Neurodevelopmental delays: a review on integration between- WES, WGS and AI guided accelerated and precise diagnosis
DOI:
https://doi.org/10.18203/2349-3291.ijcp20254195Keywords:
Artificial intelligence, Attention-deficit/hyperactivity disorder, Autism spectrum disorder, Intellectual disability, Neurodevelopmental delays, Whole exome sequencing, Whole genome sequencingAbstract
Neurodevelopmental delays (NDDs) are a significant public health concern, and their early, accurate diagnosis is crucial for an effective intervention. This comprehensive literature review examines the transformative impact of integrating whole exome sequencing (WES), whole genome sequencing (WGS), and artificial intelligence (AI) into the diagnostic pathway for NDDs. A systematic search was conducted across scholarly databases to synthesize the latest research on the clinical utility, diagnostic yield, and implementation challenges of these technologies. The review confirms that WES and WGS have become indispensable first-tier diagnostic tools, providing a significantly higher diagnostic yield (30-50%) compared to traditional methods by identifying underlying genetic etiologies, including de novo mutations and structural variants. Moreover, the analysis highlights AI's pivotal role in accelerating and enhancing this process, from automating complex genomic data interpretation to enabling earlier clinical diagnosis through the analysis of behavioral, physiological, and electronic health record data. Despite challenges such as cost, inconsistent insurance coverage, and the need for standardized data-sharing, the synergy between genomics and AI is creating a paradigm shift toward a more precise, equitable, and patient-centered model of care. This integration holds immense promise for shortening the diagnostic journey for affected children and profoundly improving their long-term developmental trajectories.
Metrics
References
Villagomez AN, Muñoz FM, Peterson RL, Colbert AM, Gladstone M, MacDonald B, et al. Neurodevelopmental delay: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2019;37(52):7623-41. DOI: https://doi.org/10.1016/j.vaccine.2019.05.027
Kim SW, Jeon HR, Jung HJ. Clinical Characteristics of Developmentally Delayed Children based on Interdisciplinary Evaluation. Sci Rep. 2020;10(1):8148. DOI: https://doi.org/10.1038/s41598-020-64875-8
National Center for Health Statistics. NCHS Data Brief, Number 473, 2023. Available at: https://www.cdc.gov/nchs/data/databriefs. Accessed on 22 December 2025.
Mithyantha R, Kneen R, McCann E, Gladstone M. Current evidence-based recommendations on investigating children with global developmental delay. Arch Dis Child. 2017;102(11):1071-6. DOI: https://doi.org/10.1136/archdischild-2016-311271
Aldharman SS, Al-Jabr KH, Alharbi YS, Alnajar NK, Alkhanani JJ, Alghamdi A, et al. Implications of Early Diagnosis and Intervention in the Management of Neurodevelopmental Delay (NDD) in Children: A Systematic Review and Meta-Analysis. Cureus. 2023;15(5):e38745. DOI: https://doi.org/10.7759/cureus.38745
Tetreault M, Bareke E, Nadaf J, Alirezaie N, Majewski J. Whole-exome sequencing as a diagnostic tool: current challenges and future opportunities. Expert Rev Mol Diagn. 2015;15(6):749-60. DOI: https://doi.org/10.1586/14737159.2015.1039516
Srivastava S, Cohen JS, Vernon H, Barañano K, McClellan R, Jamal L, et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol. 2014;76(4):473-83. DOI: https://doi.org/10.1002/ana.24251
Soden SE, Saunders CJ, Willig LK. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014;6(265):265ra168. DOI: https://doi.org/10.1126/scitranslmed.3010076
Sánchez Suárez A, Martínez Menéndez B, Escolar Escamilla E, et al. Whole Exome Sequencing and Panel-Based Analysis in 176 Spanish Children with Neurodevelopmental Disorders: Focus on Autism Spectrum Disorder and/or Intellectual Disability/Global Developmental Delay. Genes (Basel). 2024;15(10):1310. DOI: https://doi.org/10.3390/genes15101310
Lin X, Yang Y, Melton PE. Integrating Genetic Structural Variations and Whole-Genome Sequencing Into Clinical Neurology. Neurol Genet. 2022;8(4):e200005. DOI: https://doi.org/10.1212/NXG.0000000000200005
Sanden BPGH, Schobers G, Corominas Galbany J. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet. 2023;31(1):81-8. DOI: https://doi.org/10.1038/s41431-022-01185-9
Uddin M, Wang Y, Woodbury-Smith M. Artificial intelligence for precision medicine in neurodevelopmental disorders. NPJ Digit Med. 2019;2(1):112.
Bertier G, Hétu M, Joly Y. Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users' views. BMC Med Genomics. 2016;9(1):52. DOI: https://doi.org/10.1186/s12920-016-0213-6
Messner DA, Koay P, Al Naber J. Barriers to clinical adoption of next-generation sequencing: a policy Delphi panel's solutions. Per Med. 2017;14(4):339-54. DOI: https://doi.org/10.2217/pme-2016-0104
Vetri L, Calì F, Saccone S, Vinci M, Chiavetta NV, Carotenuto M, et al. Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies. Int J Mol Sci. 2024;25(2):1146. DOI: https://doi.org/10.3390/ijms25021146
Arteche-López A, Gómez Rodríguez MJ, Sánchez Calvin MT, Vinci M, Chiavetta NV, Carotenuto M, et al. Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test. Genes (Basel). 2021;12(4):560. DOI: https://doi.org/10.3390/genes12040560
Lei T, Zhen L, Yang X. Prenatal Diagnosis of PPP2R1A-Related Neurodevelopmental Disorders Using Whole Exome Sequencing: Clinical Report and Review of Literature. Genes (Basel). 2023;14(1):126. DOI: https://doi.org/10.3390/genes14010126
Wu R, Li X, Meng Z, Meng Z, Li P, He Z, et al. Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing. Orphanet J Rare Dis. 2024;19(1):205. DOI: https://doi.org/10.1186/s13023-024-03214-w
Srivastava S, Love-Nichols JA, Dies KA, Dies KA, Ledbetter DH, Martin CL, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019;21(11):2413-21. DOI: https://doi.org/10.1038/s41436-019-0554-6
Stoyanova M, Yahya D, Hachmeriyan M, Levkova M. Diagnostic Yield of Next-Generation Sequencing for Rare Pediatric Genetic Disorders: A Single-Center Experience. Med Sci (Basel). 2025;13(2):75. DOI: https://doi.org/10.3390/medsci13020075
Ko MH, Chen HJ. Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities-A Narrative Review. Children (Basel). 2023;10(3):501. DOI: https://doi.org/10.3390/children10030501
Shchubelka K, Turova L, Wolfsberger W, Kalanquin K, Williston K, Kurutsa O, et al. Genetic determinants of global developmental delay and intellectual disability in Ukrainian children. J Neurodev Disord. 2024;16(1):13. DOI: https://doi.org/10.1186/s11689-024-09528-x
Xu J, Su W, Wang Y, Luo Y, Ye F, Xu Y, Chen L, et al. Genetic analysis of 280 children with unexplained developmental delay or intellectual disability using whole exome sequencing. BMC Pediatr. 2024;24(1):766. DOI: https://doi.org/10.1186/s12887-024-05245-5
Alotibi RS, Sannan NS, AlEissa M, Aldriwesh MG, Al Tuwaijri A, Akiel MA, et al. The diagnostic yield of CGH and WES in neurodevelopmental disorders. Front Pediatr. 2023;11:1133789. DOI: https://doi.org/10.3389/fped.2023.1133789
Boyarchuk O, Volianska L, Smashna O, Makukh H. Exome sequencing in 90 children with developmental delay: a single-center experience. Front Genet. 2024;15:1505254. DOI: https://doi.org/10.3389/fgene.2024.1505254
Seo GH, Lee H, Lee J, Han H, Cho YK, Kim M, Choi Y, et al. Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay. Mol Med. 2022;28(1):38.
Rosina E, Pezzani L, Apuril E, Pezzoli L, Marchetti D, et al. Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study. Mol Genet Genomic Med. 2024;12(1):e2316. DOI: https://doi.org/10.1002/mgg3.2316
Stefanski A, Calle-López Y, Leu C, Pérez-Palma E, Pestana-Knight E, et al. Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability: A systematic review and meta-analysis. Epilepsia. 2021;62(1):143-51. DOI: https://doi.org/10.1111/epi.16755
Kim MJ, Yum MS, Seo GH, Lee Y, Jang HN, Ko TS, et al. Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders. J Clin Med. 2020;9(11):3724. DOI: https://doi.org/10.3390/jcm9113724
Lamilla J, Castro-Cuesta TA, Rueda-Gaitán P, Rios Pinto LC, Rodríguez Gutiérrez DA, Sanchez Rubio YN, et al. A Robust and Comprehensive Study of the Molecular and Genetic Basis of Neurodevelopmental Delay in a Sample of 3244 Patients, Evaluated by Exome Analysis in a Latin Population. Diagnostics (Basel). 2025;15(3):376. DOI: https://doi.org/10.3390/diagnostics15030376
Costain G, Cohn RD, Scherer SW, Marshall CR. Genome sequencing as a diagnostic test. CMAJ. 2021;193(42):E1626-E1629.
Bagger FO, Borgwardt L, Jespersen AS, et al. Whole genome sequencing in clinical practice. BMC Med Genomics. 2024;17(1):39. DOI: https://doi.org/10.1186/s12920-024-01795-w
Shin S, Lee J, Kim YG, Ha C, Park JH, Kim JW, et al. Genetic Diagnosis of Children With Neurodevelopmental Disorders Using Whole Genome Sequencing. Pediatr Neurol. 2023;149:44-52. DOI: https://doi.org/10.1016/j.pediatrneurol.2023.09.003
Charouf D, Miller D, Haddad L, White FA, Boustany RM, Obeid M. High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study. Int J Mol Sci. 2024;25(17):9645. DOI: https://doi.org/10.3390/ijms25179645
Sundaramurthi JC, Bagley AM, Blau H, Carmody L, Crandall A, Danis D, et al. De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy. Cold Spring Harb Mol Case Stud. 2024;9(4):a006293. DOI: https://doi.org/10.1101/mcs.a006293
Ćuk M, Lovrenčić L, Unal B, Walker M, Hayes CP, Krakar G, et al. Novel de Novo Nonsense Variants in AGO3 and KHSRP: Insights into Global Developmental Delay and Autism Spectrum Disorders through Whole Genome Analysis. Am J Case Rep. 2024;25:e943641. DOI: https://doi.org/10.12659/AJCR.943641
Deng R, Medico-Salsench E, Nikoncuk A, Ramakrishnan R, Lanko K, Kühn NA, et al. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model. Acta Neuropathol. 2023;146(2):353-68. DOI: https://doi.org/10.1007/s00401-023-02579-9
Yu JH, MacDuffie KE, Sommerland O, Theoryn T, Murali P, Anderson K, et al. Expanding implementation of pediatric whole genome sequencing: insights from SeqFirst providers to inform equitable access to a precise genetic diagnosis. HGG Adv. 2025:100464. DOI: https://doi.org/10.1016/j.xhgg.2025.100464
Grand View Horizon. The United States Whole Genome Sequencing Market Size and Outlook, 2030. Available at: https://www.grandviewresearch.com/horizon/outlook/whole-genome-sequencing-market/us. Accessed on 02 November 2025.
Costain G, Cohn RD, Scherer SW, Marshall CR. Genome sequencing as a diagnostic test. CMAJ. 2021;193(42):E1626-E1629. DOI: https://doi.org/10.1503/cmaj.210549
Griffiths R, Lewis C. Mainstreaming genomics in the National Health Service in England: a survey to understand preparedness and confidence among paediatricians. BMJ Paediatr Open. 2025;9(1):e003286. DOI: https://doi.org/10.1136/bmjpo-2024-003286
Katsuya Y. Current and future trends in whole genome sequencing in cancer. Cancer Biol Med. 2024 Feb 15;21(1):16-20. DOI: https://doi.org/10.20892/j.issn.2095-3941.2023.0420
Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11). DOI: https://doi.org/10.1038/s41436-021-01242-6
Dixon-Salazar TJ, Silhavy JL, Udpa N, Schroth J, Bielas S, Schaffer AE, et al. Exome Sequencing Can Improve Diagnosis and Alter Patient Management. Science Translational Medicine. 2012;4(138):138ra78-8. DOI: https://doi.org/10.1126/scitranslmed.3003544
Go Hun Seo, Lee H, Lee J, Han H, You Kyung Cho, Kim M, et al. Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay. Molecular Medicine. 2022;28(1). DOI: https://doi.org/10.1186/s10020-022-00464-x
Megerian JT, Dey S, Melmed RD, Coury DL, Lerner M, Nicholls CJ, et al. Evaluation of an artificial intelligence-based medical device for diagnosis of autism spectrum disorder. NPJ Digital Med. 2022;5(1):1-11. DOI: https://doi.org/10.1038/s41746-022-00598-6
Perochon S, Di Martino JM, Carpenter KLH, Compton S, Davis N, et al. Early detection of autism using digital behavioral phenotyping. Nature Med. 2023;29(10):2489-97. DOI: https://doi.org/10.1038/s41591-023-02574-3
Uddin M, Wang Y, Woodbury-Smith M. Artificial intelligence for precision medicine in neurodevelopmental disorders. NPJ Dig Med. 2019;2(1). DOI: https://doi.org/10.1038/s41746-019-0191-0
Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RKC, et al. The human splicing code reveals new insights into the genetic determinants of disease. Sci. 2014. DOI: https://doi.org/10.1126/science.1254806
Zhou J, Troyanskaya OG. Predicting effects of noncoding variants with deep learning-based sequence model. Nature Methods. 201;12(10):931-4. DOI: https://doi.org/10.1038/nmeth.3547
Jeste SS, Frohlich J, Loo SK. Electrophysiological biomarkers of diagnosis and outcome in neurodevelopmental disorders. Current Opinion in Neurology. 2015;28(2):110-6. DOI: https://doi.org/10.1097/WCO.0000000000000181
Bosl W, Tierney A, Tager-Flusberg H, Nelson C. EEG complexity as a biomarker for autism spectrum disorder risk. BMC Medicine. 2011;9(1). DOI: https://doi.org/10.1186/1741-7015-9-18
Goodspeed K, Armstrong D, Dolce A, Evans P, Said R, Tsai P, et al. Electroencephalographic (EEG) Biomarkers in Genetic Neurodevelopmental Disorders. J Child Neurology. 2023;38(6-7):466-77. DOI: https://doi.org/10.1177/08830738231177386
Chen H, Song Y, Li X. Use of deep learning to detect personalized spatial-frequency abnormalities in EEGs of children with ADHD. J Neural Eng. 2019;16(6):066046. DOI: https://doi.org/10.1088/1741-2552/ab3a0a
Tenev A, Markovska-Simoska S, Kocarev L, Pop-Jordanov J, Müller A, Candrian G. Machine learning approach for classification of ADHD adults. Int J Psycho. 2014;93(1):162-6. DOI: https://doi.org/10.1016/j.ijpsycho.2013.01.008
Movaghar A, Page D, Scholze D, Hong J, DaWalt LS, Kuusisto F, et al. Artificial intelligence–assisted phenotype discovery of fragile X syndrome in a population-based sample. Genet Med. 2021;23(7):1273-80. DOI: https://doi.org/10.1038/s41436-021-01144-7
Koivu A, Korpimäki T, Kivelä P, Pahikkala T, Sairanen M. Evaluation of machine learning algorithms for improved risk assessment for Down’s syndrome. Comp Biol Med. 2018;98:1-7. DOI: https://doi.org/10.1016/j.compbiomed.2018.05.004
Abbas H, Garberson F, Liu-Mayo S, Glover E, Wall DP. Multi-modular AI Approach to Streamline Autism Diagnosis in Young Children. Scientific Reports. 2020;10(1):1-8. DOI: https://doi.org/10.1038/s41598-020-61213-w
Moniruzzaman M, Khan R, Nipa RN, Hussain MR, Meraj J. AI-Driven Early Detection of Autism Spectrum Disorder in American Children. Periodic Reviews on Artificial Intelligence in Health Informatics. 2024;1(1):9-9. DOI: https://doi.org/10.63471/Hi24003
Ye DH, Kim TW, Kim SM, Seo JW, Chang J, Lee JG, et al. Can AI-Based Video Analysis Help Evaluate the Performance of the Items in the Bayley Scales of Infant Development? Children. 2025;12(3):276-6. DOI: https://doi.org/10.3390/children12030276
Stahl A, Schellewald C, Stavdahl O, Aamo OM, Adde L, Kirkerod H. An Optical Flow-Based Method to Predict Infantile Cerebral Palsy. IEEE Transactions on Neural Systems and Rehabilitation Engineering. 2012;20(4):605-14. DOI: https://doi.org/10.1109/TNSRE.2012.2195030
Hu C, Thrasher J, Li W, Ruan M, Yu X, Paul LK, et al. Speech pattern disorders in verbally fluent individuals with autism spectrum disorder: a machine learning analysis. Front Neuroinform. 2025;19:1647194. DOI: https://doi.org/10.3389/fninf.2025.1647194
Sohl K, Kilian R, Brewer Curran A, Mahurin M, Nanclares-Nogués V, Liu-Mayo S, et al. Feasibility and Impact of Integrating an Artificial Intelligence–Based Diagnosis Aid for Autism Into the Extension for Community Health Outcomes Autism Primary Care Model: Protocol for a Prospective Observational Study. JMIR Res Prot. 2022;11(7):e37576. DOI: https://doi.org/10.2196/37576
Choudhury A, Saremi ML, Urena E. Perception, Trust, and Accountability Affecting Acceptance of Artificial Intelligence: From Research to Clinician Viewpoint. 2022;105-24. DOI: https://doi.org/10.4018/978-1-6684-5092-5.ch005
Guthrie W, Wallis K, Bennett A, Brooks E, Dudley J, Gerdes M, et al. Accuracy of Autism Screening in a Large Pediatric Network. Pediatrics. 2019;144(4). DOI: https://doi.org/10.1542/peds.2018-3963
Downloads
Published
How to Cite
Issue
Section
