Genetic analysis of intellectual disability and autism

Main Article Content

Pietro Chiurazzi
Aysha Karim Kiani
Jan Miertus
Stefano Paolacci
Shila Barati
Elena Manara
Liborio Stuppia
Fiorella Gurrieri
Matteo Bertelli

Keywords

Intellectual Disability, Autism Spectrum Disorders, Next-Generation Sequencing, Targeted Gene Panels

Abstract

Background and aim: Intellectual disability (ID) and autism spectrum disorders (ASD) are neurodevelopmental conditions that often co-exist and affect children from birth, impacting on their cognition and adaptive behaviour. Social interaction and communication ability are also severely impaired in ASD. Almost 1-3% of the population is affected and it has been estimated that approximately 30% of intellectual disability and autism is caused by genetic factors. The aim of this review is to summarize monogenic conditions characterized by intellectual disability and/or autism for which the causative genes have been identified. Methods and Results: We identified monogenic ID/ASD conditions through PubMed and other NCBI databases. Many such genes are located on the X chromosome (>150 out of 900 X-linked protein-coding genes), but at least 2000 human genes are estimated to be involved in ID/ASD. We selected 174 genes (64 X-linked and 110 autosomal) for an NGS panel in order to screen patients with ID and/or ASD, after fragile X syndrome and significant Copy Number Variants have been excluded. Conclusions: Accurate clinical and genetic diagnosis is required for precise treatment of these disorders, but due to their genetic heterogeneity, most cases remain undiagnosed. Next generation sequencing technologies have greatly enhanced the identification of new genes associated with intellectual disability and autism, ultimately leading to the development of better treatment options.

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References

1. Chiurazzi P, Pirozzi F. Advances in understanding - Genetic basis of intellectual disability. F1000Res 2016; 5: 599.
2. Erger F, Schaaf CP, Netzer C. Which genes to assess in the NGS diagnostics of intellectual disability? The case for a consensus database-driven and expert-curated approach. Mol Cell Probes 2019; 45: 84-8.
3. Chiurazzi P. Mental retardation: is naming the real issue? Am J Med Genet A 2011; 155A: 974-5.
4. Zablotsky B, Black LI, Blumberg SJ. Estimated prevalence of children with diagnosed developmental disabilities in the United States, 2014-2016. NCHS Data Brief 2017; 291: 1-8.
5. Kochinke K, Zweier C, Nijhof B, et al. Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am J Hum Genet 2016; 98: 149-64.
6. Piton A, Redin C, Mandel JL. XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am J Hum Genet 2013; 93: 368-83.
7. Tabolacci E, Chiurazzi P. Epigenetics, fragile X syndrome and transcriptional therapy. Am J Med Genet A 2013; 161A: 2797-808.
8. Hamdan FF, Gauthier J, Araki Y, et al. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 2011; 88: 306-16.
9. Sharma SR, Gonda X, Tarazi FI. Autism spectrum disorder: Classification, diagnosis and therapy. Pharmacol Ther 2018; 190: 91-104.
10. Totsika V, Hastings RP, Emerson E, Lancaster GA, Berridge DM. A population‐based investigation of behavioural and emotional problems and maternal mental health: Associations with autism spectrum disorder and intellectual disability. J Child Psychol Psychiatry 2011; 52: 91-9.
11. Verma V, Paul A, Amrapali Vishwanath A, Vaidya B, Clement JP. Understanding intellectual disability and autism spectrum disorders from common mouse models: Synapses to behaviour. Open Biol 2019; 9: 180265.
12. Ropers HH. Genetics of intellectual disability. Curr Opin Genet Dev 2008; 18: 241-50.
13. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86: 749-64.
14. Borch LA, Parboosingh J, Thomas MA, Veale P. Re-evaluating the first-tier status of fragile X testing in neurodevelopmental disorders. Genet Med 2020; 22: 1036-9.
15. Chiurazzi P, Schwartz CE, Gecz J, Neri G. XLMR genes: Update 2007. Eur J Hum Genet 2008; 16: 422-34.
16. Hu H, Kahrizi K, Musante L, et al. Genetics of intellectual disability in consanguineous families. Mol Psychiatry 2019; 24: 1027-39.
17. Vissers LE, de Ligt J, Gilissen C, et al. A de novo paradigm for mental retardation. Nat Genet 2010; 42: 1109-12.
18. Srivastava AK, Schwartz CE. Intellectual disability and autism spectrum disorders: Causal genes and molecular mechanisms. Neurosci Biobehav Rev 2014; 46: 161-74.
19. Krumm N, O’Roak BJ, Shendure J, Eichler EE. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci 2014; 37: 95-105.
20. Pinto D, Delaby E, Merico D, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 2014; 94: 677-94.
21. Harripaul R, Noor A, Ayub M, Vincent JB. The use of next-generation sequencing for research and diagnostics for intellectual disability. Cold Spring Harb Perspect Med 2017; 7: a026864.
22. Han JY, Lee IG. Genetic tests by next-generation sequencing in children with developmental delay and/or intellectual disability. Clin Exp Pediatr 2020; 63: 195-202.
23. Bruel AL, Vitobello A, Tran Mau-Them F, et al. Next-generation sequencing approaches and challenges in the diagnosis of developmental anomalies and intellectual disability. Clin Genet 2020. doi: 10.1111/cge.13764.
24. Gajecka M. Unrevealed mosaicism in the next-generation sequencing era. Mol Genet Genomics 2016; 291: 513-30.
25. Redin C, Gérard B, Lauer J, et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet 2014; 51: 724-36.
26. Grozeva D, Carss K, Spasic-Boskovic O, et al. Targeted next-generation sequencing analysis of 1,000 individuals with intellectual disability. Hum Mutat 2015; 36: 1197-204.
27. Yan H, Shi Z, Wu Y, et al. Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: novel mutations and candidate gene. BMC Med Genet 2019; 20: 80.
28. Aspromonte MC, Bellini M, Gasparini A, et al. Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Hum Mutat 2019; 40: 1346-63.
29. Lu YF, Goldstein DB, Angrist M, Cavalleri G. Personalized medicine and human genetic diversity. Cold Spring Harb Perspect Med 2014; 4: a008581.