Open research questions in Genetics and Neurodevelopmental Disorders

What the literature leaves open

• While more than 30 largely de novo MAPK8IP3 variants have been reported, the functional impact of variants across JIP3 protein structural domains is poorly defined.

  Pathogenic MAPK8IP3 variants drive distinct motor and behavioral phenotypes in humans and mice · 2026 · DOI

• While the underlying mechanisms remain to be fully elucidated, these findings position KCNK3 as a candidate gene for molecular screening and pave the way for future functional studies and therapeutic exploration in NDDs.

  Expanding the Phenotypic and Functional Evidence for <scp> <i>KCNK3</i> </scp> as a Neurodevelopmental Disorder Gene: A New Chinese Case and <i>Drosophila</i> Validation · 2026 · DOI

• We report 11 individuals with NFIC variants, including four with de novo SNVs and seven with deletions encompassing the gene, of whom nine have not been previously reported.

  Delineation of a Novel Mirror Syndrome: <i>NFIC</i> Variants Cause Syndromic Intellectual Disability With Macrocephaly · 2026 · DOI

• While NFIA , NFIB , and NFIX are linked to neurodevelopmental disorders, the role of NFIC (MIM: 600729) in human disease remains unclear.

  Delineation of a Novel Mirror Syndrome: <i>NFIC</i> Variants Cause Syndromic Intellectual Disability With Macrocephaly · 2026 · DOI

• Germline mutations in PTPN11 cause Noonan syndrome (NS) and NS with multiple lentigines (NSML), yet how specific variants drive divergent clinical outcomes through distinct signaling and developmental mechanisms remains unclear.

  An integrated computational, clinical, and functional framework for assessing PTPN11 (SHP2) variant effects on ERK signaling and neural crest cell behavior in Noonan spectrum disorders · 2026 · DOI

• Pathogenic variants in genes involved in transcriptional regulation and RNA processing have emerged as points of functional convergence in neurodevelopmental disorders (NDDs), but their specific disease mechanisms remain unknown.

  INTS6 loss of function disrupts transcriptional regulation in mild intellectual disability · 2026 · DOI

• Both STXBP1 ‐RD and SYNGAP1 ‐RD are potential targets for disease‐modifying therapies, but there is limited information in the literature describing the natural history of either disorder, which impedes outcome selection for future clinical trials.

  A prospective natural history study protocol for clinical trial readiness in synaptic disorders · 2026 · DOI

• This suggests that GIGYF2’s role in IGF-1R signaling may be independent of GRB10, although the precise molecular mechanisms by which GIGYF2 regulates IGF-1R remain unclear. Second, while our data demonstrate dysregulation of IGF-1R/AKT-mTOR signaling downstream of GIGYF2 deficiency, the precise molecular mechan- isms linking GIGYF2 to receptor trafficking or signaling regulation remain to be fully elucidated, including potential roles for adaptor proteins such as GRB10 or endocytic pathways. Several limitations of this study should be acknowledged. In addition, because the Nestin- Cre driver used in this study targets both neuronal and glial lineages and our rescue experiments were limited to the cellular level, genetic employing approaches and in vivo behavioral rescue will be important to further define cell-type-specific and therapeutic effects. The functional roles of GIGYF2 in neuronal synapse development have not been previously characterized. One possibility is that the association between macrocephaly and GIGYF2 haploinsufficiency remains uncertain, as macrocephaly was observed in only approximately one third of affected probands. Finally and importantly, although our rescue experiments demonstrate robust synaptic recovery at the cellular level, in vivo behavioral rescue experiments are still lacking and represent an important direction for future work.

  Evidence supporting the role of GIGYF2 in synapse development and autism · 2026 · DOI

• Whether re-expression of the FMR1 gene and encoded Fragile X Messenger Ribonucleoprotein (FMRP) can restore sensory circuit dysfunction remains unclear.

  FMR1 gene therapy restores activity-driven inhibition and prevents audiogenic seizures in Fmr1-/y mice · 2026 · DOI

• Abstract CC2D1A is a multidomain scaffold protein implicated in transcriptional regulation and autosomal recessive non-syndromic intellectual disability (NSID), yet its molecular mechanism is still poorly understood due to a lack of structural information.

  Structural characterization of the human CC2D1A fragment associated with non-syndromic intellectual disability (NSID) · 2026 · DOI

• Heterozygous frameshifting mutations account for the majority of HVDAS mutations, but it remains unclear how HVDAS mutations affect ADNP dosage, and how dosage in turn relates to neurodevelopmental and behavioral phenotypes.

  An allelic series reveals the genetic requirement for Adnp in cortical neurogenesis and learning behavior · 2026 · DOI

• There are several limitations to the current study. First, data on environmental and lifestyle factors are not available in the NHIRD, where these factors may also confound the interpre- tations of our results.42 For instance, smoking and nicotine use disorder was high- ly associated with MMD,45,46 where smoking also increases risk of CRC.47 Such history of problematic lifestyle and envi- ronmental factors may confound the association between the risk of an MMD and CRC. Second, although we adjusted for several confounders, residual confounding factors may still exist. However, a naturalistic study may better reflect real-world clinical practice. Third, as a case-control study, time effect of MMDs in FDRs on CRC cannot be identified, such as time ordering between them. For instance, whether the psychiatric diagnosis in the relative occurs before or after the CRC diag- nosis date in the proband remains unclear. Fourth, detection or surveillance bias may exist in this registry-based study, as FDRs of individuals with CRC may have increased healthcare contact and thus a higher probability of receiving psychiatric diagnoses. . x e d n I y t i d i b r o m o C n o s l r a h C , I C C ; r e d r o s i d y t i v i t c a C R C f o s R D F s l a u d i v i d n i , ) 4 2 0 8 3 = N ( . ) 3 2 ( 5 6 8 r e c n a C . ) 8 0 ( 1 1 3 a i n e r h p o z i h c S D D M D S A D B D H D A 742 Psychiatry Investig 2026;23(6):738-745 Mental Disorders in Relatives of Colorectal Cancer Probands Figure 1. Relative risks of major mental disorders between FDRs of individuals with CRC and matched controls, stratified by kinship. CI, confidence interval; FDR, first-degree relative; ASD, autism spectrum disorder; ADHD, attention-deficit/hyperactivity disorder; Na, not appli- cable.

  Risks and Familial Coaggregation of Autism Spectrum Disorder Among First-Degree Relatives of Individuals With Colorectal Cancer · 2026 · DOI

• For quick reference, a summary of the major recommendations from this section, stratified by variants and clinical context is provided (box 1). Criteria for genetic testing of RYR1 Suspected clinical diagnosis of malignant hyperthermia. Patients who had features of a hypermetabolic reaction under general 4 Box 1 R.L. Robinson et al.

  EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders · 2026 · DOI

• However, there is much more that needs to be done on multiple fronts: (1) Clinicians need more accessible procedures for measuring ID in community-based settings for those across the ID spectrum; (2) Measures need to be validated in those with ID; and (3) Measures in clinical trials need to be incorporated that address some of the real-world challenges of those with ID, acknowledging that these individuals may have very different experiences than those with average or higher IQs.

  Scientists Can Do Better Including Those With Intellectual Disability in Clinical Trials · 2025 · DOI

• In several instances, especially with comorbid disorders - intellectual disability, epilepsy and dysmorphias - a detailed molecular diagnostics is warranted, which currently may elucidate the genetic background of disorder in about 20% of cases.

  The role of genetic factors and pre- and perinatal influences in the etiology of autism spectrum disorders – indications for genetic referral · 2016 · DOI

• However, the ENS cell types affected by this enhancer and the mechanisms by which these transcriptional changes lead to HSCR remain unknown.

  Combined effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system · 2026 · DOI

• While evoked potentials (EPs) show delayed and attenuated sensory responses in RTT, the underlying mechanisms of these impairments remain unclear.

  Variability in sensory processing and evoked potentials in Rett syndrome · 2026 · DOI

• These findings could be replicated using CRISPRi-based TRIM28 silencing, which suggests that the two variants result in a loss of function.

  De novo missense variants in TRIM28 identified in individuals with neurodevelopmental delay show features of transposable element activation · 2026 · DOI

• Existing pharmaceutical compounds demonstrated efficacy in some people with Down syndrome, but phenotypic variability in this population has led to inconsistent findings (Kishnani et al.

  Introduction to the Special Issue on the Development of People With Down Syndrome Throughout the Lifespan (Part 1) · 2017 · DOI

• From the still scarce literature on GNAO1 mutations, a clear genotype-phenotype correlation emerged.

  Recurrent <i>GNAO1</i> Mutations Associated With Developmental Delay and a Movement Disorder · 2016 · DOI

• Despite this remarkable achievement, very little is known about the mechanism(s) whereby increased gene copy number (gene dosage) results in the characteristic phenotype of Down syndrome.

  Down Syndrome: Advances in Molecular Biology and the Neurosciences · 2001 · DOI

Most-cited papers in Genetics and Neurodevelopmental Disorders

• Human Dysbindin (DTNBP1) Gene Expression inNormal Brain and in Schizophrenic Prefrontal Cortex and Midbrain · Archives of General Psychiatry · 2004 · 301 citations
• The prevalence and phenomenology of self‐injurious and aggressive behaviour in genetic syndromes · Journal of Intellectual Disability Research · 2010 · 220 citations
• A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome · Journal of Developmental & Behavioral Pediatrics · 2013 · 214 citations
• Behavioral and Cognitive Aspects of Tuberous Sclerosis Complex · Journal of Child Neurology · 2004 · 196 citations
• Open-Label Treatment Trial of Lithium to Target the Underlying Defect in Fragile X Syndrome · Journal of Developmental & Behavioral Pediatrics · 2008 · 191 citations
• High intelligence: A risk factor for psychological and physiological overexcitabilities · Intelligence · 2017 · 164 citations
• Genetic contributions to autism spectrum disorder · Psychological Medicine · 2021 · 161 citations
• The genetic architecture of structural left–right asymmetry of the human brain · Nature Human Behaviour · 2021 · 132 citations
• 2023 FDA TIDES (Peptides and Oligonucleotides) Harvest · Pharmaceuticals · 2024 · 90 citations
• Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia. · Behavioral Neuroscience · 2015 · 82 citations

Most recent work

• EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders · European Journal of Human Genetics · 2026
• Clinical Clues to the Diagnostic Yield of Genetic Testing in Adults With Late-Onset Behavioral Change · Neurology Genetics · 2026
• Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency · Science Advances · 2026
• Fmr1 Deletion and Early-Life Stress Interact to Increase Cell Proliferation and Glial Populations at the Expense of Immature Neurons in the Adult Dentate Gyrus · International Journal of Molecular Sciences · 2026
• Dysfunction of a SET3-like complex underlies a family of related neurological disorders · Nature Communications · 2026
• nELAVL phosphorylation by CDKL5 regulates RNA metabolism and condensates communication to promote experience-dependent maturation of the visual cortex · bioRxiv · 2026
• Upregulated SEMA3C in astrocytes contributes to Rett Syndrome phenotypes · bioRxiv · 2026
• Publisher Correction: Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome · Nature · 2026
• Structural characterization of the human CC2D1A fragment associated with non-syndromic intellectual disability (NSID) · Bioscience Reports · 2026
• [Genetic analysis of a boy with congenital variant Rett syndrome due to a novel variant of FOXG1 gene and literature review]. · PubMed · 2026

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