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The yield of testing for genetic anomalies in children with intellectual disability

The yield of testing for genetic anomalies in children with intellectual disability
Population tested Diagnostic yield*
(percent of patients with positive results)		 Comments
Chromosomal microarray analysis (CMA, also known as comparative genomic hybridization [CGH])
GDD/ID 15 to 20 Recommended as first-line test for most patients with GDD/ID, unless the patient has features suggesting a specific disorder
Karyotype
GDD/ID 10 to 15 Recommended as first-line test for the following:
  • Patients with features of Down or other chromosomal syndrome
  • Family history of chromosomal abnormalities
  • Parent with multiple miscarriages
Subtelomeric fluorescence in situ hybridization (FISH)
GDD/ID or MCA 4 to 6 Where available, CMA is generally preferred over FISH
Mild GDD/ID 1 to 2
Whole exome sequencing
Unexplained GDD/ID or MCA 16 to 25 Where available, based on the cost and institutional resources
General metabolic screening
Unexplained GDD/ID <1 to 3Δ Recommended (in addition to CMA) in patients with the following features:
  • Parental consanguinity
  • Family with other children with similar problems, or unexplained fetal demise
  • Episodic symptoms, including seizures or encephalopathy
  • Multiple organ dysfunction
  • Failure to thrive, dietary selectivity, unusual body odor, hearing loss, hepatomegaly
  • Developmental regression
Testing the whole X chromosome or testing multiple X-linked genes specifically
Definitely X-linked 42
  • Testing the whole X chromosome or multiple X-linked ID genes specifically is recommended in male patients with a family history suggestive of X-linked inheritance of ID
  • Mutations in X-linked genes account for 10 percent of all cases with ID
Possibly X-linked 17
Specific testing for fragile X (trinucleotide repeat expansion of the FMR1 gene)
Males with clinical features of fragile X syndrome 15 Testing is suggested in children with the following characteristics:
  • Male or female children with ID and clinical features suggestive of fragile X syndrome, such as macrocephaly, large ears, enlarged testes, perseverative speech, lack of eye contact
  • Male or female children with ID and a family history of ID
  • Children with unexplained ID whose first-line CMA testing is normal (or benign)
Males with unexplained GDD/ID 3
Males or females with mild to moderate unexplained GDD/ID 2-3
Females with unexplained GDD/ID 1
CMA: chromosomal microarray analysis (also known as comparative genomic hybridization [CGH]); FISH: fluorescence in situ hybridization; GDD: global developmental delay; ID: intellectual disability; MCA: multiple congenital anomalies.
* Represents approximate diagnostic yield, based on a meta-analysis of population studies. Most of the included studies were "class III," defined as a sample of patients studied during the course of a condition, rather than a population-based sample.
¶ Screening for metabolic disorders varies among institutions. It typically includes urine for amino acids, organic acids, mucopolysaccharides, oligosaccharides, uric acid, sialic acid, purines, and pyrimidines; and plasma for amino acids, acylcarnitines, and sialotransferrins.
Δ The diagnostic yield of metabolic screening depends on the presence of clinical indicators of metabolic disease and the range of testing performed. Initial metabolic screening does not definitively exclude some diagnoses such as mucopolysaccharidosis and a congenital disorder of glycosylation, and some tests should be repeated if the clinical features are suspicious for one of these disorders.
References:
  1. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 2015; 519:223.
  2. Engbers HM, Berger R, van Hasselt P, et al. Yield of additional metabolic studies in neurodevelopmental disorders. Ann Neurol 2008; 64:212.
  3. Hagerman RJ, Amiri K, Cronister A. Fragile X chechlist. Am J Med Genet 1991; 38:283.
  4. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay. Neurology 2011; 77:1629.
  5. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86:749.
  6. van Karnebeek CD, Jansweijer MC, Leenders AG, et al. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005; 13:6.
  7. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014; 312:1870.
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