Genetic and Genomic Insights Into Cerebral Palsy: Relevance for Precision Diagnosis and Personalised Outcomes
Dhavendra Kumar, Divya AgarwalIntroduction:
Cerebral palsy (CP) is a debilitating heterogeneous clinical condition manifesting with non-progressive neurodevelopmental difficulties of posture and movement. Multiple causes are associated with the onset of CP, all directly or indirectly linked with the structural and/or functional damage to the developing brain. The majority of the causes are acquired during or soon after childbirth, notably hypoxic-ischaemic encephalopathy. However, over several decades, evidence has accumulated for pre-conceptional (genetic and genomic), prenatal factors (post-conceptional foetal development) and maternal factors associated with CP. Genetic and genomic factors include pathogenic changes in specific genes or genome-wide sequence variation.
Aim and Objectives:
This review is presented with the sole aim and objectives to appraise paediatricians, developmental paediatricians, paediatric neurologists and all other healthcare providers about the potential inherited and genetic causative factors either causally associated with or predisposing to non-genetic or acquired factors, particularly resulting in diminished blood supply.
Methods:
This review is based on the personal experience of the authors as paediatricians and clinical geneticists. Extensive research has been carried out through published research reports and meta-analyses. All publications (see list of references) were selected from PubMed, Google Scholar and other medical databases.
Results:
Applications of next-generation genome sequencing techniques have revealed copy number variations, single nucleotide polymorphisms and sequence changes at specific genetic loci. Some of these genomic changes associated with CP are heritable and recognisable as a rare genetic disorder or syndrome. Advances in genetic and genomic laboratory diagnosis, particularly the next-generation sequencing-based multi-gene panel, whole exome sequencing, and whole genome sequencing, now offer an opportunity for precision molecular diagnosis.
Conclusion:
There is now a major paradigm shift from investigating a child with CP with a large battery of investigations to single genomic analysis. This approach saves time and resources and facilitates specific diagnostic interventions, targeted personalised treatment, focused multi-disciplinary care, genetic counselling and options for parental reproductive decisions.