Intellectual Disability and Borderline Intellectual Functioning: An Updated Pediatric Neurology Perspective

Youngkyu Shim; Dong Hwa Yang; Baik-Lin Eun; Jung Hye Byeon

doi:10.26815/acn.2025.01060

Ann Child Neurol > Volume 34(1); 2026 > Article

Shim, Yang, Eun, and Byeon: Intellectual Disability and Borderline Intellectual Functioning: An Updated Pediatric Neurology Perspective

Review article

Annals of Child Neurology 2026;34(1):13-24.

Published online: December 24, 2025

DOI: https://doi.org/10.26815/acn.2025.01060

Intellectual Disability and Borderline Intellectual Functioning: An Updated Pediatric Neurology Perspective

Youngkyu Shim, MD

, Dong Hwa Yang, MD, Baik-Lin Eun, PhD, Jung Hye Byeon, PhD

Department of Pediatrics, Korea University College of Medicine, Seoul, Korea

Corresponding author: Jung Hye Byeon, PhD Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea
Tel: +82-2-920-6263 E-mail: pedbyeon@naver.com

Received September 7, 2025 Revised October 31, 2025 Accepted November 1, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Intellectual disability (ID) affects 1%-3% of the population, while borderline intellectual functioning (BIF) affects 13%-14% of individuals, together representing a substantial burden in pediatric neurology. This review synthesizes current evidence on diagnostic frameworks, genomic advances, and targeted therapeutics relevant to pediatric practice. We reviewed recent literature focusing on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) and International Classification of Diseases, 11th Revision (ICD-11) updates, genomic diagnostic innovations, and emerging therapies identified through PubMed and clinical trial registries (2019-2024). Diagnostic frameworks now emphasize adaptive functioning rather than intelligence quotient (IQ)-based classifications, with severity defined by required support levels rather than cognitive scores. Genomic testing has progressed from chromosomal microarray (10%-20% yield) to trio whole-exome sequencing (30%-45% yield), with professional guidelines endorsing genome-first approaches as first-line testing. Common comorbidities require systematic management, including autism spectrum disorder (15%-20%), attention-deficit/hyperactivity disorder (20%), epilepsy (20%-30% in moderate-to-severe cases), and mental health disorders. Traditional management continues to prioritize early intervention, educational support, and comprehensive medical care, while emerging targeted therapies show clinical benefit, including U.S. Food and Drug Administration-approved trofinetide for Rett syndrome and investigational antisense therapies for Angelman syndrome. Contemporary ID management demands genome-first diagnostic strategies, structured comorbidity assessment, and integration of targeted therapeutics. The BIF population requires formal diagnostic recognition and broader service eligibility. Optimal outcomes depend on collaboration among pediatric neurologists, geneticists, and developmental specialists through precision-medicine-based approaches.

Keywords: Intellectual disability; Borderline intellectual functioning; Genomic testing; Adaptive functioning; Precision medicine

Introduction

Intellectual disability and borderline intellectual functioning encompass a complex spectrum of neurodevelopmental presentations that present major challenges for affected individuals, their families, and healthcare systems worldwide. Intellectual disability affects 1%-3% of the global population, ranking among the most common neurodevelopmental disorders encountered in pediatric practice [1]. Borderline intellectual functioning affects an estimated 12%-16% of individuals but remains largely unrecognized in formal diagnostic systems [2]. This population exhibits cognitive abilities that fall between those of individuals with intellectual disability and those with average intelligence, with prevalence estimates varying by diagnostic criteria and population characteristics. Collectively, these conditions account for a significant proportion of referrals to pediatric neurology services, encompassing children with diverse etiologies, clinical manifestations, and levels of support need.

The conceptualization of intellectual disability has undergone remarkable transformation over the past decade, driven by converging advances in scientific understanding and clinical methodology. Most notably, the theoretical foundation of intellectual disability has shifted from historical models centered on intelligence quotient (IQ) scores toward more nuanced frameworks emphasizing adaptive functioning, individualized support requirements, and quality-of-life outcomes. This paradigm shift is reflected in the revised diagnostic criteria of both the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) and the International Classification of Diseases, 11th Revision (ICD-11), which have moved decisively away from rigid IQ-based classifications toward adaptive-functioning-centered approaches [3,4].

The field has simultaneously experienced a genomic revolution, with next-generation sequencing technologies dramatically increasing diagnostic yields from 10%-20% with chromosomal microarray to 30%-50% with whole-exome or whole-genome sequencing [5,6]. This genome-first paradigm has accelerated gene discovery and enabled precision-medicine approaches for specific genetic subtypes, though its implementation must consider healthcare system resources, infrastructure, and accessibility constraints.

This review synthesizes current evidence across updated diagnostic frameworks, genomic advances, clinical assessment strategies, and emerging therapeutics, while also highlighting the persistent gaps in recognition and service provision for individuals with borderline intellectual functioning.

Methods

This review synthesized contemporary evidence from PubMed and clinical trial registries (ClinicalTrials.gov, EudraCT) spanning 2019-2024, with seminal earlier works included for historical context. Search terms combined ‘intellectual disability,’ ‘borderline intellectual functioning,’ ‘whole-exome sequencing,’ ‘targeted therapy,’ and ‘precision medicine‘ in pediatric populations. We prioritized systematic reviews and meta-analyses, randomized controlled trials, regulatory documents, and clinical practice guidelines issued by professional societies. Expert consensus papers and case series were included where high-quality evidence remained limited, particularly for emerging therapeutics.

Updated Diagnostic Frameworks

1. Intellectual disability: evolution of diagnostic frameworks

The diagnostic approach to intellectual disability has undergone substantial refinement in recent years, with both the DSM-5-TR and ICD-11 reflecting a fundamental shift away from historically IQ-centric models toward comprehensive, adaptive functioning-based frameworks [3,4]. This evolution recognizes that while IQ scores remain valuable, they are insufficient to predict an individual’s functional capacity, support requirements, or potential for independence. Current diagnostic criteria mandate evidence of deficits in general mental abilities and significant limitations in adaptive functioning across conceptual, social, and practical domains. These deficits must originate during early childhood, distinguishing intellectual disability from acquired cognitive impairments.

Severity classification now centers on patterns of adaptive behavior rather than IQ scores [3,4]. Individuals with mild intellectual disability typically require support for complex tasks but can achieve substantial independence. Those with moderate intellectual disability exhibit greater developmental delays and need supervision in daily activities. Severe intellectual disability necessitates extensive support, whereas profound intellectual disability involves minimal communication and continuous care needs.

This emphasis on adaptive functioning has proven superior to IQ-based classifications in predicting support requirements, educational programming needs, and long-term outcomes, thus providing a more functional and person-centered basis for diagnosis and intervention planning [7]. The shift carries major implications for clinical practice, educational placement, and service eligibility, encouraging clinicians to perform comprehensive evaluations that capture the full spectrum of an individual’s strengths and challenges rather than relying primarily on cognitive testing.

2. Borderline intellectual functioning: the forgotten population

Borderline intellectual functioning occupies a particularly problematic position within current diagnostic taxonomies, representing what many experts view as a major gap in classification systems. Historically, the DSM-IV-TR treated borderline intellectual functioning as a distinct clinical condition, defined by an IQ range of 71-84 and recognized as a group with meaningful clinical needs. With the transition to DSM-5, however, borderline intellectual functioning was reclassified as a V-code (‘other condition that may be a focus of clinical attention’) without formal diagnostic criteria, effectively diminishing its status as a clearly delineated diagnostic entity [8]. Similarly, the ICD-11 lacks a standalone diagnostic category for borderline intellectual functioning, instead subsuming it under normal variation unless it produces marked impairment.

This diagnostic gap presents significant challenges across service delivery, research, and clinical recognition. Affected individuals often lack access to appropriate support services, while research progress is hindered by inconsistent diagnostic definitions. Most clinicians operationally define borderline intellectual functioning as cognitive performance one to two standard deviations below the mean (IQ, 70-85) accompanied by adaptive functioning difficulties [2]. This situation creates a clinical paradox: individuals experience substantial challenges yet lack the formal recognition required for support eligibility.

Clinical significance extends well beyond academic performance. Dropout rates exceed 40% compared to less than 10% in average populations. Mental health vulnerabilities include heightened risks of anxiety, depression, and behavioral disorders. Employment outcomes are poor, characterized by higher rates of unemployment and underemployment. Concerningly, individuals with borderline intellectual functioning are more vulnerable to victimization and involvement with the justice system due to difficulties recognizing exploitation and comprehending complex social interactions [2].

The functional impairments experienced by individuals with borderline intellectual functioning often parallel those of mild intellectual disability, yet the arbitrary IQ cutoff of 70 creates major barriers to service eligibility. Despite comparable cognitive and adaptive difficulties, individuals with borderline intellectual functioning frequently fall through the gaps in educational, vocational, and social support systems. The increasing cognitive complexity of modern life, encompassing digital literacy, financial management, and bureaucratic navigation, further magnifies these vulnerabilities, which were less evident in earlier generations.

In pediatric neurology practice, borderline intellectual functioning presents distinct challenges that differ from those associated with intellectual disability. Families often express frustration when comprehensive assessments confirm cognitive difficulties but conclude that the child ‘does not qualify’ for special education services. Consequently, these children are excluded from specialized instruction and related therapies such as speech or occupational therapy, despite clear functional needs.

Within educational systems, conflicting pressures exacerbate the problem. Limited funding frequently drives conservative application of eligibility criteria, restricting access to individualized support even when educators acknowledge that these students require assistance beyond standard classroom differentiation. This systemic tension often delays intervention until academic failure becomes pronounced, missing the crucial early period when timely support could prevent cascading educational and psychosocial difficulties.

Healthcare systems encounter parallel obstacles. Insurance coverage for developmental or rehabilitative therapies typically requires a formal diagnosis, which borderline intellectual functioning lacks. Transition to adult healthcare introduces additional complexity, as adult providers may have limited familiarity with developmental conditions, and documentation of functional support needs is often incomplete. Mental health services also remain inadequate: many clinicians lack training in cognitively adapted therapeutic approaches, while programs for intellectual disability often exclude individuals with borderline intellectual functioning as ‘too high functioning.’

Recent expert consensus supports unifying mild intellectual disability and borderline intellectual functioning categories to extend service eligibility to individuals with IQ scores up to 85, thereby reducing arbitrary exclusions based on cutoffs that fail to reflect meaningful functional differences [9]. However, this proposal faces major implementation challenges, including cost implications for educational and social service systems that are already strained by limited resources.

Bridging the service gap for individuals with borderline intellectual functioning demands both policy reform and practical clinical strategies. A transition from IQ-based to function-based eligibility criteria anchored in adaptive behavior assessments would better align with contemporary understanding of disability. Incorporating borderline intellectual functioning into vocational rehabilitation programs and extending insurance coverage for developmental and mental health services regardless of IQ thresholds would mitigate systemic exclusions.

From a pediatric neurology standpoint, effective advocacy for individuals with borderline intellectual functioning begins with thorough documentation of adaptive behavior deficits to strengthen eligibility for services. Clinicians should promote connections to community and vocational resources and ensure longitudinal follow-up through adolescence, when service discontinuities and increasing functional demands often become most evident.

The pediatric neurologist’s role extends beyond diagnosis to coordinated advocacy across educational and social systems. Collaboration with school psychologists, educators, and social service professionals increases the likelihood of securing appropriate support. Clinical documentation should emphasize functional limitations in daily activities rather than relying solely on psychometric scores, thereby reflecting the practical criteria by which service eligibility is typically determined.

Research priorities include longitudinal outcome studies comparing supported and unsupported individuals with borderline intellectual functioning, intervention trials evaluating educational and therapeutic approaches, and health economic analyses quantifying the long-term benefits of early and sustained intervention. Policy initiatives should prioritize formal diagnostic recognition of borderline intellectual functioning, expanded service eligibility within educational and healthcare frameworks, and workforce development to enhance clinical competency in the assessment and management of this underrecognized population.

Table 1 presents comprehensive diagnostic guidelines for intellectual disability and borderline intellectual functioning, integrating DSM-5-TR and ICD-11 criteria with prevalence data and etiologic associations. This framework underscores adaptive functioning rather than IQ scores and highlights the significant yet underrecognized borderline intellectual functioning population affecting 12% to 16% of individuals [1-4].

Genomic Revolution in Etiologic Diagnosis

1. Genetic heterogeneity and diagnostic evolution

The etiologic landscape of intellectual disability exhibits extensive genetic heterogeneity, with current evidence indicating that more than 1,000 genes can contribute to various forms of the disorder when disrupted [10]. This genetic diversity encompasses single nucleotide variants, copy number variations, chromosomal abnormalities, and complex genomic rearrangements, each producing intellectual disability through distinct pathogenic mechanisms. Such complexity carries major implications for both diagnostic approaches and therapeutic development, suggesting that effective interventions may need to target specific molecular subtypes rather than apply uniformly across all cases of intellectual disability.

Diagnostic strategies have advanced markedly over the past two decades. Whereas traditional karyotyping identified abnormalities in approximately 3% of cases, chromosomal microarray analysis increased yields to 10%-20% by detecting submicroscopic deletions and duplications. The introduction of next-generation sequencing further expanded diagnostic capacity. Whole-exome sequencing achieves yields of 25%-40%, roughly doubling the detection rate compared with microarray analysis, while whole-genome sequencing offers yields of 30%-50%, though interpretation of non-coding variants continues to pose challenges. Trio sequencing enhances detection of de novo variants, which are responsible for 20%-30% of severe cases, while simultaneously providing immediate recurrence-risk data. Moreover, trio-based approaches improve variant interpretation accuracy and streamline clinical decision-making by reducing the diagnostic odyssey [5,6].

This superior performance prompted the American College of Medical Genetics and Genomics in 2021 to recommend whole-exome or whole-genome sequencing as first-line testing for unexplained intellectual disability when feasible and cost-effective [9]. Systematic reviews support its superior yield and emerging cost-effectiveness relative to stepwise testing algorithms, though tiered approaches may remain necessary in resource-limited healthcare settings [11].

2. Clinical impact of genomic diagnosis

Genetic diagnosis enables syndrome-specific medical management, access to targeted therapeutics and clinical trials, precise genetic counseling with accurate Mendelian recurrence-risk assessment, and engagement with condition-specific support networks. A confirmed molecular diagnosis facilitates participation in natural history studies and emerging treatment opportunities. Although trio sequencing costs approximately $3,000-$5,000, it demonstrates cost-effectiveness when the diagnostic yield exceeds 25%, as it reduces healthcare utilization and enables appropriate condition-specific management [11].

3. Practical implementation of genome-first diagnosis

The implementation of genome-first approaches requires careful consideration of clinical presentation, available resources, and family preferences. Trio whole-exome or whole-genome sequencing offers the highest diagnostic yield when feasible. Nonetheless, practical factors such as cost, institutional infrastructure, and local expertise may influence the selection of testing modality. Where genomic sequencing is unavailable, chromosomal microarray analysis remains an appropriate first-line diagnostic tool.

Testing for fragile X syndrome continues to hold a central place in the diagnostic algorithm, particularly for males presenting with intellectual disability, autism spectrum features, or a family history suggestive of X-linked inheritance. The fragile X messenger ribonucleoprotein 1 (FMR1) CGG trinucleotide repeat expansion responsible for fragile X syndrome cannot be detected by standard genomic sequencing, necessitating dedicated targeted testing. Some institutions employ reflex protocols that automatically proceed to FMR1 analysis if genomic sequencing is negative in males with compatible clinical features [9].

Beyond first-line genetic testing, indication-based investigations remain essential for comprehensive evaluation. Brain magnetic resonance imaging provides valuable diagnostic information in the presence of focal neurological signs, significant microcephaly or macrocephaly, refractory epilepsy, or developmental regression. The diagnostic yield of neuroimaging varies considerably depending on patient selection, with substantially higher yields observed in clinically indicated evaluations compared to routine screening [12].

Metabolic studies also remain important in cases suggesting inborn errors of metabolism. Episodic decompensation triggered by illness or fasting, multisystem organ involvement, or consanguinity should prompt targeted metabolic testing, including plasma amino acid analysis, urine organic acid profiling, and acylcarnitine evaluation. However, broad metabolic screening in unselected populations consistently shows low diagnostic yield, underscoring the importance of phenotype-guided testing strategies [13].

Targeted gene panels continue to play a role in cases where the clinical presentation strongly indicates a particular diagnostic category [9]. For example, epilepsy panels are appropriate for children presenting primarily with seizures and developmental delay, while movement disorder panels may be indicated for patients with prominent extrapyramidal features. Nevertheless, the superior sensitivity and cost-effectiveness of genomic sequencing have led many centers to adopt comprehensive sequencing approaches as their preferred strategy [9].

Table 2 provides practical guidance on genomic testing modalities available to pediatric practitioners. This summary outlines the transition from traditional chromosomal analysis to next-generation sequencing, highlighting diagnostic yields, implementation considerations, and clinical utility scores derived from published meta-analyses in pediatric intellectual disability populations [5,6,13,14].

Clinical Assessment and Comorbidity Management

1. Clinical assessment principles

Comprehensive evaluation requires systematic assessment across developmental, medical, and psychosocial domains [9]. Key components include a detailed developmental history with a three-generation pedigree, physical examination with growth measurements and dysmorphology assessment, and neurological evaluation for focal deficits or syndromic indicators.

Cognitive assessment using age-appropriate standardized instruments must account for developmental level, language proficiency, and cultural background [14]. Adaptive functioning assessment is equally crucial and often provides stronger predictive value for long-term outcomes than cognitive scores alone [7]. Standardized measures such as the Vineland Adaptive Behavior Scales evaluate conceptual, social, and practical domains across multiple settings [14].

Essential screening includes hearing and vision testing, educational evaluation of academic achievement, and consideration of cultural and linguistic factors to ensure accurate interpretation and equitable service recommendations [14].

2. Comorbidity recognition and integrated management

The relationship between intellectual disability and other neurodevelopmental conditions is both complex and bidirectional [1]. Shared genetic mechanisms, environmental exposures, and overlapping phenotypes complicate diagnosis and management, necessitating integrated and multidisciplinary care planning.

1) Autism spectrum disorder

Autism spectrum disorder represents one of the most common comorbidities, occurring in approximately 15%-20% of individuals with intellectual disability. Conversely, 30%-50% of individuals with autism spectrum disorder have coexisting intellectual disability [1]. This substantial overlap reflects shared genetic etiologies, with numerous genes implicated in both conditions [10]. Assessment of autism spectrum features in individuals with intellectual disability requires tailored approaches. Traditional diagnostic tools may be inadequate for minimally verbal individuals, necessitating modified evaluation protocols that rely on behavioral observation and caregiver reporting, such as Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) module 1, to ensure accurate diagnosis [15].

2) Attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder occurs at markedly elevated rates among individuals with intellectual disability, with prevalence estimates around 20%, compared to 5%-7% in the general population [1]. This increased prevalence likely reflects overlapping neurobiological vulnerabilities and diagnostic complexity. Research demonstrates that individuals with intellectual disability respond to standard pharmacologic treatments, with methylphenidate showing efficacy comparable to that seen in typically developing populations [16]. Behavioral interventions, such as parent training, classroom accommodations, and social skills instruction, provide additional benefit and should be considered first-line interventions either alongside or instead of medication.

3) Epilepsy

Epilepsy affects 20%-30% of individuals with moderate-to-severe intellectual disability, representing a much higher prevalence than the approximately 1% observed in the general population [1]. The relationship between seizures and intellectual disability is multifaceted. Some genetic syndromes predispose to both epilepsy and cognitive impairment, while poorly controlled seizures can exacerbate developmental regression. Specific conditions such as tuberous sclerosis complex, Dravet syndrome, and Lennox-Gastaut syndrome are associated with particularly high rates of both intellectual disability and treatment-resistant epilepsy. Aggressive seizure management is critical for ensuring safety and may also improve cognitive performance, attention, and behavioral outcomes [17].

4) Mental health considerations

Mental health disorders occur at significantly higher rates across the intellectual disability spectrum. Approximately 40% of children with intellectual disability meet criteria for a diagnosable mental disorder—roughly twice the rate observed among children without intellectual disability. The most common comorbid conditions include attention-deficit/hyperactivity disorder (39%), anxiety disorders (7%-34%), and depression (3%-5%). Psychiatric presentations are frequently atypical, necessitating adapted diagnostic methods and treatment frameworks [18]. Individuals with borderline intellectual functioning are particularly vulnerable due to heightened cognitive awareness of their limitations [2]. They often experience frustration, social rejection, and academic failure, all of which contribute to increased mental health risk. Adapted interventions—such as simplified cognitive-behavioral therapy, social skills training, and family-based therapeutic models—have shown efficacy in improving psychological outcomes within this population [18].

Treatment and Management Approaches

1. Traditional management strategies

1) Early intervention: the critical window

High-quality evidence supports the effectiveness of early intervention services initiated before 3 years of age, with the greatest benefit achieved when services are comprehensive and family-centered. Core components include physical therapy for gross motor development, occupational therapy for fine motor and adaptive skills, speech-language therapy for communication, and developmental therapy targeting cognitive and social growth. Comprehensive family education, including parent training, support networks, and advocacy skill development, is an essential element. Condition-specific interventions must be tailored to individual needs. For metabolic disorders, dietary modification and enzyme replacement therapy are central. Seizure management requires individualized antiepileptic therapy and seizure action planning. Sensory impairments are addressed through hearing aids, vision correction, and environmental accommodations to optimize engagement and learning [19].

2) Educational support and transition planning

The special education framework encompasses development of individualized education programs, informed placement decisions, coordination of related services, and structured transition planning beginning by age 16 years [20]. Evidence-based teaching methods emphasize multisensory learning, task analysis, positive behavioral supports, and functional curricula focused on life skills [19]. Educational planning for individuals with borderline intellectual functioning presents unique challenges. Many such students do not meet eligibility criteria for special education despite substantial learning difficulties. These individuals benefit from Section 504 accommodations, such as extended time, reduced workload, and modified assignments [2]. Without appropriate academic and vocational support, they are at increased risk of dropout and underemployment, underscoring the need for proactive transition planning and vocational pathway development.

3) Medical management and preventive care

Systematic comorbidity management requires comprehensive, individualized approaches. attention-deficit/hyperactivity disorder is treated with standard pharmacotherapy, supplemented by close monitoring for efficacy and side effects [16]. Seizure management includes appropriate antiepileptic medications and lifestyle modifications [17]. Sleep disturbances are addressed through sleep hygiene education and melatonin supplementation when indicated [21]. Behavioral difficulties are best managed with structured behavioral interventions as first-line therapy, with cautious pharmacologic augmentation as needed [18]. Preventive care follows standard pediatric protocols, including routine immunizations and comprehensive health maintenance. After genetic diagnosis, syndrome-specific surveillance should address potential cardiac, renal, and ophthalmologic complications in accordance with American Academy of Pediatrics guidelines [22]. Systematic mental health screening is also essential to enable early identification and intervention for psychiatric comorbidities [18].

4) Innovations in service delivery

Emerging digital technologies are expanding care delivery options for individuals with intellectual disability. Telehealth platforms now enable remote access to specialized clinical services, particularly valuable for families in geographically underserved regions [23]. Artificial intelligence-based diagnostic tools assist in phenotypic assessment and syndrome recognition, with facial recognition algorithms achieving greater than 90% accuracy for certain genetic syndromes [24]. Digital therapeutics platforms provide adaptive cognitive training and behavioral interventions specifically tailored to intellectual disability populations [25]. Remote monitoring systems can track seizure activity, sleep patterns, and behavioral changes, supporting proactive and data-driven care management [26]. Collectively, these innovations address workforce shortages and geographic disparities while maintaining continuity and quality of care [23].

2. Emerging targeted therapeutics

While traditional management approaches remain essential, recent breakthroughs have introduced targeted therapeutics aimed at the molecular mechanisms underlying specific genetic causes of intellectual disability. This development marks a paradigm shift from purely supportive care to mechanism-based interventions that directly address disease pathophysiology.

1) U.S. Food and Drug Administration-approved targeted therapies

Trofinetide (DAYBUE, Acadia Pharmaceuticals Inc., San Diego, CA, USA) represents the first targeted therapy approved for syndromic intellectual disability in children, indicated for Rett syndrome in girls aged ≥2 years. This insulin-like growth factor 1 analog targets synaptic dysfunction and demonstrated significant behavioral improvement in the phase3 trial (n=187), where 75% of participants receiving trofinetide achieved clinically meaningful improvement compared with 47% on placebo, based on the Rett syndrome behavioral questionnaire [27]. Although the primary approval indication focuses on behavioral symptoms rather than direct cognitive endpoints, the underlying mechanism suggests potential cognitive benefit through synaptic enhancement.

Eladocagene exuparvovec (Upstaza, PTC Therapeutics, Warren, NJ, USA) became the first approved gene therapy for metabolic intellectual disability, targeting aromatic L-amino acid decarboxylase (AADC) deficiency via AAV2-mediated dopa decarboxylase (DDC) gene delivery. Clinical trials demonstrated remarkable motor milestone gains, with 91% of treated patients achieving head control versus 7% in natural history cohorts [28]. The primary approval indication addresses motor function, though secondary cognitive improvements are frequently observed in parallel with motor recovery.

2) Investigational therapies with high promise

Antisense oligonucleotide therapy for Angelman syndrome (rugonersen) has demonstrated biomarker engagement through restoration of ubiquitin-protein ligase E3A (UBE3A) protein expression and electroencephalography (EEG) normalization in phase 1/2 studies [29]. This strategy targets the fundamental genetic defect by reducing antisense RNA that silences the paternal UBE3A allele.

Precision pharmacology approaches in glutamate ionotropic receptor NMDA type subunit (GRIN)-related disorders employ patient-specific functional assays to guide N-methyl-D-aspartic acid (NMDA) receptor modulation. Case reports and small series have shown dramatic improvements in appropriately selected patients harboring specific gain- or loss-of-function variants [30].

Ercanetide (NNZ-2591), a cyclic glycine-proline analog that modulates neuroplasticity pathways and enhances memory performance in preclinical studies [31], is under active investigation for Phelan-McDermid syndrome. Preliminary clinical data indicate improvements across multiple developmental domains, supporting its potential as a mechanism-targeted therapy.

3) Therapeutic development challenges

Significant translational failures highlight the complexity of developing therapies for intellectual disability. For example, several phase 3 trials of metabotropic glutamate receptor 5 (mGluR5) antagonists in fragile X syndrome failed to reproduce promising preclinical results [32], reflecting both biological heterogeneity and methodological limitations. In individuals with severe intellectual disability, assessment difficulties compound these challenges, as behavioral measures often serve as imperfect surrogates for cognitive improvement.

Clinical trials in this population face unique methodological constraints. Standard cognitive assessments are often inappropriate, necessitating reliance on caregiver-reported outcomes that are susceptible to placebo and observer bias. Validated instruments remain scarce, with persistent problems such as floor effects, etiologic diversity, and uncertain minimal clinically important differences. Recruitment is also difficult due to small, geographically dispersed patient cohorts, complex consent and assent processes, and limited natural history data, all of which hinder accurate power calculations and interpretation of treatment effects.

4) Assessment and biomarker development

Therapeutic development for intellectual disability populations requires innovative outcome measures [33]. Traditional cognitive testing is unsuitable for severe cases, prompting the use of behavioral endpoints as proxies for cognitive change. This limitation explains why regulatory approvals often rely on caregiver-reported outcomes rather than direct cognitive metrics. Emerging biomarkers offer objective tools to quantify target engagement and treatment response [34]. Quantitative EEG provides measurable indicators of neural function, showing particular promise in Angelman syndrome, where antisense therapy normalizes characteristic EEG patterns [29]. Digital phenotyping using smartphone sensors and wearable devices enables real-world monitoring of behavioral and functional changes [35]. Cerebrospinal fluid biomarker studies further support antisense therapy development by demonstrating molecular target restoration [29]. Together, these advances enable more precise trial design, improve endpoint reliability, and accelerate translation from preclinical discovery to clinical application.

Table 3 provides a comprehensive overview of emerging targeted therapies for syndromic intellectual disability. It distinguishes approved indications from potential cognitive benefits and summarizes mechanisms of action, regulatory status, and current evidence to guide pediatric neurologists in integrating novel therapeutics into practice [7-9,31,32].

Prognosis and Long-Term Outcomes

Individuals with mild intellectual disability typically achieve basic academic proficiency equivalent to elementary-level skills, semi-independent living with structured support, and meaningful employment through job coaching programs [7]. Those with borderline intellectual functioning exhibit variable outcomes depending on the quality of support received, facing dropout rates as high as 40% without intervention and elevated risks of social and occupational difficulties during adolescence [2]. Positive prognostic factors include early diagnosis, strong family involvement, and high-quality educational environments, while late identification and inadequate service access are key risk factors for poor outcomes [36].

Optimizing adult outcomes requires comprehensive transition planning encompassing vocational training, independent living skills development, healthcare continuity, and legal and financial guidance. Long-term needs include medical and psychiatric follow-up, social inclusion initiatives, and sustained family and community support [36].

Fig. 1 provides a schematic overview of the comprehensive clinical workflow, integrating initial assessment, genomic diagnostic pathways, emerging therapeutic strategies, and structured transition planning across the lifespan.

Future Directions

The therapeutic landscape continues to expand, driven by next-generation gene therapies, clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing, and enhanced antisense oligonucleotide platforms [37]. Integration of precision medicine with digital therapeutics offers further promise for personalized intervention [25]. Policy priorities include extending formal service eligibility to individuals with IQ scores up to 85 to ensure recognition and support for borderline intellectual functioning [9].

Conclusions

The field of intellectual disability has been fundamentally transformed by advances in diagnostic frameworks, genomic technologies, and targeted therapeutics, reshaping contemporary pediatric neurology practice. Modern approaches emphasize adaptive functioning over IQ-based classification, promote genome-first diagnostic strategies yielding 30%-45% success through trio sequencing, and highlight emerging precision-medicine therapies that address the molecular mechanisms of disease.

Key clinical priorities include systematic genomic evaluation as first-line testing, comprehensive management of common comorbidities—such as autism spectrum disorder (15%-20%), attention-deficit/hyperactivity (20%), and epilepsy (20%-30% in moderate-to-severe cases)—and access to targeted therapies such as trofinetide for Rett syndrome and investigational antisense agents for Angelman syndrome.

Borderline intellectual functioning remains a critical yet underrecognized domain, affecting 13%-14% of individuals who often lack diagnostic acknowledgment and service access. Addressing this gap requires formal recognition and expanded eligibility frameworks within healthcare and educational systems.

Optimal outcomes across the cognitive spectrum depend on sustained collaboration among pediatric neurologists, geneticists, developmental specialists, educators, families, and policymakers. Together, these efforts can deliver comprehensive, evidence-based care that addresses both current needs and emerging therapeutic opportunities.

Conflicts of interest

Baik-Lin Eun is an editorial board member of the journal, but he was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Author contribution

Conceptualization: YS, DHY, BLE, and JHB. Data curation: YS. Formal analysis: YS. Funding acquisition: BLE. Methodology: JHB. Project administration: JHB. Visualization: BLE, JHB. Writing - original draft: YS. Writing - review & editing: JHB.

Acknowledgments

This study was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2023-00266781).

The authors thank the multidisciplinary clinical teams and families who have contributed to advancing knowledge and care in intellectual disability and borderline intellectual functioning.

Fig. 1.

Integrated diagnostic and management roadmap for intellectual disability and borderline intellectual functioning. Five-phase framework for intellectual disability (ID)/borderline intellectual functioning (BIF) evaluation and management. Phase 1 (blue): Clinical presentation and standardized assessment. Phase 2 (green): Genomic diagnosis using trio whole-exome or whole-genome sequencing as first-line testing (diagnostic yield 30-45%), supplemented by indication-based studies such as fragile X messenger ribonucleoprotein 1 (FMR1; fragile X) analysis, brain magnetic resonance imaging (MRI), metabolic screening, and targeted gene panels. Phase 3 (orange): Comorbidity assessment and integrated management, including early intervention, educational and medical support, and family counseling. Phase 4 (red): Precision medicine incorporating U.S. Food and Drug Administration (FDA)-approved targeted therapies (trofinetide for Rett syndrome; eladocagene exuparvovec for aromatic L-amino acid decarboxylase [AADC] deficiency) and investigational interventions. Phase 5 (purple): Long-term outcomes and transition planning. IQ, intelligence quotient; ACMG, American College of Medical Genetics and Genomics; CMA, chromosomal microarray analysis; WES, whole-exome sequencing; Hx, history; ASD, autism spectrum disorder; Prev, prevalence; ADOS-2, Autism Diagnostic Observation Schedule, Second Edition; Rx, prescription; ADHD, attention-deficit/hyperactivity disorder; CBT, cognitive-behavioral therapy; ASM, antiseizure medication; SSRI, selective serotonin reuptake inhibitor; IGF-1, insulin-like growth factor 1; AAV2, adeno-associated virus serotype 2; GRIN, glutamate ionotropic receptor NMDA type subunit; CRISPR, clustered regularly interspaced short palindromic repeats; BIF, borderline intellectual functioning.

Table 1.

Diagnostic guidelines for intellectual disability and borderline intellectual functioning

Category	IQ range^a	Prevalence (%)	Adaptive functioning	Common etiologies	Diagnostic yield of genetic causes (%)	Support needs
Borderline intellectual functioning	70-85	12-16	Mild limitations in conceptual, social, or practical domains	Multifactorial; environmental factors; mild genetic variants	10-20	Variable; often unrecognized
Mild ID	50-69	0.8-1.0	Support needed for complex tasks (finances, healthcare decisions)	Polygenic (~50%); environmental (~30%); monogenic (~20%)	25-35	Intermittent support
Moderate ID	35-49	0.3-0.4	Marked delays; requires daily support for independent living	Chromosomal (15%-20%); monogenic (30%-40%); CNVs (10%-15%)	40-50	Limited to extensive
Severe ID	20-34	0.12-0.15	Extensive support for all daily activities; limited communication	De novo variants (40%-50%); chromosomal (10%-15%); metabolic (5%-10%)	50-60	Extensive support
Profound ID	<20	0.05-0.08	Complete dependence; minimal communication; 24-hour care	De novo variants (50%-60%); perinatal injury (20%-30%); metabolic (10%)	60-70	Pervasive support

IQ, intelligence quotient; ID, intellectual disability; CNV, copy number variant.

^aIQ ranges provided for reference but adaptive functioning determines diagnosis per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR)/International Classification of Diseases, 11th Revision (ICD-11).

Table 2.

Genomic testing yields and considerations for clinical implementation

Testing method	Diagnostic yield (%)	Turnaround time	Primary indications	Advantages	Limitations
Karyotype	2-3	1-2 weeks	Suspected chromosomal abnormality	Rapid, inexpensive	Large abnormalities only
Chromosomal microarray	10-20	2-3 weeks	ID/DD, multiple congenital anomalies	CNVs, established interpretation	Misses SNVs, small indels
Fragile X (FMR1)	2-6 (males with ID)	1-2 weeks	Males with ID, family history	High yield in appropriate cases	Single gene, repeat expansion
Targeted gene panels	15-30	3-6 weeks	Specific phenotypic features	Focused, faster reporting	Limited gene coverage
Whole-exome sequencing (WES)	25-40	6-12 weeks	Unexplained ID/DD first-line	Comprehensive, cost-effective	Coding regions only
Trio WES	30-45	8-16 weeks	Severe ID, de novo variants	De novo variants, family info	Higher cost, longer TAT
Whole-genome sequencing (WGS)	30-50	8-20 weeks	WES negative, research setting	Non-coding variants, SVs	Interpretation challenges
Trio WGS	40-55	10-24 weeks	Complex cases, structural variants	Highest yield, comprehensive	Highest cost, VUS burden
Methylation studies	1-5	2-4 weeks	Suspected imprinting disorders	Specific disorders (PWS, AS)	Limited to specific conditions
Mitochondrial studies	5-15 (selected cases)	4-8 weeks	Multisystem involvement, myopathy	Maternal inheritance, deletions	Complex interpretation

ID, intellectual disability; DD, developmental delay; CNV, copy number variant; SNV, single nucleotide variant; FMR1, fragile X messenger ribonucleoprotein 1; TAT, turnaround time; SV, structural variant; VUS, variants of uncertain significance; PWS, Prader-Willi syndrome; AS, Angelman syndrome.

Table 3.

Genomic testing yields and considerations for clinical implementation^a

Therapy	Target condition	Mechanism	Development stage	Approved indication	Cognitive potential	Evidence level
Trofinetide (DAYBUE) [7]	Rett syndrome (girls ≥2 yr)	IGF-1 analog, synaptic function	FDA approved (2023)	Rett syndrome behavioral symptoms	High: synaptic enhancement mechanism	Phase 3 RCT (n=187)
Eladocagene exuparvovec (Upstaza) [8]	AADC deficiency	AAV2-DDC gene therapy	FDA/EMA approved (2022)	AADC deficiency motor milestones	Moderate: dopamine pathway restoration	Open-label (n=41)
Rugonersen (RO7248824) [9]	Angelman syndrome	UBE3A antisense oligonucleotide	Phase 3 ongoing	Not approved: trial ongoing	High: UBE3A restoration, EEG normalization	Phase 1/2 (n=61)
NNZ-2591 (Ercanetide) [32]	Phelan-McDermid syndrome	Cyclic glycine-proline analog	Phase 2 completed	Not approved: investigational	Moderate: multi-domain improvements	Open-label (n=31)
TSHA-102 (Gene therapy) [37]	Rett syndrome	AAV9-MECP2 gene therapy	Phase 1/2 ongoing	Not approved: investigational	High: MECP2 replacement therapy	Early phase
NGN-401 (Gene therapy) [37]	Rett syndrome	AAV-PHP.B-MECP2 gene therapy	Phase 1/2 ongoing	Not approved: investigational	High: MECP2 replacement therapy	Early phase
Precision GRIN modulators [31]	GRIN-related disorders	NMDA receptor modulation	Case reports/series	Not approved: case series	High: NMDA receptor optimization	Case series

IGF-1, insulin-like growth factor 1; FDA, U.S. Food and Drug Administration; RCT, randomized controlled trial; AADC, aromatic L-amino acid decarboxylase; AAV2, adeno-associated virus serotype 2; DDC, dopa decarboxylase; EMA, European Medicines Agency; UBE3A, ubiquitin-protein ligase E3A; EEG, electroencephalography; AAV9, adeno-associated virus serotype 9; MECP2, methyl-CpG-binding protein 2; PHP.B-MECP2, AAV-PHP.B vector encoding MECP2; GRIN, glutamate ionotropic receptor NMDA type subunit; NMDA, N-methyl-D-aspartic acid.

^aTherapeutic approaches for genetic forms of intellectual disability, distinguishing between approved indications and potential cognitive benefits. Includes treatments targeting synaptic function, neuroplasticity, and developmental pathways that may enhance cognitive outcomes beyond primary approval indications [7-9,31,32].

References

1. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil 2011;32:419-36.

2. Wieland J, Zitman FG. It is time to bring borderline intellectual functioning back into the main fold of classification systems. BJPsych Bull 2016;40:204-6.

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed., Text Revision (DSM-5-TR). Washington DC: American Psychiatric Association Publishing; 2022.

4. World Health Organization. ICD-11: International Classification of Diseases 11th Revision. Geneva: WHO; 2019.

5. Srivastava S, Love-Nichols JA, Dies KA, Ledbetter DH, Martin CL, Chung WK, 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;21:2413-21.

6. Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, et al. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom Med 2018;3:16.

7. Tasse MJ, Luckasson R, Nygren M. AAIDD proposed recommendations for ICD-11 and the condition previously known as mental retardation. Intellect Dev Disabil 2013;51:127-31.

8. Salvador-Carulla L, Reed GM, Vaez-Azizi LM, Cooper SA, Martinez-Leal R, Bertelli M, et al. Intellectual developmental disorders: towards a new name, definition and framework for “mental retardation/intellectual disability” in ICD-11. World Psychiatry 2011;10:175-80.

9. 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;23:2029-37.

10. Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet 2016;17:9-18.

11. Monroe GR, Frederix GW, Savelberg SM, de Vries TI, Duran KJ, van der Smagt JJ, et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med 2016;18:949-56.

12. Alamri A, Aljadhai YI, Alrashed A, Alfheed B, Abdelmoaty R, Alenazi S, et al. Identifying clinical clues in children with global developmental delay/intellectual disability with abnormal brain magnetic resonance imaging (MRI). J Child Neurol 2021;36:432-9.

13. van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012;105:368-81.

14. Sparrow SS, Cicchetti DV, Saulnier CA. Vineland adaptive behavior scales, third edition (Vineland-3). San Antonio: Pearson; 2016.

15. Lord C, Rutter M, DiLavore PC, Risi S, Gotham K, Bishop S. Autism diagnostic observation schedule, second edition (ADOS-2). Torrance: Western Psychological Services; 2012.

16. Storebo OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2015;2015:CD009885.

17. Symonds JD, Zuberi SM, Stewart K, McLellan A, O’Regan M, MacLeod S, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain 2019;142:2303-18.

18. Buckley N, Glasson EJ, Chen W, Epstein A, Leonard H, Skoss R, et al. Prevalence estimates of mental health problems in children and adolescents with intellectual disability: a systematic review and meta-analysis. Aust N Z J Psychiatry 2020;54:970-84.

19. Reichow B, Barton EE, Boyd BA, Hume K. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev 2012;10:CD009260.

20. Congress.GOV. Individuals with Disabilities Education Improvement Act of 2004: PUBLIC LAW 108-446—DEC. 3, 2004 [Internet]. Washington DC: Law Library of Congress; 2004 [cited 2025 Dec 3]. https://www.congress.gov/108/plaws/publ446/PLAW-108publ446.pdf

21. Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM. Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis. Dev Med Child Neurol 2009;51:340-9.

22. Rodan LH, Stoler J, Chen E, Geleske T. Genetic evaluation of the child with intellectual disability or global developmental delay: clinical report. Pediatrics 2025;156:e2025072219.

23. Burke BL, Hall RW. Telemedicine: pediatric applications. Pediatrics 2015;136:e293-308.

24. Gurovich Y, Hanani Y, Bar O, Nadav G, Fleischer N, Gelbman D, et al. Identifying facial phenotypes of genetic disorders using deep learning. Nat Med 2019;25:60-4.

25. Torra Moreno M, Canals Sans J, Colomina Fosch MT. Behavioral and cognitive interventions with digital devices in subjects with intellectual disability: a systematic review. Front Psychiatry 2021;12:647399.

26. Bruno E, Simblett S, Lang A, Biondi A, Odoi C, Schulze-Bonhage A, et al. Wearable technology in epilepsy: the views of patients, caregivers, and healthcare professionals. Epilepsy Behav 2018;85:141-9.

27. Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Marsh ED, et al. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nat Med 2023;29:1468-75.

28. Tai CH, Lee NC, Chien YH, Byrne BJ, Muramatsu SI, Tseng SH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther 2022;30:509-18.

29. Wolter JM, Mao H, Fragola G, Simon JM, Krantz JL, Bazick HO, et al. Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA. Nature 2020;587:281-4.

30. Carvill GL, Regan BM, Yendle SC, O’Roak BJ, Lozovaya N, Bruneau N, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013;45:1073-6.

31. Guan J, Zhang R, Dale-Gandar L, Hodgkinson S, Vickers MH. NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat. Behav Brain Res 2010;210:221-8.

32. Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med 2016;8:321ra5.

33. Wolraich ML, Hagan JF, Allan C, Chan E, Davison D, Earls M, et al. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics 2019;144:e20192528.

34. Sahin M, Sur M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science 2015;350:aab3897.

35. Goodwin MS, Mazefsky CA, Ioannidis S, Erdogmus D, Siegel M. Predicting aggression to others in youth with autism using a wearable biosensor. Autism Res 2019;12:1286-96.

36. Moore EJ, Schelling A. Postsecondary inclusion for individuals with an intellectual disability and its effects on employment. J Intellect Disabil 2015;19:130-48.

37. Copping NA, McTighe SM, Fink KD, Silverman JL. Emerging gene and small molecule therapies for the neurodevelopmental disorder Angelman syndrome. Neurotherapeutics 2021;18:1535-47.