The genomics of cerebral palsy : are copy number variants associated with cerebral palsy?

Background Cerebral palsy describes a group of permanent disorders of the development of movement and posture that are attributed to non-progressive disturbances occurring in the developing fetal or infant brain. It is often accompanied by additional features including intellectual disability, autism, epilepsy and visual and hearing impairment. The overall incidence of cerebral palsy has not changed in the last 50 years despite major improvements in perinatal medicine, and remains at around 2- 2.5/1,000 deliveries world-wide. Treatment is symptomatic rather than curative. A child under 18 years of age is three times more likely to be diagnosed with cerebral palsy than cancer. There are major social, economic and quality of life issues for both the child with cerebral palsy and their family. In Australia, approximately 600 children are diagnosed with cerebral palsy each year. Several studies have suggested that genetic susceptibility factors and adverse environmental triggers such as perinatal viral infection can act both independently and in combination to contribute to the neuropathology of cerebral palsy. For the majority of cases the exact determinants responsible for injury to the child’s developing brain have not been defined. This thesis hypothesises that cerebral palsy is genetically highly heterogeneous and caused by many diverse and individually rare mutations of large effect in genes involving brain development, the most common of which are copy number variants (CNVs). Study design To explore the hypothesis that CNVs contribute to the aetiology of cerebral palsy, 50 DNA samples from individuals with cerebral palsy were tested on a custom-designed 180K chromosomal microarray with targeted plus whole genome coverage. The targeted coverage includes known clinically relevant regions such as microdeletion/duplication syndromes, telomeres and centromeres at a resolution of ~20-50 kb plus exon-level coverage of >1200 genes involved in neurodevelopmental disorders. The whole-genome backbone results in a resolution in unique DNA of ~225kb. These same samples were also separately assessed on a 135K custom designed array with targeted coverage of ~50kb in all genomic hotspots and backbone coverage of 350kb. Combined results were compared with 8,329 adult controls with no known neurological disorders. Results Three out of 50 cases were identified with a CNV that included candidate genes of special interest for the cerebral palsy phenotype; CTNND2 (446 kb duplication including the first exon), MCPH1 (219 kb duplication including exons 1-8) and COPS (4 kb deletion including exons 6-8). All three CNVs were shown to be inherited from an unaffected parent. Several additional CNVs of possible interest to the cerebral palsy phenotype were selected from 30 out of 50 cases, including the above three mentioned cases, as they encompassed genes expressed in the brain or were previously recognized in other neurodevelopmental disorders. These included Histone Cluster genes, 7q21 and 12p12.1p12.2, single-gene CNVs across CNTNAP3, MC2R, FSCB, PTCHD3, NPHP1 and TARP and intragenic CNVs in DLGAP2, PARK2, NBEA, PAK2, MACROD2, CNTN1, MPV17L, NF1, NCOR2, NOS3, SH3G13 and TBX1. Conclusion Copy number changes in cerebral palsy cases have been identified in this largest study to date. Amongst 50 cases there were three potential candidate genes for cerebral palsy and several additional variants involved in brain developmental genes. The pathogenicity of these rare CNVs is not currently resolved but these preliminary studies justify further evaluation of CNVs in a larger cohort of cerebral palsy families and functional studies. This is currently underway.Thesis (M.Med.Sc.) -- University of Adelaide, School of Paediatrics & Reproductive Health, 2011