Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review
Abstract
:1. Introduction
2. Genetic Etiologies of Intellectual Disabilities and Global Developmental Delay
3. Genetic Diagnostic Tools for Unexplained Intellectual Disabilities and Global Developmental Delay
3.1. Chromosome Microarray
3.2. Massive Parallel Sequencing
3.2.1. Gene Panels
3.2.2. Exome Sequencing
3.2.3. Genome Sequencing
3.2.4. Beyond Genomic Sequencing
4. Discussion
Proposed Evaluations Algorithm for Unexplained Intellectual Disabilities or Global Developmental Delay
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Location | Phenotypes Other than GDD/ID | Ref. |
---|---|---|---|
ARID1B | 6q25.3 | Coffin–Siris syndrome | [2,18] |
DDX3X | X | Verbal dyspraxia, hypotonia Mostly in females; rare in males | [2,19] |
KMT2A | 11q23 | Wiedemann–Steiner Syndrome, characteristic dysmorphism | [2,20] |
DYRK1A | 21q22.13 | Characteristic facial features, feeding difficulty, speech impairment, microcephaly, epilepsy | [2,21] |
CTNNB1 | 3p22.1 | Exudative vitreoretinopathy, truncal hypotonia, peripheral spasticity, microcephaly | [2,22] |
ADNP | 20q13.13 | Syndromic autism, dysmorphic facial features, seizure, hypotonia, early tooth eruption | [2,23] |
STXBP1 | 9q34.11 | Early infantile epileptic encephalopathy 4 (EIEE4), epilepsy, behavior problems, movement disorders | [2,24,25,26] |
SCN2A | 2q24.3 | Epilepsy syndromes, non-syndromic ID, ASD | [2,27,28] |
MED13L | 12q24.2 | Distinctive facial features with macroglossia, macrostomia, congenital heart defects | [2,29,30] |
SATB2 | 2q33.1 | SAS syndrome, hypotonia, feeding difficulty, craniofacial anomalies | [2,31] |
Terms | Definition |
---|---|
Recurrent copy number variant (CNV) | Genetic rearrangements that recur in multiple individuals, with similar length and breakpoint. |
Non-recurrent CNV | Genetic rearrangements with scattered breakpoints and different sizes that are usually different among different individuals. |
Single-nucleotide variants (SNV) | Substitution of a single nucleotide for another. The exchange is non-synchronous if the SNV results in a change in amino acid, and synchronous if the SNV does not result in a change in amino acid. The SNV can also be a stop gain, resulting in premature termination of protein transcription. |
Small insertions and deletions (Indels) | Insertion or deletion of less than 50 base pairs length of DNA, often resulting in frameshift changes. |
Structural variants | Changes in the DNA length of greater than 50 base pairs, including deletion, duplication, inversion and translocation. Copy number variants are examples of imbalanced structural variants. |
Runs of homozygosity (ROH) | Continuous homozygous DNA segments in diploid genomes, commonly used to diagnose uniparental isodisomy, consanguinity, and replicative DNA repair events. |
Repeat expansions/short tandem repeats (STR) | Trinucleotide repeat expansions that are unstable mutations and increase in size in the successive generations. |
Mitochondrial variants | Changes similar to nuclear genomic variations, including SNV, indels, and structural variants. Additionally, if heteroplasmic, analytical validity must be carefully reviewed with clinical phenotypes. |
Mosaic variants | Genetic variations that occur after fertilization, resulting in two or more genetically different cell lines. |
Null variants | Canonical nonsense or frameshift deletion, resulting in loss of function in a gene |
Variant calling | The process of variant identification, which is an integral part of genetic assessment |
In silico predictive programs | Computational analysis tools that aim to prioritize variant triage and to determine the potential effect of the sequence variant on the gene transcript and the protein products. |
Sequencing coverage | Number of reads that covers a DNA segment and is defined by the Lander/Waterman equation: C = LN/G (C is coverage, L is the read length, N is the number of reads, and G is the haploid genome length). |
Variant allele frequency (VAF) | Prevalence of a specific gene within a population. Variants associated with rare conditions typically have low allele frequencies (<1%). To increase the sensitivity of the variant calling algorithm, the threshold of allele frequency is usually set higher, from 3% to 10%. |
Diagnostic yield | Proportion of individuals carrying a pathogenic/likely pathogenic variant in a cohort. |
Study | Country | N | Cohort Phenotype | DY | Ref. |
---|---|---|---|---|---|
Subjects with Normal Karyotypes | |||||
Leite et al. (2022) | Brazil | 83 | GDD/ID +/− MCA | 33% | [36] |
Levchenko et al. (2022) | Russia | 91 | Non-specific ID | 18% | [8] |
Liu et al. (2022) | China | 251 | Unexplained ID/DD | 32% | [37] |
Yuan et al. (2021) | China | 2688 | Non-syndromic ID/DD | 21% | [38] |
Espeché et al. (2020) | Argentina | 133 | ID with dysmorphic features | 12% | [39] |
Lee et al. (2019) | Taiwan | 177 | ID/DD | 32% | [40] |
Wang et al. (2019) | China | 358 | Isolated ID/DD | 25% | [41] |
Chan et al. (2018) | Hong Kong | 138 | Moderate–profound GDD/ID | 12% | [42] |
Chen et al. (2018) | China | 60 | Moderate–severe ID | 20% | [43] |
Kim et al. (2018) | Korea | 50 | Severe ID/DD | 36% | [44] |
Subjects Without Karyotype Results | |||||
Kamath et al. (2022) | India | 67 | GDD/ID +/− comorbidities | 21% | [45] |
Miclea et al. (2022) | Romania | 189 | GDD/ID +/− comorbidities | 19% | [46] |
Chen et al. (2021) | Taiwan | 61 | Unexplained moderate–severe ID/DD | 20% | [47] |
Ogûz et al. (2021) | Turkey | 302 | GDD/ID +/− abnormal head size, behavior, epilepsy activity | 11% | [48] |
Yang et al. (2021) | Korea | 308 | Unexplained ID/DD +/− MCA | 19% | [49] |
Arican et al. (2019) | Turkey | 210 | Unexplained ID/DD | 12% | [50] |
Hu et al. (2019) | China | 332 | Isolated ID/DD | 18% | [51] |
Ceylan et al. (2018) | Turkey | 124 | GDD/ID | 17% | [52] |
Pinheiro et al. (2020) | Spain | 215 | Unexplained GDD/ID | 23% | [53] |
Study | Country | N | Previous Investigation | Cohort Phenotype | No. Genes | DY | Ref. |
---|---|---|---|---|---|---|---|
Leite et al. (2022) | Brazil | 19 | CMA, K | GDD/ID +/− MCA | 1252 | 63% | [36] |
Ibarluzea et al. (2020) | Spain | 47 | K, Fragile X | Male with unexplained GDD/ID | 82 * | 26% | [57] |
Pekeles et al. (2019) | Turkey | 48 | CMA, K | GDD/ID | 143−2308 ** | 21% | [58] |
Yan et al. (2019) | China | 112 | Nil | Unexplained ID/DD | 454 | 8% | [59] |
Gieldon et al. (2018) | Germany | 106 | CMA, K | Unexplained ID/DD +/− MCA | 66 | 34% | [60] |
Han et al. (2018) | Korea | 35 | CMA | Unexplained ID/DD | 4813 | 29% | [9] |
Study | Country | N | Previous Investigation | Cohort Phenotype | DY | Ref |
---|---|---|---|---|---|---|
Studies with singleton approach | ||||||
Al-Kasbi et al. (2022) | Oman | 188 | K, CMA, TGP | GDD/ID | 27% | [67] |
Levchenko et al. (2022) | Russia | 133 | K or CMA | Non-specific GDD/ID | 27% | [8] |
Chen et al. (2021) | Taiwan | 49 | CMA | Unexplained moderate–severe ID | 51% | [47] |
Nouri et al. (2021) | Iran | 61 | K | Unexplained ID/DD | 66% | [68] |
Valentino et al. (2021) | Italy | 84 | CMA | ID, without ASD | 39% | [69] |
Hu et al. (2019) | Iran | 404 | NA | Unexplained ID in consanguineous family | 54% | [70] |
Xiao et al. (2018) | China | 33 | CMA | Unexplained ID/DD | 57% | [71] |
Studies with trio or familial approach | ||||||
Guo et al. (2021) | China | 21 | NA | ID | 42% | [72] |
Hiraide et al. (2021) | Japan | 101 | NA | Unexplained ID/DD | 54% | [73] |
McSherry et al. (2021) | Turkey | 21 | NA | Clinical suspicion of non-syndromic ARID | 48% | [74] |
Taskiran et al. (2021) | Turkey | 59 | CMA | ID, born to consanguineous parents | 49% | [75] |
Xiang et al. (2021) | China | 17 | NA | Unexplained ID | 59% | [76] |
Harripaul et al. (2018) | Pakistan and Iran | 192 | CMA | Unexplained ID in consanguineous family | 46% | [77] |
Snoeijen-Schouwenaars et al. (2018) | Netherland | 100 | Single-gene testing | Unexplained Epilepsy and ID | 25% | [78] |
Zhao et al. (2018) | Sweden | 28 | NA | ID/DD with dysmorphic features/congenital anomalies | 21% | [79] |
Study | Country | N | Previous Investigation | Cohort Phenotype | DY | Ref. |
Abe-Hatano et al. (2022) | Japan | 45 | NA | ID | 24% | [88] |
Zahir et al. (2021) | Canada | 8 | CMA | Moderate–severe ID with brain malformation | 63% | [89] |
Sun et al. (2017) | China | 100 | CMA, ES | GDD/ID | 21% | [7] |
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Ko, M.H.-J.; Chen, H.-J. Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review. Children 2023, 10, 501. https://doi.org/10.3390/children10030501
Ko MH-J, Chen H-J. Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review. Children. 2023; 10(3):501. https://doi.org/10.3390/children10030501
Chicago/Turabian StyleKo, Mary Hsin-Ju, and Hui-Ju Chen. 2023. "Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review" Children 10, no. 3: 501. https://doi.org/10.3390/children10030501