ID	30 to 55%	Among the preferred first-tier tests for unexplained ID (where available, based on the cost and institutional resources) Diagnostic yield can be enhanced by performing trio-based testing (testing the child and parents) Does not identify CNVs (deletions, duplications) or triplet repeat disorders (eg, fragile X)
Whole genome sequencing (WGS)
Unexplained GDD/ID	40 to 60%	Among the preferred first-tier tests for unexplained ID (where available, based on the cost and institutional resources) Diagnostic yield can be enhanced by performing trio-based testing (testing the child and parents) Can identify CNVs and triplet repeat disorders (eg, fragile X)
Karyotype
GDD/ID	5 to 6%	Used as first-line test primarily for patients with features of Down or other chromosomal syndrome and those with a family history of chromosomal abnormalities
Subtelomeric fluorescence in situ hybridization (FISH)
GDD/ID	1 to 5%	FISH has largely been replaced by CMA Use of FISH is generally limited to instances wherein a specific telomeric disorder is clinically suspected (eg, DiGeorge syndrome, Cri-du-chat syndrome)
General metabolic testing*
Unexplained GDD/ID	0.8 to 3%	Many inborn errors of metabolism are detected on routine newborn screening In addition, WES/WGS techniques increasingly identify genetic abnormalities that cause inborn errors of metabolism
Testing for fragile X (FMR1 DNA analysis)
Nonselective testing in males with GDD/ID	1 to 3%	A selective testing approach is preferred over nonselective testing given the low yield of nonselective testing. Selective testing is suggested for children (males or females) with ID plus either of the following: Clinical features suggesting fragile X syndrome (eg, macrocephaly, large ears, enlarged testes after puberty in males, perseverative speech, and poor eye contact) Family history of ID
Nonselective testing in females with GDD/ID	<1%

GDD: global developmental delay; ID: intellectual disability; CNV: copy number variant.

* Testing for metabolic disorders varies among institutions. It typically includes measurement of serum electrolytes, ammonia, and lactate levels; plasma amino acid concentrations; and urine organic acids. Additional testing should be guided by a metabolic specialist. The diagnostic yield depends on the specific tests performed.

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The yield of different genetic tests in the evaluation of unexplained intellectual disability in children