Cerebral palsy and clinically relevant copy number variations

Maryam Oskoui, Matthew J. Gazzellone, Bhooma Thiruvahindrapuram, Mehdi Zarrei, John Andersen, John Wei, Zhuozhi Wang, Richard F. Wintle, Christian R. Marshall, Ronald D. Cohn, Rosanna Weksberg, Dimitri J. Stavropoulos, Darcy Fehlings, Michael I. Shevell,  Stephen W. Scherer.  Clinically relevant copy number variations detected in cerebral palsy.  Nature Communications.  Published 03 August 2015.

Abstract

Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (~1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families.

From the article: 

Taken together, there is a surge of new CNV data, and sequencing results that suggests a genomic basis for CP needs to be considered. In our systematic study, we determined a 7.0% de novo CNV rate in a population-based CP cohort, and ~10% of the families studied carried clinically relevant CNVs that either explain the aetiologic basis of CP or possibly account for associated medical complications. The differences in our findings compared with other studies are likely due to the small samples sizes so far examined and different ascertainment strategies for CP, both being compounded by what appears to be a genetically heterogeneous disorder.

Notwithstanding these complexities, for the majority of families in Table 3, having the genetic data early would have enabled the recognition of a specific aetiology/diagnosis facilitating more accurate management, and counselling regarding recurrence risk. For example, case 13-026C was eventually clinically diagnosed with Angelman syndrome at age 5 years and had microarray analysis been performed earlier, his family would have received more accurate information about the natural history of his diagnosis (there is minimal, if any, speech development in Angelman syndrome). Similarly, in cases 4-13C, 10-032C and 10-012C carrying large CNVs aetiologic for the CP, a more accurate attribution of cause and genetic counselling would have ensued. In our experience, the remaining seven CP cases in Table 3 would also have been seen in clinical genetics and directed to the appropriate specialist.

Importantly, finding another primary diagnosis (for example, microarray-based detection of chromosomal abnormalities and Wolf–Hirschhorn syndrome in 10-032C) does not negate a diagnosis of CP. A complete understanding of the effects of genotypes and environmental stressors on the clinical presentation(s) and manifestations of CP will require larger studies. In light of our new findings, however, we recommend that genomic analyses, in particular, high-resolution microarrays as a first tier and ultimately whole-genome sequencing, be integrated into the standard of practice for diagnosis and clinical categorization of CP.

See:  http://www.theglobeandmail.com/news/national/cerebral-palsy-may-have-genetic-causes-canadian-study-suggests/article25815886/
Courtesy of: http://www.foxnews.com/health/2015/08/04/shocking-study-alters-understanding-cerebral-palsy/