Genetic Mechanisms in Neurodevelopmental Disorders

Neurodevelopmental disorders encompass a spectrum of conditions in which genetic variation disrupts the development and function of the central nervous system. Advances in genomic technologies have revealed that both rare and common variants contribute to risk, including de novo mutations, copy-number variants and inherited polymorphisms. Many of the implicated genes converge on core biological pathways such as synaptic development and plasticity, chromatin remodelling, intracellular signalling through the mammalian target of rapamycin (mTOR) axis and immune modulation. Mutational burden and gene vulnerability interact dynamically with environmental factors, suggesting a two-hit model in which a primary genetic lesion may be exacerbated by secondary events. These insights underpin efforts to stratify patients for precision diagnostics and to develop targeted therapeutic approaches, with global initiatives expanding cohort diversity to ensure broad applicability of findings.

Research from Nature Portfolio

Randomised clinical studies in a rare Rett-syndrome cohort have demonstrated that a synthetic tripeptide analogue can ameliorate core behavioural and communication deficits when administered orally over a twelve-week period. Improvements were observed in standardised behavioural questionnaires and clinician-rated global impression scores, providing proof of principle for synapse-oriented therapy in monogenic neurodevelopmental syndromes. In parallel, large-scale sequencing of more than fifteen hundred patients with autism spectrum disorder in an under-represented population uncovered a significant excess of loss-of-function de novo mutations. A set of recurrently mutated genes was established, including voltage-gated sodium channel and chromatin-remodelling loci, and a number of novel candidates was highlighted. These findings broaden the catalogue of high-risk genes and emphasise the importance of inclusive cohorts for delineating mutational spectra and informing variant interpretation.

Genetic Mechanisms in Neurodevelopmental Disorders publication trend

The graph below shows the total number of articles in genetic mechanisms in neurodevelopmental disorders across all publications each year (not limited to Nature Index journals).

Technical terms

De novo mutation: A genetic alteration present for the first time in one individual, arising spontaneously in a gamete or early embryo.

Haploinsufficiency: A state in which loss of one functional copy of a gene results in an insufficient gene product to maintain normal function.

Synaptic plasticity: The capacity of synapses to strengthen or weaken over time in response to changes in activity, essential for learning and memory.

Chromatin remodelling: The dynamic modification of chromatin structure by specialised protein complexes, regulating access of transcription machinery to DNA.

mTOR pathway: A key intracellular signalling cascade that integrates nutrient and growth factor signals to regulate cell growth, proliferation and synaptic function.

References

1. SCGN deficiency is a risk factor for autism spectrum disorder. Signal Transduction and Targeted Therapy (2023).
2. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nature Medicine (2023).
3. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Molecular Autism (2017).
4. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nature Communications (2016).
5. Neurodevelopmental Disorders: From Genetics to Functional Pathways. Trends in Neurosciences (2020).