Reeval Segel1, Hilla Ben-Pazi2, Sharon Zeligson2, Aviva Fatal-Valevski2, Adi Aran2, Varda Gross-Tsur2, Nira Schneebaum-Sender2, Dorit Shmueli2, Dorit Lev2, Shira Perlberg2, Luba Blumkin2, Lisa Deutsch2, Ephrat Levy-Lahad2. 1. From the Medical Genetics Institute (R.S., S.Z., S.P., E.L.-L.) and Neuropediatric Unit (H.B.-P., A.A., V.G.-T.), Shaare Zedek Medical Center, Jerusalem; Pediatric Neurology Unit (A.F.-V., N.S.-S.), Dana Children's Hospital, Tel Aviv; Jerusalem Child Development Center (D.S.), Clalit, Jerusalem; Metabolic-Neurogenetic Clinic (D.L., L.B.), Wolfson Medical Center, Holon; and Biostatistical Consulting (L.D.), BioStats, Israel. reevals@szmc.org.il. 2. From the Medical Genetics Institute (R.S., S.Z., S.P., E.L.-L.) and Neuropediatric Unit (H.B.-P., A.A., V.G.-T.), Shaare Zedek Medical Center, Jerusalem; Pediatric Neurology Unit (A.F.-V., N.S.-S.), Dana Children's Hospital, Tel Aviv; Jerusalem Child Development Center (D.S.), Clalit, Jerusalem; Metabolic-Neurogenetic Clinic (D.L., L.B.), Wolfson Medical Center, Holon; and Biostatistical Consulting (L.D.), BioStats, Israel.
Abstract
OBJECTIVE: To determine the prevalence and characteristics of copy number variations (CNVs) in children with cerebral palsy (CP) of unknown etiology, comprising approximately 20% of the CP population. METHODS: Fifty-two participants (age 10.5 ± 7.8 years; Gross Motor Function Classification System scale 2.8 ± 1.3) with nonprogressive pyramidal and/or extrapyramidal signs since infancy and no identified etiology were enrolled. Individuals with evidence of acquired causes were excluded. Participants underwent neurologic and clinical genetic examinations before the genomic testing. Chromosomal microarray analysis to detect CNVs was performed using the Affymetrix platform. CNVs identified were classified as pathogenic, likely pathogenic, likely benign, or benign. Only pathogenic and likely pathogenic CNVs were defined as clinically significant. RESULTS: Thirty-nine CNVs were found in 25 of 52 participants (48%). Sixteen participants (31%) had clinically significant CNVs: 10 pathogenic and 6 likely pathogenic, of which 7 were not previously associated with motor disability. Nine participants had likely benign CNVs. Clinically significant CNVs were more frequently de novo (12/16; p < 0.001) including in 5 of 8 individuals who had a first- or second-degree relative with a major neurologic disorder. Dysmorphic features and nonmotor comorbidities were more prevalent in individuals with clinically significant CNVs (p < 0.05 for both). CONCLUSION: CNVs, most frequently de novo, are common in individuals with cryptogenic CP. We recommend CNV testing in individuals with CP of unknown etiology.
OBJECTIVE: To determine the prevalence and characteristics of copy number variations (CNVs) in children with cerebral palsy (CP) of unknown etiology, comprising approximately 20% of the CP population. METHODS: Fifty-two participants (age 10.5 ± 7.8 years; Gross Motor Function Classification System scale 2.8 ± 1.3) with nonprogressive pyramidal and/or extrapyramidal signs since infancy and no identified etiology were enrolled. Individuals with evidence of acquired causes were excluded. Participants underwent neurologic and clinical genetic examinations before the genomic testing. Chromosomal microarray analysis to detect CNVs was performed using the Affymetrix platform. CNVs identified were classified as pathogenic, likely pathogenic, likely benign, or benign. Only pathogenic and likely pathogenic CNVs were defined as clinically significant. RESULTS: Thirty-nine CNVs were found in 25 of 52 participants (48%). Sixteen participants (31%) had clinically significant CNVs: 10 pathogenic and 6 likely pathogenic, of which 7 were not previously associated with motor disability. Nine participants had likely benign CNVs. Clinically significant CNVs were more frequently de novo (12/16; p < 0.001) including in 5 of 8 individuals who had a first- or second-degree relative with a major neurologic disorder. Dysmorphic features and nonmotor comorbidities were more prevalent in individuals with clinically significant CNVs (p < 0.05 for both). CONCLUSION: CNVs, most frequently de novo, are common in individuals with cryptogenic CP. We recommend CNV testing in individuals with CP of unknown etiology.
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