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Review
. 2021 Nov 17;11(11):1713.
doi: 10.3390/biom11111713.

Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era

Mattia Zaghi  1 , Federica Banfi  1   2 , Edoardo Bellini  1 , Alessandro Sessa  1
Affiliations
Review

Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era

Mattia Zaghi et al. Biomolecules. .

Abstract

The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and rare genomic variants and to perform detailed phenotypic characterizations of both physiological organs and experimental models. Recent years have seen the introduction of multiple techniques using NGS to profile transcription, DNA and chromatin modifications, protein binding, etc., that are now allowing us to profile cells in bulk or even at a single-cell level. Although rare and ultra-rare diseases only affect a few people, each of these diseases represent scholarly cases from which a great deal can be learned about the pathological and physiological function of genes, pathways, and mechanisms. Therefore, for rare diseases, state-of-the-art investigations using NGS have double valence: their genomic cause (new variants) and the characterize the underlining the mechanisms associated with them (discovery of gene function) can be found. In a non-exhaustive manner, this review will outline the main usage of NGS-based techniques for the diagnosis and characterization of neurodevelopmental disorders (NDDs), under whose umbrella many rare and ultra-rare diseases fall.

Keywords: diagnosis; experimental modelling; gene function; neurodevelopmental disorders (NDDs); next-generation sequencing (NGS).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Main gene categories affected in NDDs with some relevant examples. Chromatin remodelers are genes that are implied to be involved in the regulation of chromatin in an activatory (EP300, MLL2) or repressive manner (EZH2, MLL2). Others control transcriptional processivity, such as (SETD2 and SETD5). Cytoskeleton proteins such as CTTNBP2 and MAP2 are associated with the cytoskeleton and help to preserve its integrity. Others, such TUBB2A, are structural proteins that directly form its structure. Synaptic proteins and ion channels can be associated with different tasks, functionally active channels (SCN2A), neurotransmitter receptors (GRIA1 and GRBRA1), calcium-responsive proteins (CAMK2A), and proteins that are associated with the synaptic structure (SHANK2).
Figure 2
Figure 2
Investigation framework of NDDs fostered by NGS: from patient diagnose to basic pathogenic mechanism research.
See this image and copyright information in PMC

References

    1. Parenti I., Rabaneda L.G., Schoen H., Novarino G. Neurodevelopmental Disorders: From Genetics to Functional Pathways. Trends Neurosci. 2020;43:608–621. doi: 10.1016/j.tins.2020.05.004. - DOI - PubMed
    1. Gilissen C., Hehir-Kwa J.Y., Thung D.T., van de Vorst M., van Bon B.W.M., Willemsen M.H., Kwint M., Janssen I.M., Hoischen A., Schenck A., et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–347. doi: 10.1038/nature13394. - DOI - PubMed
    1. Roberts E., Hampshire D.J., Pattison L., Springell K., Jafri H., Corry P., Mannon J., Rashid Y., Crow Y., Bond J., et al. Autosomal recessive primary microcephaly: An analysis of locus heterogeneity and phenotypic variation. J. Med. Genet. 2002;39:718–721. doi: 10.1136/jmg.39.10.718. - DOI - PMC - PubMed
    1. Lo Nigro C., Chong S.S., Smith A.C.M., Dobyns W.B., Carrozzo R., Ledbetter D.H. Point Mutations and an Intragenic Deletion in LIS1, the Lissencephaly Causative Gene in Isolated Lissencephaly Sequence and Miller-Dieker Syndrome. Hum. Mol. Genet. 1997;6:157–164. doi: 10.1093/hmg/6.2.157. - DOI - PubMed
    1. Des Portes V., Pinard J.M., Billuart P., Vinet M.C., Koulakoff A., Carrié A., Gelot A., Dupuis E., Motte J., Berwald-Netter Y., et al. A Novel CNS Gene Required for Neuronal Migration and Involved in X-Linked Subcortical Laminar Heterotopia and Lissencephaly Syndrome. Cell. 1998;92:51–61. doi: 10.1016/S0092-8674(00)80898-3. - DOI - PubMed

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