Cerebral Palsy Research Group publications

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Browsing Cerebral Palsy Research Group publications by Author "Gecz, J."

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    NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy
    (Editions Scientifiques Medicales Elsevier, 2013) McMichael, G.; Haan, E.; Gardner, A.; Yap, T.; Thompson, S.; Ouvrier, R.; Dale, R.; Gecz, J.; MacLennan, A.; Robinson Institute
    Benign hereditary chorea caused by mutations in the NK2 homeobox 1 gene (NKX2-1), shares clinical features with ataxic and dyskinetic cerebral palsy (CP), resulting in the possibility of misdiagnosis. A father and his two children were considered to have ataxic CP until a possible diagnosis of benign familial chorea was made in the children in early teenage. The father's neurological condition had not been appreciated prior to examination of the affected son. Whole exome sequencing of blood derived DNA and bioinformatics analysis were performed. A 7 bp deletion in exon 1 of NKX2-1, resulting in a frame shift and creation of a premature termination codon, was identified in all affected individuals. Screening of 60 unrelated individuals with a diagnosis of dyskinetic or ataxic CP did not identify NKX2-1 mutations. BHC can be confused with ataxic and dyskinetic CP. Occasionally these children have a mutation in NKX2-1.
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    Rare copy number variation in cerebral palsy
    (Nature Publishing Group, 2013) McMichael, G.; Girirajan, S.; Moreno-De-Luca, A.; Gecz, J.; Shard, C.; Nguyen, L.; Nicholl, J.; Gibson, C.; Haan, E.; Eichler, E.; Martin, C.; MacLennan, A.
    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 (<1% 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 <0.1% (<8/8329) 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.
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    ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity
    (Univ Chicago Press, 2013) Hirata, H.; McMichael, G.; Haan, E.; MacLennan, A.; Yap, T.; Nguyen, L.; Shaw, M.; Gecz, J.
    Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.