Rare copy number variation in cerebral palsy

Abstract

Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (o1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in o0.1% (o8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.

Cerebral palsy: causes, pathways, and the role of genetic variants

“…Currently the combination of 14% of cases with individually likely pathogenic point mutations found by WES and 20-31% with CNVs of interest gives a potential genetic contribution to causation in up to 34-45% of cerebral palsy cases. This new study also reinforces the conclusions of previous CNV56 and WES 12 studies suggesting considerable genetic heterogeneity of cerebral palsy.Sophisticated functional studies are required to validate genetic findings. Plethora of approaches using either in silico tools, animal models like zebrafish, fruit fly or mice or stem cells (i.e.…”

“…Contribution of the dosage imbalances or copy number variants (CNVs) is yet to be fully assessed. Ten out of 50 singleton cerebral palsy cases had potentially relevant CNVs in our pilot study 56 . However, all these CNVs were inherited from a healthy parent suggesting another genetic or environmental contributing factor.…”

Cerebral palsy, epilepsy, and severe intellectual disability in a patient with 3q29 microduplication syndrome

“…Cerebral palsy (CP) has been occasionally described in patients with microdeletion [Peredo et al, 2013;Zahanova et al, 2012] and microduplication syndromes [Degerliyurt et al, 2012]. A recent study of 50 cases with CP revealed the presence of rare copy number variants (CNVs) of potential relevance to CP [McMichael et al, 2014]. Accordingly, rare CNVs with probable causative roles have been identified in up to 19% of patients with Lennox-Gastaut syndrome, a severe epileptic encephalopathy [Lund et al, 2013]; thus, a-CGH has been suggested as the first-line genetic analysis for West syndrome [Hansen et al, 2012].…”

The genetic basis of cerebral palsy

“…[20][21][22] CNV analysis may be diagnostically and prognostically valuable in clinical settings, and CNV studies of CP cohorts have already been instructive by implicating genes relevant to CP neurobiology within the genomic interval that has been duplicated or deleted. [20][21][22] CNV analysis may be diagnostically and prognostically valuable in clinical settings, and CNV studies of CP cohorts have already been instructive by implicating genes relevant to CP neurobiology within the genomic interval that has been duplicated or deleted.…”