Skip to main content

Advertisement

SpringerLink
Log in

Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy

  • Original Article
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

Pathogenic sequence variants in the IQ motif– and Sec7 domain–containing protein 2 (IQSEC2) gene have been confirmed as causative in the aetiopathogenesis of neurodevelopmental disorders (intellectual disability, autism) and epilepsy. We report on a case of a family with three sons; two of them manifest delayed psychomotor development and epilepsy. Initially proband A was examined using a multistep molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, both with negative results. Therefore, probands A and B and their unaffected parents were enrolled for an analysis using targeted “next-generation” sequencing (NGS) with a gene panel ClearSeq Inherited DiseaseXT (Agilent Technologies) and verification analysis by Sanger sequencing. A novel frameshift variant in the X-linked IQSEC2 gene NM_001111125.2:c.1813_1814del, p.(Asp605Profs*3) on protein level, was identified in both affected probands and their asymptomatic mother, having skewed X chromosome inactivation (XCI) (100:0). As the IQSEC2 gene is a known gene escaping from XCI in humans, we expect the existence of mechanisms maintaining the normal or enough level of the IQSEC2 protein in the asymptomatic mother. Further analyses may help to the characterization of the presented novel frameshift variant in the IQSEC2 gene as well as to elucidate the mechanisms leading to the rare asymptomatic phenotypes in females.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The microarray data obtained in the present study are available in the Array Express database (https://www.ebi.ac.uk/arrayexpress/) in the txt format under the accession number E-MTAB-8147. The NGS data analyzed in this study are available in the Array Express database (https://www.ebi.ac.uk/arrayexpress/) in fastq and bam formats under the accession number E-MTAB-8131. Sanger sequencing data, including the chromatograms of the probands and the parents, are stored in the Figshare online digital repository (https://doi.org/10.6084/m9.figshare.8667800.v1). The novel IQSEC2 gene variant NM_001111125.2:c.1813_1814del was submitted to Leiden Open Variation Database v.3.0 (Global Variome shared LOVD) under the accession number #0000629453 (https://databases.lovd.nl/shared/variants/0000629453). The variants and phenotypes were submitted to Leiden Open Variation Database v.3.0 (Global Variome shared LOVD). The novel IQSEC2 gene variant NM_001111125.2:c.1813_1814del is available under the accession number #0000629453 (https://databases.lovd.nl/shared/variants/0000629453). The BTD gene variant NM_000060.2:c.1330G>C is available under the accession number #0000629454 (https://databases.lovd.nl/shared/variants/0000629454).

References

  1. Kochinke K, Zweier C, Nijhof B, Fenckova M, Cizek P, Honti F, Keerthikumar S, Oortveld MA, Kleefstra T, Kramer JM et al (2016) Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am J Hum Genet 98(1):149–164

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Neri G, Schwartz CE, Lubs HA, Stevenson RE (2018) X-linked intellectual disability update 2017. Am J Med Genet A 176(6):1375–1388

    PubMed  PubMed Central  Google Scholar 

  3. Shoubridge C, Harvey RJ, Dudding-Byth T (2019) IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy. Hum Mutat 40(1):5–24

    CAS  PubMed  Google Scholar 

  4. Rogers EJ, Jada R, Schragenheim-Rozales K, Sah M, Cortes M, Florence M, Levy NS, Moss R, Walikonis RS, Palty R, Shalgi R, Lichtman D, Kavushansky A, Gerges NZ, Kahn I, Umanah GKE, Levy AP (2019) An IQSEC2 mutation associated with intellectual disability and autism results in decreased surface AMPA receptors. Front Mol Neurosci 12:43. https://doi.org/10.3389/fnmol.2019.00043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zerem A, Haginoya K, Lev D, Blumkin L, Kivity S, Linder I, Shoubridge C, Palmer EE, Field M, Boyle J, Chitayat D, Gaillard WD, Kossoff EH, Willems M, Geneviève D, Tran-Mau-Them F, Epstein O, Heyman E, Dugan S, Masurel-Paulet A, Piton A', Kleefstra T, Pfundt R, Sato R, Tzschach A, Matsumoto N, Saitsu H, Leshinsky-Silver E, Lerman-Sagie T (2016) The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia 57(11):1858–1869

    PubMed  Google Scholar 

  6. Wayhelova M, Oppelt J, Smetana J, Hladilkova E, Filkova H, Makaturova E, Nikolova P, Beharka R, Gaillyova R, Kuglik P (2019) Novel de novo frameshift variant in the ASXL3 gene in a child with microcephaly and global developmental delay. Mol Med Rep 20(1):505–512

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A (2019) VarSome: the human genomic variant search engine. Bioinformatics 35(11):1978–1980

    CAS  PubMed  Google Scholar 

  9. Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) Mutation Taster2: mutation prediction for deep-sequencing age. Nat Methods 11(4):361–362

    CAS  PubMed  Google Scholar 

  10. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A et al (2016) The Ensembl Variant Effect Predictor. Genome Biol 17(1):122. https://doi.org/10.1186/s13059-016-0974-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Coban-Akdemir Z, White JJ, Song X, Jhangiani SN, Faith JM, Gambin T, Bayram Y, Chinn IK, Karaca E, Punetha J et al (2018) Identifying genes whose mutant transcripts cause dominant disease traits by potential gain-of-function alleles. Am J Hum Genet 103(2):171–187

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lindeboom RGH, Vermeulen M, Lehner B, Supek F (2019) The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat Genet 51(11):1645–1651

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51(6):1229–1239

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG (2011) Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease. Clin Genet 79(2):176–182

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kanaan SB, Onat OE, Balandraud N, Martin GV, Nelson JL, Azzouz DF, Auger I, Arnoux F, Martin M, Roudier J, Ozcelik T, Lambert NC (2016) Evaluation of X chromosome inactivation with respect to HLA genetic susceptibility in rheumatoid arthritis and systemic sclerosis. PLos One 11(6):e0158550. https://doi.org/10.1371/journal.pone.0158550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E et al (2015) 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 17(5):405–424

    PubMed  PubMed Central  Google Scholar 

  17. Shoubridge C, Tarpey PS, Abidi F, Ramsden SL, Rujirabanjerd S, Murphy JA, Boyle J, Shaw M, Gardner A, Proos A, Puusepp H, Raymond FL, Schwartz CE, Stevenson RE, Turner G, Field M, Walikonis RS, Harvey RJ, Hackett A, Futreal PA, Stratton MR, Gécz J (2010) Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat Genet 42(6):486–468

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mignot C, McMahon AC, Bar C, Campeau PM, Davidson C, Buratti J, Nava C, Jacquemont ML, Tallot M, Milh M et al (2019) IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients. Genet Med 21(4):837–849

    CAS  PubMed  Google Scholar 

  19. Kalscheuer VM, James VM, Himelright ML, Long P, Oegema R, Jensen C, Bienek M, Hu H, Haas SA, Topf M, Hoogeboom AJM, Harvey K, Walikonis R, Harvey RJ (2016) Novel missense mutation A789V in IQSEC2 underlies X-linked intellectual disability in the MRX78 family. Front Mol Neurosci 8:85. https://doi.org/10.3389/fnmol.2015.00085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hinze SJ, Jackson MR, Lie S, Jolly L, Field M, Barry SC, Harvey RJ, Shoubridge C (2017) Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphology. Transl Psychiatry 7(5):e1110. https://doi.org/10.1038/tp.2017.81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Levy NS, Umanah GKE, Rogers EJ, Jada R, Lache O, Levy AP (2019) IQSEC2-associated intellectual disability and autism. Int J Mol Sci 20(12):E3038. https://doi.org/10.3390/ijms20123038

    Article  CAS  PubMed  Google Scholar 

  22. Ewans LJ, Field M, Zhu Y, Turner G, Leffler M, Dinger ME, Cowley MJ, Buckley MF, Scheffer IE, Jackson MR, Roscioli T, Shoubridge C (2017) Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy. Eur J Hum Genet 25(6):763–767

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lindeboom RG, Supek F, Lehner B (2016) The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet 48(10):1112–1118

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kurosaki T, Maquat LE (2016) Nonsense-mediated mRNA decay in humans at a glance. J Cell Sci 129(3):461–467

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Radley JA, O’Sullivan RBG, Turton SE, Cox H, Vogt J, Morton J, Jones E, Smithson S, Lachlan K, Rankin J et al (2019) Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype. Clin Genet 95(4):496–506

    CAS  PubMed  Google Scholar 

  26. Bittel DC, Theodoro MF, Kibiryeva N, Fischer W, Talebizadeh Z, Butler MG (2008) Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet 45(5):309–313

    CAS  PubMed  Google Scholar 

  27. Li G, Zhang Z, Jin T, Liang H, Tu Y, Gong L, Chen Z, Gao G (2013) High frequency of the X-chromosome inactivation in young female patients with high-grade glioma. Diagn Pathol 8:101. https://doi.org/10.1186/1746-1596-8-101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Szelinger S, Malenica I, Corneveaux JJ, Siniard AL, Kurdoglu AA, Ramsey KM, Schrauwen I, Trent JM, Narayanan V, Huentelman MJ, Craig DW (2014) Characterization of X chromosome inactivation using integrated analysis of whole-exome and mRNA sequencing. PLoS One 9(12):e113036. https://doi.org/10.1371/journal.pone.0113036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wong CC, Caspi A, Williams B, Houts R, Craig IW, Mill J (2011) A longitudinal twin study of skewed X-chromosome inactivation. PLoS One 6(3):e17873. https://doi.org/10.1371/journal.pone.0017873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hatakeyama C, Anderson CL, Beever CL, Penaherrera MS, Brown CJ, Robinson WP (2004) The dynamics of X-inactivation skewing as women age. Clin Genet 66(4):327–332

    CAS  PubMed  Google Scholar 

  31. Van den Veyver IB (2001) Skewed X inactivation in X-linked disorders. Semin Reprod Med 19(2):183–191

    PubMed  Google Scholar 

  32. Shvetsova E, Sofronova A, Monajemi R, Gagalova K, Draisma HHM, White SJ, Santen GWE, Chuva de Sousa Lopes SM, Heijmans BT, van Meurs J et al (2019) Skewed X-inactivation is common in the general female population. Eur J Hum Genet 27(3):455–465

    CAS  PubMed  Google Scholar 

  33. Barrie ES, Cottrell CE, Gastier-Foster J, Hickey SE, Patel AD, Santoro SL, Alfaro MP (2020) Genotype-phenotype correlation: inheritance and variant-type infer pathogenicity in IQSEC2 gene. Eur J Med Genet 63(3):103735. https://doi.org/10.1016/j.ejmg.2019.103735

    Article  PubMed  Google Scholar 

  34. Anderson CL, Brown CJ (1999) Polymorphic X-chromosome inactivation of the human TIMP1 gene. Am J Hum Genet 65(3):699–708

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Happ HC, Carvill GL (2020) A 2020 view on the genetics of developmental and epileptic encephalopathies. Epilepsy Curr 20:90–96. https://doi.org/10.1177/1535759720906118

    Article  PubMed  PubMed Central  Google Scholar 

  36. Epi4K Consortium (2016) De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet 99(2):287–298

    Google Scholar 

  37. Tukiainen R, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, Aguirre M, Gauthier L, Fleharty M, Kirby A et al (2017) Landscape of X chromosome inactivation across human tissues. Nature 550(7675):244–248

    PubMed  PubMed Central  Google Scholar 

  38. Peeters SB, Cotton AM, Brown CJ (2014) Variable escape from X-chromosome inactivation: identifying factors that tip the scales towards expression. Bioessays 36(8):746–756

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Cotton AM, Price EM, Jones MJ, Balaton BO, Kobor MS, Brown CJ (2015) Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation. Hum Mol Genet 24(6):1528–1539

    CAS  PubMed  Google Scholar 

  40. Toksoy G, Durmus H, Aghayev A, Bagirova G, Sevinc Rustemoglu B, Basaran S, Avci S, Karaman B, Parman Y, Altunoglu U, Yapici Z, Tekturk P, Deymeer F, Topaloglu H, Kayserili H, Oflazer-Serdaroglu P, Uyguner ZO (2019) Mutation spectrum of 260 dystrophinopathy patients from Turkey and important highlights for genetic counseling. Neuromuscul Disord 29(8):601–613

    CAS  PubMed  Google Scholar 

  41. Filippova GN, Cheng MK, Moore JM, Truong JP, Hu YJ, Nguyen DK, Tsuchiya KD, Disteche CM (2005) Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CPG methylation during early development. Dev Cell 8(1):31–42

    CAS  PubMed  Google Scholar 

  42. Dandulakis MG, Meganathan K, Kroll KL, Bonni A, Constantino JN (2016) Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research. J Neurodev Disord 8:22. https://doi.org/10.1186/s11689-016-9155-8

    Article  PubMed  PubMed Central  Google Scholar 

  43. Geens M, Chuva De Sousa Lopes SM (2017) X chromosome inactivation in human pluripotent stem cells as a model for human development: back to the drawing board? Hum Reprod Update 23(5):502–532

    Google Scholar 

  44. Bragança J, Lopes JA, Mendes-Silva L, Almeida Santos JM (2019) Induced pluripotent stem cells, a giant leap for mankind therapeutic applications. World J Stem Cells 11(7):421–430

    PubMed  PubMed Central  Google Scholar 

  45. Hymes J, Fleischhauer K, Wolf B (1995) Biotinylation of histones by human serum biotinidase: assessment of biotinyl-transferase activity in sera from normal individuals and children with biotinidase deficiency. Biochem Mol Med 56(1):76–83

    CAS  PubMed  Google Scholar 

  46. Küry S, Ramaekers V, Bézieau S, Wolf B (2016) Clinical utility gene card for: Biotinidase deficiency-update 2015. Eur J Hum Genet 24(7):3–5. https://doi.org/10.1038/ejhg.2015.246

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Core Facility Bioinformatics of CEITEC Masaryk University is gratefully acknowledged for obtaining of the scientific data presented in this paper. Computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided under the programme “Projects of Large Research, Development, and Innovations Infrastructures”. The authors are thankful to the family for its participation, and all physicians and medical staff providing the specialized medical examinations supporting and completing the diagnosis of our patients. This work greatly extends the poster presentation by the second author MR on AES 2019 Annual Meeting.

Funding

This work was supported by the grant of the Ministry of Health, Czech Republic, Conceptual Development of Research Organization (FNBr, 65269705); by the grant of the Faculty of Science, Masaryk University, Brno, Czech Republic (MUNI/A/1127/2019); and by the grant of the Ministry of Health, Czech Republic, Czech Health Research Council (NU20-07-00145).

Author information

Authors and Affiliations

  1. Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic

    Marketa Wayhelova, Vladimira Vallova, Hana Polackova & Petr Kuglik

  2. Department of Medical Genetics, University Hospital Brno, Brno, Czech Republic

    Marketa Wayhelova, Eva Hladilkova, Vladimira Vallova, Marcela Vilemova, Renata Gaillyova & Petr Kuglik

  3. Clinic of Children’s Neurology, University Hospital Brno, Brno, Czech Republic

    Michal Ryzí

  4. CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic

    Jan Oppelt

  5. Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic

    Lenka Krskova

Authors
  1. Marketa Wayhelova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michal Ryzí
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Oppelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eva Hladilkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vladimira Vallova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lenka Krskova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcela Vilemova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hana Polackova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renata Gaillyova
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Petr Kuglik
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. MW analyzed and interpreted the NGS data regarding the probands’ phenotypes using relevant literature, bioinformatics databases, and in silico tools. MW was a major contributor in writing the manuscript. MR provided specialized neurological examination and clinical data from the Clinic of Children’s Neurology. JO processed raw NGS data using advanced bioinformatics tools through a unique multistep pipeline. VV, EH, and HP participated in microarray and NGS data analyses and targeted Sanger sequencing analyses. LK performed X chromosome inactivation analysis. MV performed the cytogenetic analysis of karyotype. RG provided specialized genetic counselling for the probands and their family and interpreted the findings in the clinical context. PK contributed towards the interpretation of data and performed general scientific supervision and general critical revision of the manuscript.

Corresponding author

Correspondence to Petr Kuglik.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval was obtained from the Ethics Committee of the University Hospital Brno.

Informed Consent

Written institutional informed consent (University Hospital Brno, Czech Republic) was obtained from the parents of the patients before the procedure of genetic analyses. Our case report does not include any personal information leading to the identification of any participants.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 49 kb)

ESM 2

(PDF 62 kb)

ESM 3

(PDF 23 kb)

ESM 4

(XLSX 22 kb)

ESM 5

(PDF 206 kb)

ESM 6

(PDF 150 kb)

ESM 7

(XLSX 11 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wayhelova, M., Ryzí, M., Oppelt, J. et al. Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy. Neurogenetics 21, 269–278 (2020). https://doi.org/10.1007/s10048-020-00616-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-020-00616-3

Keywords

Search

Navigation