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Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability

Abstract

Intellectual disability (ID), a neurodevelopmental disorder affecting 1–3% of the general population, is characterized by limitations in both intellectual function and adaptive skills. The high number of conditions associated with ID underlines its heterogeneous origin and reveals the difficulty of obtaining a rapid and accurate genetic diagnosis. However, the Next Generation Sequencing, and the whole exome sequencing (WES) in particular, has boosted the diagnosis rate associated with ID. In this study, WES performed on 244 trios of patients clinically diagnosed with isolated or syndromic ID and their respective unaffected parents has allowed the identification of the underlying genetic basis of ID in 64 patients, yielding a diagnosis rate of 25.2%. Our results suggest that trio-based WES facilitates ID’s genetic diagnosis, particularly in patients who have been extensively waiting for a definitive molecular diagnosis. Moreover, genotypic information from parents provided by trio-based WES enabled the detection of a high percentage (61.5%) of de novo variants inside our cohort. Establishing a quick genetic diagnosis of ID would allow early intervention and better clinical management, thus improving the quality of life of these patients and their families.

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Data availability

Identified variants have been deposited on the Leiden OpenVariation Database (LOVD, https://www.lovd.nl/). Complementary data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Patel DR, Cabral MD, Ho A, Merrick J. A clinical primer on intellectual disability. Transl Pediatr. 2020;9:S23–35.

    PubMed  PubMed Central  Article  Google Scholar 

  2. Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet. 2010;11:161–87.

    CAS  PubMed  Article  Google Scholar 

  3. Casanova EL, Sharp JL, Chakraborty H, Sumi NS, Casanova MF. Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression. Mol Autism. 2016;7:18.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. Darvish H, Azcona LJ, Tafakhori A, Mesias R, Ahmadifard A, Sanchez E, et al. Phenotypic and genotypic characterization of families with complex intellectual disability identified pathogenic genetic variations in known and novel disease genes. Sci Rep. 2020;10:968.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Ellison JW, Rosenfeld JA, Shaffer LG. Genetic basis of intellectual disability. Annu Rev Med. 2013;64:441–50.

    CAS  PubMed  Article  Google Scholar 

  6. Jamra R. Genetics of autosomal recessive intellectual disability. medizinische Genet. 2018;30:323–7.

    CAS  Article  Google Scholar 

  7. Wieczorek D. Autosomal dominant intellectual disability. Medizinische Genet. 2018;30:318–22.

    CAS  Article  Google Scholar 

  8. Neri G, Schwartz CE, Lubs HA, Stevenson RE. X-linked intellectual disability update 2017. Am J Med Genet Part A. 2018;176:1375–88.

    PubMed  Article  Google Scholar 

  9. Musante L, Ropers HH. Genetics of recessive cognitive disorders. Trends Genet. 2014;30:32–9.

    CAS  PubMed  Article  Google Scholar 

  10. Chiurazzi P, Pirozzi F. Advances in understanding—genetic basis of intellectual disability. F1000Research. 2016;5:599.

    Article  CAS  Google Scholar 

  11. Ilyas M, Mir A, Efthymiou S, Houlden H. The genetics of intellectual disability: advancing technology and gene editing. F1000Research. 2020;9:22.

    CAS  Article  Google Scholar 

  12. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Amor DJ. Investigating the child with intellectual disability. J Paediatr Child Health. 2018;54:1154–8.

    PubMed  Article  Google Scholar 

  14. Bass N, Skuse D. Genetic testing in children and adolescents with intellectual disability. Curr Opin Psychiatry. 2018;31:490–5.

    PubMed  Article  Google Scholar 

  15. Vickers RR, Gibson JS. A review of the genomic analysis of children presenting with developmental delay/intellectual disability and associated dysmorphic features. Cureus. 2019;11:e3873.

    PubMed  PubMed Central  Google Scholar 

  16. Bowling KM, Thompson ML, Amaral MD, Finnila CR, Hiatt SM, Engel KL, et al. Genomic diagnosis for children with intellectual disability and/or developmental delay. Genome Med. 2017;9:43.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. Wright CF, McRae JF, Clayton S, Gallone G, Aitken S, FitzGerald TW, et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. Genet Med. 2018;20:1216–23.

    PubMed  PubMed Central  Article  Google Scholar 

  18. Sabo A, Murdock D, Dugan S, Meng Q, Gingras M-C, Hu J, et al. Community‐based recruitment and exome sequencing indicates high diagnostic yield in adults with intellectual disability. Mol Genet Genom Med. 2020;8:e1439.

    CAS  Google Scholar 

  19. Benson KA, White M, Allen NM, Byrne S, Carton R, Comerford E, et al. A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability. Eur J Hum Genet. 2020;28:1066–77.

    PubMed  PubMed Central  Article  Google Scholar 

  20. Topper S, Ober C, Das S. Exome sequencing and the genetics of intellectual disability. Clin Genet. 2011;80:117–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, van Mierlo P, Braakman HMH, Smeets EE, et al. Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. Epilepsia 2019;60:155–64.

    PubMed  Article  Google Scholar 

  22. Smaili W, Elalaoui SC, Zrhidri A, Raymond L, Egéa G, Taoudi M, et al. Exome sequencing revealed a novel homozygous METTL23 gene mutation leading to familial mild intellectual disability with dysmorphic features. Eur J Med Genet. 2020;63:103951.

    CAS  PubMed  Article  Google Scholar 

  23. Banihashemi S, Tahmasebi-Birgani M, Mohammadiasl J, Hajjari M. Whole exome sequencing identified a novel nonsense INPP4A mutation in a family with intellectual disability. Eur J Med Genet. 2020;63:103846.

    PubMed  Article  Google Scholar 

  24. Palumbo P, Di Muro E, Accadia M, Benvenuto M, Di Giacomo MC, Castellana S, et al. Whole exome sequencing reveals a novel AUTS2 in-frame deletion in a boy with global developmental delay, absent speech, dysmorphic features, and cerebral anomalies. Genes. 2021;12:229.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Martínez F, Caro-Llopis A, Roselló M, Oltra S, Mayo S, Monfort S, et al. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J Med Genet. 2017;54:87–92.

    PubMed  Article  CAS  Google Scholar 

  26. Pekeles H, Accogli A, Boudrahem-Addour N, Russell L, Parente F, Srour M. Diagnostic yield of intellectual disability gene panels. Pediatr Neurol. 2019;92:32–6.

    PubMed  Article  Google Scholar 

  27. Stojanovic JR, Miletic A, Peterlin B, Maver A, Mijovic M, Borlja N, et al. Diagnostic and clinical utility of clinical exome sequencing in children with moderate and severe global developmental delay / intellectual disability. J Child Neurol. 2020;35:116–31.

    PubMed  Article  Google Scholar 

  28. de Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921–9.

    PubMed  Article  CAS  Google Scholar 

  29. Farwell KD, Shahmirzadi L, El-Khechen D, Powis Z, Chao EC, Tippin Davis B, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med. 2015;17:578–86.

    CAS  PubMed  Article  Google Scholar 

  30. Carneiro T, Krepischi A, Souza da Costa S, Tojal da Silva I, Vianna-Morgante A, Valieris R, et al. Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases. Appl Clin Genet. 2018;11:93–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Srivastava S, Love-Nichols JA, Dies KA, Ledbetter DH, Martin CL, Chung WK, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019;21:2413–21.

    PubMed  PubMed Central  Article  Google Scholar 

  32. LELM Vissers, Van Nimwegen KJM, Schieving JH, Kamsteeg EJ, Kleefstra T, Yntema HG, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017;19:1055–63.

    Article  Google Scholar 

  33. Vrijenhoek T, Middelburg EM, Monroe GR, van Gassen KLI, Geenen JW, Hövels AM, et al. Whole-exome sequencing in intellectual disability; cost before and after a diagnosis. Eur J Hum Genet. 2018;26:1566–71.

    PubMed  PubMed Central  Article  Google Scholar 

  34. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An J-Y, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of Autism. Cell. 2020;180:568–584. e23

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–23.

    PubMed  PubMed Central  Article  Google Scholar 

  36. Di Resta C, Pipitone G, Carrera P, Ferrari M. Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing. Neural Regen Res. 2021;16:475–81.

    PubMed  Article  Google Scholar 

  37. Fell CW, Nagy V. Cellular models and high-throughput screening for genetic causality of intellectual disability. Trends Mol Med. 2021;27:220–30.

    CAS  PubMed  Article  Google Scholar 

  38. The Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 2017;542:433–8.

    PubMed Central  Article  CAS  Google Scholar 

  39. Reichenberg A, Cederlöf M, McMillan A, Trzaskowski M, Kapra O, Fruchter E, et al. Discontinuity in the genetic and environmental causes of the intellectual disability spectrum. Proc Natl Acad Sci. 2016;113:1098–103.

    CAS  PubMed  Article  Google Scholar 

  40. Wilfert AB, Sulovari A, Turner TN, Coe BP, Eichler EE. Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Med. 2017;9:101.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Wenger AM, Guturu H, Bernstein JA, Bejerano G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med. 2017;19:209–14.

    PubMed  Article  Google Scholar 

  42. Wang J, Wang Y, Wang L, Chen WY, Sheng M. The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing. BMC Med Genomics. 2020;13:70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. De Luca C, Race V, Keldermans L, Bauters M, Van Esch H. Challenges in molecular diagnosis of X-linked Intellectual disability. Br Med Bull. 2020;133:36–48.

    PubMed  Google Scholar 

  44. Gao C, Wang X, Mei S, Li D, Duan J, Zhang P, et al. Diagnostic yields of trio-WES accompanied by CNVseq for rare neurodevelopmental disorders. Front Genet. 2019;10:485.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Smpokou P, Samanta M, Berry GT, Hecht L, Engle EC, Lichter-Konecki U. Menkes disease in affected females: The clinical disease spectrum. Am J Med Genet Part A. 2015;167:417–20.

    CAS  Article  Google Scholar 

  46. Fitzgerald TW. Large-scale discovery of novel genetic causes of developmental disorders. Nature 2015;519:223–8.

    CAS  Article  Google Scholar 

  47. Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376:21–31.

    CAS  PubMed  Article  Google Scholar 

  48. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BWM, Willemsen MH, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–7.

    CAS  PubMed  Article  Google Scholar 

  49. Shinawi M, Liu P, Kang SHL, Shen J, Belmont JW, Scott DA, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet. 2010;47:332–41.

    CAS  PubMed  Article  Google Scholar 

  50. Phelan K, McDermid HE. The 22q13.3 deletion syndrome (Phelan-McDermid syndrome). Mol Syndromol. 2011;2:186–201.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are sincerely grateful to patients and their families for participating in this study. This study has been funded by Instituto de Salud Carlos III through the project PI19/00809 (Co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”). We also acknowledge support from Fundación María José Jove.

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AJBF and MAB should be considered joint first author. Study concept and design, AJBF, MAB, JB, AC; writing – original draft preparation, AJBF, MAB; writing – review and editing, JB, AC, AJBF, MAB; clinical diagnosis or clinical data gathering, MTF, MFP, PC; bioinformatic analysis, JA, AJBF, SDR; genetic data acquisition or analysis, AJBF, MAB, FB, SDR. All authors have approved the final version of the manuscript.

Corresponding author

Correspondence to Alejandro J. Brea-Fernández.

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The authors declare no competing interests.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the Research Ethics Committee of Galicia (Comité Ético de Investigación Galicia; the only IEC authorized in this autonomous region); Number: 2015/608; Approval: 18-November-2015; Title: DISECMAS: Bases genéticas de la discapacidad intelectual: aplicación de las nuevas tecnologías de secuenciación masiva al análisis de variantes genéticas. Informed consent was obtained from all participants included in the study.

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Brea-Fernández, A.J., Álvarez-Barona, M., Amigo, J. et al. Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01087-w

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