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Neurogenetics
Original research
Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy
  1. Michal Yechieli1,
  2. Suleyman Gulsuner2,
  3. Hilla Ben-Pazi3,4,
  4. Aviva Fattal5,6,
  5. Adi Aran3,4,
  6. Alla Kuzminsky7,
  7. Liora Sagi5,6,
  8. Dafna Guttman8,
  9. Nira Schneebaum Sender5,6,
  10. Varda Gross-Tsur4,9,
  11. Tehila Klopstock4,10,
  12. Tom Walsh2,
  13. Paul Renbaum10,
  14. Sharon Zeligson10,
  15. Lilach Shemer Meiri11,
  16. Dorit Lev6,12,
  17. Dorit Shmueli13,
  18. Luba Blumkin6,14,
  19. Amnon Lahad15,16,
  20. Mary-Claire King2,
  21. Ephrat Lahad Levy4,10,
  22. Reeval Segel4,10
  1. 1 Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel
  2. 2 Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, Washington, USA
  3. 3 Pediatric Neurology, Shaare Zedek Medical Center, Jerusalem, Israel
  4. 4 Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
  5. 5 Pediatric Neurology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
  6. 6 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  7. 7 Pediatric Neurology Institute, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
  8. 8 Pediatric Rehabilitation Department, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  9. 9 Pediatric Neurology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
  10. 10 Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel
  11. 11 Pediatric Neurology unit, Carmel Hospital, Haifa, Israel
  12. 12 Institute of Medical Genetics, Edith Wolfson Medical Center, Holon, Israel
  13. 13 Child Development Services, Clalit Health Services, Tel Aviv, Israel
  14. 14 Pediatric Neurology, Edith Wolfson Hospital, Holon, Israel
  15. 15 Braun School of Public Health, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
  16. 16 Department of Family Medicine, Clalit Health Services, Jerusalem, Israel
  1. Correspondence to Dr Reeval Segel, Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Jerusalem, Israel; reevals{at}szmc.org.il

Abstract

Objective To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).

Methods Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.

Results Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3.

Conclusions Cryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

  • central nervous system diseases
  • comparative genomic hybridisation
  • genetics
  • medical
  • genetic testing
  • movement disorders

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The authors declare that the data supporting the findings of this study are available within the paper. The remainder of the data are available from the corresponding author on request, consistent with institutional review board requirements.

https://doi.org/10.1136/jmedgenet-2021-107884

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    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The authors declare that the data supporting the findings of this study are available within the paper. The remainder of the data are available from the corresponding author on request, consistent with institutional review board requirements.

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    Footnotes

    • Contributors MY, HB-P, M-CK, ELL, RS: design and conceptualised the study, analysed the data, drafted the manuscript for intellectual content. SG: major role in acquisition of data, analysed and interpreted the data, revised the manuscript for intellectual content. AF, AA, AK, LS, DG, NSS, VG-T, LSM, DL, DS, LB: major role in acquisition of data, revised/reviewed the MS. TK, PR, SZ: interpreted the data, revised the manuscript for intellectual content. TW: major role in acquisition of data, interpreted the data, revised the manuscript for intellectual content. AL: performed biostatistical review of results, revised/reviewed the MS.

    • Funding RS received research support from the Joint Research Fund of the Hebrew University of Jerusalem and Shaare Zedek Medical Center.

    • 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.