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Neurogenetics
Original research
Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals
  1. Lottie D. Morison1,2,
  2. Milou G.P. Kennis3,
  3. Dmitrijs Rots4,
  4. Arianne Bouman3,
  5. Joost Kummeling3,
  6. Elizabeth Palmer5,6,
  7. Adam P. Vogel2,7,
  8. Frederique Liegeois8,
  9. Amanda Brignell9,10,
  10. Siddharth Srivastava11,
  11. Zoe Frazier11,
  12. Di Milnes12,
  13. Himanshu Goel13,
  14. David J. Amor1,14,
  15. Ingrid E. Scheffer15,16,
  16. Tjitske Kleefstra3,4,
  17. Angela T. Morgan1,2
  1. 1 Speech and Language, Murdoch Children's Research Institute, Parkville, Victoria, Australia
  2. 2 Department of Audiology and Speech Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  3. 3 Department of Clinical Genetics, Radboudumc, Nijmegen, Netherlands
  4. 4 Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
  5. 5 Sydney Children’s Hospital Network, Randwick, New South Wales, Australia
  6. 6 Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
  7. 7 Redenlab, Melbourne, Victoria, Australia
  8. 8 Great Ormond Street Institute of Child Health, University College London, London, UK
  9. 9 Department of Paediatrics, Monash University, Clayton, Victoria, Australia
  10. 10 Department of Developmental Paediatrics, Monash Children’s Hospital, Clayton, Victoria, Australia
  11. 11 Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts, USA
  12. 12 Genetic Health Queensland, Herston, Queensland, Australia
  13. 13 Hunter Genetics, Waratah, New South Wales, Australia
  14. 14 Department of Paediatrics, Royal Children's Hospital, Parkville, Victoria, Australia
  15. 15 Melbourne Brain Centre, Austin Health, Heidelberg, Victoria, Australia
  16. 16 The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
  1. Correspondence to Professor Angela T. Morgan, Speech and Language, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; angela.morgan{at}mcri.edu.au

Abstract

Objectives Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome.

Method 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1–43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained.

Results The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression.

Conclusions The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.

  • Phenotype
  • Neurology
  • Genetics, Behavioral
  • Human Genetics
  • Pediatrics

Data availability statement

Data are available upon reasonable request. The data from this study are available upon reasonable request to the corresponding author.

https://doi.org/10.1136/jmg-2023-109702

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    Data availability statement

    Data are available upon reasonable request. The data from this study are available upon reasonable request to the corresponding author.

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    Footnotes

    • TK and ATM are joint senior authors.

    • X @MCRI_SpeechLang

    • Contributors Conceptualisation: TK, ATM, LDM. Data curation: LDM, ATM. Formal analysis: LDM, DR, APV, DJA. Funding acquisition: ATM, TK, LDM, APV, SS. Investigation: LDM. Methodology: ATM, LDM, MGPK, APV, FL, ABr, TK, IES. Project administration: LDM, ATM. Resources: LDM, TK, ATM, MGPK, ABo, JK, EP, FL, SS, ZF, DM, HG. Software: APV. Supervision: IES, ATM. Visualisation: LDM. Writing the manuscript: LDM, IES, ATM. Review and editing the manuscript: LDM, ATM, TK, IES, MGPK, DR, ABo, JK, EP, APV, FL, ABr, SS, ZF, DM, HG, DJA, Guarantor: ATM.

    • Funding Funding was provided by the National Health and Medical Research Council (NHMRC) Practitioner Fellowship (1105008; ATM); NHMRC Investigator Grant (1195955; ATM); NHMRC Centre of Research Excellence Translational Centre for Speech Disorders (2015727; ATM); Dutch Research Council Grant (015.014.036 and 1160.18.320; TK); the Netherlands Organisation for Health Research and Development (91718310 and 10250022110003; TK); NHMRC Postgraduate Scholarship (2022156; LDM); Australian Research Council Future Fellowship (220100253; AV); and the National Institutes of Health/National Institutes of Neurological Disorders and Stroke (K23NS119666; SS). This work was supported by the Victorian Government’s Operational Infrastructure Support Program.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.