The human brain is composed of billions of neurons, each precisely positioned and connected with other neurons through thousands of synapses. Defects of patterning, neurogenesis, astrogliogenesis, or synaptogenesis can lead to developmental brain disorders, including structural and cognitive phenotypes, collectively referred to as Neurodevelopmental Disorders (NDDs). NDDs account for nearly 25% of pediatric chronic disease, burdening families with serious financial and psychological hardship for the life of the child. With advances in next-generation sequencing (NGS) technology, profound progress has been made in deciphering genetic causes of NDDs, providing key insights into molecular mechanisms. However, despite the fast-moving whole exome/genome sequencing (WE/GS), very few have resulted in a change in care or new therapy.

There are many reasons for the gap between diagnosis and treatment for NDDs. Among them, the limited understanding of the role of non-genetic factors, such as toxins, neuroendocrine factors, and environmental factors has become a key hurdle. Clinical and pathological studies have demonstrated the importance of hormones and chemicals during brain development and related developmental and psychiatric diseases. In addition to these studies, experimental evidence from molecular, cellular, and genetic studies to support these clinical findings is largely missing. Filling this gap in the literature requires:

1] A comprehensive understanding of the roles of non-genetic factors during human brain development.

2] Unbiased large-scale analysis to link the non-genetic and genetic factors in neurodevelopmental disorders.

3] Clear standards to measure the levels of non-genetic factors such as toxins, neuroendocrine factors, and hormones during brain development in healthy and pathological conditions.

4] Impact of non-genetic factors on the neural circuit assembly in neurodevelopmental disorders.

5] Reliable model systems closely mimicking the functions of non-genetic factors during human brain development in healthy and pathological conditions.

6] Solid molecular and cellular evidence providing potential clues for treatments.

The fast development of NGS combining state-of-the-art GWAS analysis provides a comprehensive genotype-phenotype correlation in a wide range of disease categories. Several studies have tried to demonstrate the correlation between the genetic and environmental factors. However, more efforts are needed to provide a comprehensive association between genetic and non-genetic factors, especially with the perspective of neuroendocrine, toxin, hormone, and environmental factors. Cutting edge stem cell technologies, especially brain organoid models, made a profound impact on the understanding of neurological disorders. Their value in modeling the functions of non-genetic factors in neurological disorders has been increasingly recognized and needs to be expanded.

Areas of interest in this Research Topic include the following:

• Populational level analysis of non-genetic factors and their contributions to neurodevelopmental disorders.

• Populational level bioinformatic analysis to illustrate the genetic and non-genetic interaction in neurodevelopmental disorders.

• Molecular basis for the contributions of non-genetic factors on neural circuits assembly.

• Stem cell, brain organoid modeling to demonstrate the functions of non-genetic factors in neurodevelopmental disorders.

• Molecular and cellular profiling to uncover the mechanism for non-genetic factors in neurodevelopmental disorders.

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