Evidence Report: Genetic and metabolic testing on children with global developmental delay [RETIRED]

Abstract

Objective: To systematically review the evidence concerning the diagnostic yield of genetic and metabolic evaluation of children with global developmental delay or intellectual disability (GDD/ID). Methods:Relevant literature was reviewed, abstracted, and classified according to the 4-tiered American Academy of Neurology classification of evidence scheme. Results and Conclusions:In patients with GDD/ID, microarray testing is diagnostic on average in 7.8% (Class III), G-banded karyotyping is abnormal in at least 4% (Class II and III), and subtelomeric fluorescence in situ hybridization is positive in 3.5% (Class I, II, and III). Testing for X-linked ID genes has a yield of up to 42% in males with an appropriate family history (Class III). FMR1 testing shows full expansion in at least 2% of patients with mild to moderate GDD/ID (Class II and III), and MeCP2 testing is diagnostic in 1.5% of females with moderate to severe GDD/ID (Class III). Tests for metabolic disorders have a yield of up to 5%, and tests for congenital disorders of glycosylation and cerebral creatine disorders have yields of up to 2.8% (Class III). Several genetic and metabolic screening tests have been shown to have a better than 1% diagnostic yield in selected populations of children with GDD/ID. These values should be among the many factors considered in planning the laboratory evaluation of such children. Neurology ® 2011;77:1629-1635 GLOSSARY AAN ϭ American Academy of Neurology; BAC ϭ bacterial artificial chromosome; CDG ϭ congenital disorders of glycosylation; DQ ϭ developmental quotient; DXL ϭ definite X-linkage; GDD ϭ global developmental delay; ID ϭ intellectual disability; IEM ϭ inborn errors of metabolism; PXL ϭ possible X-linkage; UXL ϭ unknown X-linkage; XLID ϭ X-linked intellectual disability.

Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

“…28 The studies vary by subject criteria and type of microarray technique and reflect rapid changes in technology over recent years. Nevertheless, the diagnostic yield for all current CMA is estimated at 12% for patients with GDD/ID.…”

“…Nevertheless, the diagnostic yield for all current CMA is estimated at 12% for patients with GDD/ID. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] CMA is the single most efficient diagnostic test, after the history and examination by a specialist in GDD/ID.…”

ACOG and SMFM guidelines for prenatal diagnosis: Is karyotyping really sufficient?

“…High‐resolution single nucleotide polymorphism (SNP)‐based microarrays can detect a variety of abnormalities, including whole chromosome aneuploidies, unbalanced rearrangements, microdeletions and microduplications, triploidy, uniparental isodisomy, and low‐level mosaicism; whereas karyotyping is limited to detecting whole chromosome aneuploidies, large deletions and duplications (≥5–10 Mb), polyploidy, and some balanced chromosomal rearrangements. Due to the significant differences in resolution and the increased detection rate of chromosomal abnormalities, CMA has been recommended as a first tier test in the pediatric setting for the evaluation of children with developmental delays, intellectual disabilities, multiple congenital abnormalities, or autism spectrum disorders for over a decade 1, 2…”

Complex Chromosome Rearrangement of 6p25.3->p23 and 12q24.32->qter in a Child With Moyamoya

“…10,11 Lastly, we confirmed the importance in primary care of a comprehensive genetic evaluation for developmental delay as well as complete genetic evaluation of patients presenting with moyamoya. 17,18 In particular, the bilateral hearing loss, developmental delay, and atypical facies in our patient warranted further chromosomal analysis independent of moyamoya presentation. …”

“…17 The American Academy of Neurology and American Academy of Pediatrics recommends evaluation, including genetic evaluation, of children and particularly those with isolated cognitive delay because of implications for prognosis, reproductive capability, and neurologic progress. 17,18 Genetic etiologies, including chromosomal and subtelomeric duplicated or deleted sequences, can be identified in ∼20% to 40% of cases. 17,19 Previously, both 6p 20 and 12q subtelomeric trisomies 21 were reported among genetic rearrangements associated with developmental delay.…”