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Almutiri, R.; Malta, M.; Shevell, M.I.; Srour, M. Genetic and Metabolic Investigations in Children with GDD/ID. Encyclopedia. Available online: https://encyclopedia.pub/entry/42835 (accessed on 24 December 2025).
Almutiri R, Malta M, Shevell MI, Srour M. Genetic and Metabolic Investigations in Children with GDD/ID. Encyclopedia. Available at: https://encyclopedia.pub/entry/42835. Accessed December 24, 2025.
Almutiri, Rowim, Maisa Malta, Michael I. Shevell, Myriam Srour. "Genetic and Metabolic Investigations in Children with GDD/ID" Encyclopedia, https://encyclopedia.pub/entry/42835 (accessed December 24, 2025).
Almutiri, R., Malta, M., Shevell, M.I., & Srour, M. (2023, April 06). Genetic and Metabolic Investigations in Children with GDD/ID. In Encyclopedia. https://encyclopedia.pub/entry/42835
Almutiri, Rowim, et al. "Genetic and Metabolic Investigations in Children with GDD/ID." Encyclopedia. Web. 06 April, 2023.
Genetic and Metabolic Investigations in Children with GDD/ID
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This entry is adapted from the peer-reviewed paper 10.3390/children10030414

Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional clinical features or co-morbidities present. Careful evaluation of children with GDD and ID, starting with detailed history followed by a thorough examination, remain the cornerstone for etiologic diagnosis, however, when initial history and examination fail to identify a probable underlying etiology, further genetic testing is warranted.

global developmental delay intellectual disability genetic testing Neurology Neuroscience Pediatric Neurology Development

1. Chromosomal Microarray

Chromosomal microarray (CMA) uses comparative genomic hybridization or single nucleotide polymorphism (SNP) testing to detect chromosomal copy number variants, i.e., gains and losses of chromosomal material. CMA can detect CNVs as small as 20–50 kb and has almost completely replaced the use of karyotyping. However, CMA cannot detect balanced chromosomal rearrangements and has a limited ability to detect low level mosaicism [1][2][3]. CNVs of uncertain established significance can be difficult to interpret. Furthermore, CMA may also detect incidental findings, unrelated to the primary indication. Finally, there are also individual susceptibility CNVs, with documented variable expressivity and/or incomplete penetrance, which are also frequently inherited [4][5][6]. The clinical utility of these susceptibility CNVs is not yet well-established [5].
The diagnostic yield of CMA in NDD overall, including GDD/ID, ranges between 10 and 20% [7][8][9][10]. The diagnostic yield of CMA is lower in individuals with mild vs. moderate to severe ID, with reported yields of 12–19% vs. 20–30% [11][12][13]. A few studies have explored CMA diagnostic yield specifically in non-syndromic GDD/ID, with a reported yield of 10.9% [14]. Note that karyotype analysis is needed to detect balanced translocations, with a diagnostic yield of 3% in cases of developmental disabilities of unknown cause [15]. All current society guidelines recommend CMA testing as a first line [16][17][18][19].

2. Exome Sequencing (ES) and Comprehensive GDD/ID Gene Panels

Exome sequencing is a massively parallel gene sequencing approach, also termed next generation sequencing (NGS), that allows examination of the DNA sequences of most of the protein-encoding exons (~1.5–2% of the genome) of an individual. ES has a few important limitations. Coverage of the exome is not complete and may vary between laboratories and technologies; therefore, not all exons are examined, potentially affecting testing yield. In addition, ES does not reliably detect mosaic variants, exon-level deletions, repetitive sequences, intronic or non-coding variants, mitochondrial DNA, epigenic variants or balanced rearrangements [20].
A recent metanalysis reviewed the diagnostic yield of ES in NDDs and found an overall diagnostic yield of 36% [1], which is well above that of CMA. The yield was 54% in syndromic NDDs and 31% in isolated NDDs [1]. While several studies examined the impact of various clinical features on the diagnostic yield of ES, none reported any statistically significant differences [21][22][23]. Higher yields were observed with abnormal head size (microcephaly and macrocephaly), developmental epileptic encephalopathy and a younger age at presentation [21][24][25][26][27]. In many studies, the yield was equivalent in syndromic and non-syndromic ID [21][22][23]. Periodic re-analysis of ES (every 1–3 years) can enhance diagnostic yield over time by 10–16% [28][29][30].
More recently, small exon-level insertion/deletion (Indel) calling is being incorporated into ES bioinformatic pipelines and has been shown to further increase diagnostic yield. In a recent study, exome-based single nucleotide variant (SNV) and Indel calling combined with exome-based CNV analysis in ES data from patients with NDD, revealed an overall diagnostic yield of 54.0% (35.1% from SNV/Indel and 18.9% from exome based CNV) [31]. A similar study explored diagnostic yield in unexplained DD/ID using exome-based exon-level Indel and CNV analysis, and reported an overall diagnostic yield of 58.8% (41.2% from SNV/Indel constitute and 17.6% CNV) [32].
Comprehensive NGS-based GDD/ID gene panels simultaneously sequence multiple genes (usually over 2000) associated with GDD/ID. A few studies have explored the diagnostic yield of comprehensive GDD/ID gene panels with reported figures of 11–39% [33][34][35][36]. Studies that compared “simulated” panels to ES demonstrated slightly lower diagnostic yields in panels vs. ES [22][37]. Multi-gene panels are usually performed on an exome back-bone, where variants are reported in only selected genes from the exome. Analysis of the remainder of the ES data is at times possible, depending on the providing clinical laboratory.
Trio testing refers to the testing of the proband and both biological parents to help identify and interpret suspected gene variants in the proband. Several studies have reported higher yield from trio testing than from proband-only testing [1][26][38][39][40][41]. Furthermore, additional advantages of trio-based testing include decreased resources for analysis, variant testing in parents and earlier time to definitive diagnosis.
Many of the professional practice guidelines do not currently formally recommend ES testing in GDD/ID, as many were published before ES and NGS testing was readily available in clinical practice. However, ES and comprehensive gene panels are routinely used as an integral part of the genetic evaluation of individuals with GDD/ID. The recent 2021 ACMG guidelines strongly recommend ES as first or second line testing in individuals with GDD/ID [1][42].
Therefore, ES, or comprehensive GDD/ID gene panels, should be considered in the specialty evaluation of children with GDD/ID, given their high yield (above all other testing). Early use of ES in the diagnostic journey, when possible, is recommended. Use will likely be dependent on locally available supports (including financial) and testing resources.

3. Genome Sequencing

Genome sequencing (GS) is an NGS approach that determines the sequence of most of the DNA of the entire genome of an individual. The main advantage of GS over ES is the ability to query intronic regions, and its superior ability compared with ES to detect structural rearrangements including small and large CNVs [20][43]. GS is not yet clinically available in most centers, and its use is still mainly restricted to research paradigms. One study demonstrated that the addition of GS to the investigation of patients with GDD/ID following unrevealing initial testing (either CMA, ES or both) had a diagnostic yield of 21% [43]. The yield was 64% if only a CMA had been previously performed and 14% if ES was performed [43].
GS is not yet recommended by any professional organization given its limited availability. However, it is likely that GS will supplant ES and CMV in the foreseeable future as decreasing testing costs and increased accessibility to clinicians emerge.

4. Fragile X Syndrome Testing

Fragile X syndrome (FXS) is an X-linked triplet repeat expansion disorder caused by the unstable expansion of CGG repeats in the 5′untranslated region of the FMR1 gene. FXS is one of the most common monogenic causes of GDD/ID with a prevalence of 1.4:10,000 males and 0.9:10,000 females. Though it is characterized by distinctive clinical features, including distinctive facial dysmorphisms (long face, large ears, prominent jaw) and macro-orchidism, these may be subtle or only apparent with entry into puberty. Fragile X testing in a cohort of 2486 individuals with NDD demonstrated a yield of 1.2% [44]. Furthermore, 96% of the FXS-positive cases had clinical features of FXS or a positive family history [44]. The yield has been shown to be significantly higher when testing is restricted to males with NDD with characteristic physical/behavioral features or family history, at 9.5–17% [45][46][47].
FXS testing is widely available. It is important to note that FXS cannot be diagnosed by CMA, ES or gene panels. Given the fact that it is an X-linked condition, prompt diagnosis is critical as it will have important impact on recurrence risk and genetic counseling.
Most professional organizations presently recommend testing for FXS as first line in all individuals with GDD/ID.

5. Metabolic/Biochemical Screening for Inherited Metabolic Diseases

Inherited metabolic disorders (IMDs) are genetic disorders that result in metabolic defects due to a deficiency of enzymes, membrane transporters or other functional proteins. Consideration of IMDs when evaluating individuals with GDD/ID is important, especially when early detection can lead to specific treatments that improve clinical outcomes. Over 100 IMDs associated with GDD/ID have potential treatment [48][49]. Furthermore, since these conditions are largely autosomal recessive, diagnosis has as impact on genetic counseling, as risk of recurrence in subsequent pregnancies is often elevated in a Mendelian fashion.
Biochemical screening should be performed in any individual displaying red flags suggestive of an IMD. These include, but are not limited to, developmental plateau or regression in the context of an abnormal exam, altered level of consciousness, observed movement disorders (such as chorea, dystonia, ataxia, and myoclonus), hepatomegaly, splenomegaly, drug-resistant seizures, coarse facial features and multisystemic involvement crossing embryonic origin of affected tissues. Individuals with these features should also be urgently referred to biochemical genetic specialists. Screening metabolic testing may include serum ammonia, lactate, copper, ceruloplasmin, homocysteine, plasma amino acids, urine organic acids, purines, pyrimidines, creatine metabolites, oligosaccharides, and glycosaminoglycan.
There is no current consensus regarding whether biochemical screening for treatable IMDs should be performed in children with non-syndromic GDD/ID in the absence of red flags. Both the Canadian Pediatric Society and the American Academy of Pediatrics recommend the systematic biochemical screening in all children with GDD/ID [18][48][50], while others recommended screening only if clinical features were suggestive of IMDs [17][51][52].
The diagnostic yield of metabolic screening in non-syndromic GDD/ID is extremely low, estimated at 0.25%−0.42% in a non-consanguineous population [52][53]. A review of the implementation of Treatable Intellectual Disability Endeavor (TIDE) screen protocol for cases of GDD/ID without clinical features suggestive of IMDs showed no significant increase in the diagnosis of IMDs, despite a four-fold increase in testing [52].
Given the low yield, routine screening for IMDs is not presently recommended without the presence of clinical features suggestive of IMDs, though should be considered if newborn screening was not previously performed.

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Rowim AlMutiri ,
Maisa Malta
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Michael I. Shevell
, Myriam Srour
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