Article Text
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.
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- 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.
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.
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