Cerebral Palsy
& Genomics

About CP

Cerebral palsy (CP) describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occur in the developing fetal of infant brain1

“There are currently 17 million
people in the world who have
cerebral palsy.”

“Worldwide the incidence of
cerebral palsy is 1 in 500 births”

Cerebral palsy affects people in different ways and can affect body movement, muscle control, muscle coordination, muscle tone, reflex, posture and balance. Cerebral palsy is a permanent life-long condition, although some of these signs of cerebral palsy can improve or worsen over time.

People who have cerebral palsy may also have visual, hearing, communicating, intellectual, behavioural and epileptic impairments.

Worldwide, the incidence of cerebral palsy is 1 in 500 births. There are currently 17 million people in the world who have CP.

There is no single cause of cerebral palsy and for most babies born with cerebral palsy, the cause remains unknown. Researchers now know that only a very small percentage of cases of CP are due to complications at birth (e.g. asphyxia or lack of oxygen). The majority of cases (85-90%) are congenital, meaning that the individual is born with CP.

There are a number of risk factors for CP, however, there is a tremendous degree of variability in outcome in the presence of these risk factors, suggesting that some individuals may have an intrinsic higher susceptibility to CP. The reasons for this are not yet well understood.

Some of the risk factors for CP are:

Low birth weight (small for gestational age)

Premature birth (less than 37 weeks)

Congenital malformations

Multiple births

Infection during pregnancy

Some of the risk factors for CP are:

Fetal growth restriction

RH or A-B-O blood type incompatibility

Birth complications

Injury

For more information about CP and its causes, please visit your local CP organisation’s webpages

Australia

Canada

United States of America

New Zealand

United States of America

About Genomics

Genomics is the study of genomes. It is a branch of biology that is concerned with the structure, function, evolution and mapping of genomes. This also can include all the different types of tools and technologies, such as sequencing machines that researchers use to learn about the genome.

Genome

You can think of your genome as the blueprint or instructions that guides your cells and their machinery on how to make you, run you and repair you. It is written in a chemical code called DNA.

Inside your cell, your genome is packaged into structures called chromosomes. In humans, we have a total of 23 pairs of chromosomes that contain all of your genomic information. Half of this information comes from your mother and the other half of the information comes from your father.

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Gene

The human genome is made up of around 20,000 genes. Genes are the instructions for making the proteins that play many critical roles in the body. Proteins do most of the work and are required for the structure, function and regulation of the body’s tissues and organs.  Genes make up about 1% of your genome. The rest of the DNA between the genes is called non-coding DNA. For a long time, this part of our genome wasn’t thought to be important at all. But we now know that the DNA between genes is important for regulating the genes and the genome. For example, it can switch genes on and off at the right time, in the right cells.

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DNA

DNA (deoxyribonucleic acid) is the hereditary material of life. It is made up of four different chemicals – adenine (A), cytosine (C), guanine (G) and thymine (T) – commonly called bases. Human DNA consists of about 6 billion letters, and the order of your DNA, or sequence, determines the information for making you, running you and repairing you. Humans are 99.9% similar, but it is this 0.1% that makes you unique.

What kind of changes do we see in the genome?

There are a few different types of changes that we can see in a genome, but first it is important to understand that not all changes to a genome are bad. In fact, many of the changes in a person’s genome is what makes them unique, and some of these changes can be inherited or can occur spontaneously during development, which scientists refer to as de novo.

Why do we want to sequence and read your genome?

Every human genome contains thousands of differences from the reference genome – these are called variants. They can affect a single nucleotide or large sections of DNA. They can be inherited from your parents, or be unique spontaneous changes. Much of the variation in our genome is normal, but some changes can result in disease, an increased susceptibility to infection, or inform doctors about the best source of treatment. Therefore, for scientists to learn more about the role of the genome in CP, and whether a variant is causative, we need to sequence as many people as possible and compare these genomes to see if any patterns arise.

How do we sequence your genome?

In order for scientists to interpret your genome they first require a biological sample. Once your biological sample has been received at the laboratory, your DNA will be extracted and stored in a biobank (a library for biological samples).

The next step is for your DNA sample to be sequenced. There are many different methods and machines that can sequence genomes; however, no machine can sequence a whole genome in one go. Instead DNA is sequenced in short pieces, around 150 letters long. Each of these short pieces of your genome are loaded onto a sequencing machine, which reads your genome and reports it as a series of A’s, C’s, T’s and G’s. Scientists don’t know which order these fragments are read in, so a very big task that scientists need to do after the machine has read your genome is to put it back together.

You can think of this like putting together a jigsaw puzzle. Luckily for scientists they have a reference genome that can help with piecing this puzzle back together. When all the pieces are put together, you have a complete genome. Once these three steps are complete, scientists can then look at your genome and compare it to thousands of others to try and understand the role of the genome in CP.

CP & Genomics

Genetic causes of CP have been suspected due to:

  • The associations with congenital anomalies;
  • The increased risk in consanguineous families, families with an affected singleton, and monozygotic twins;
  • That some other neurodevelopmental or motor disorders are single-gene, rare Mendelian disorders; and
  • That many of the risk factors associated with CP (such as, prematurity, preeclampsia, and IUGR) have genetic underpinnings.

Early genetic studies looked at familial forms of CP, and somewhat surprisingly, the genetic variants identified were not involved in inflammation or thrombosis pathways, but rather neurodevelopment.

  • Adaptor protein complex-4 subunits (AP4B1, AP4E1, AP4M1 and AP4S1) are involved in neuronal polarity, and mutations have been independently identified in multiple families with autosomal recessive, spastic paraplegic-quadriplegic CP2-6.
  • Gamma adducin (ADD3) is involved in neuron connectivity, and mutations were identified in a consanguineous family with spastic diplegia-quadriplegia7 .
  • Glutamate decarboxylase (GAD) mutations result in reduced production of a neurotransmitter called gamma-aminobutyric acid (GABA). Mutations in GAD were identified in a family with autosomal recessive, spastic CP8-9. Treatment with targeted drugs to increase GABA have ameliorated rigidity and spasticity in individuals with these mutations.
  • KANK1 is involved in neuronal signalling and microdeletions have been identified in a four-generation family with spastic quadriplegia10.

There is growing evidence that supports a role for genetics in the development of CP beyond familial pedigrees. Recently, chromosomal microdeletions and microduplications, known as copy number variants (CNVs), have emerged as a cause of various neurodevelopmental disorders. CNVs have been reported in 10% to 25% of individuals with intellectual disability, autism and epilepsies. Furthermore, these changes in the DNA can be both spontaneous (de novo) as well as rare inherited changes.

  • In an Australian study11, CNVs were identified in 20% of CP participants.
  • In a Canadian study12, CNVs were identified in 9.6% of CP participants.
  • In an Israeli study13, CNVs were identified in 31% of idiopathic CP participants (no known cause of their CP).
  • In another Canadian study14, CNVs were identified in 26% of hemiplegia-CP participants.

Only a limited number of studies have utilized high-throughput whole exome sequencing technologies, yet these studies have shown that the underlying genetic contribution to CP is complex and diverse.

  • In an Australian study15, 14% of sporadic CP cases were identified as having potentially causative de novo or inherited single-gene mutations.
  • Three de novo single-gene mutations were identified in an ataxic CP cohort16
  • In an American pediatric neurology clinic17, a presumptive genetic diagnosis was identified in 32 out of 78 patients with assorted neurological disabilities. 34% of those diagnosed had CP, which highlights the importance of genetic testing in the absence of suggestive risk factors (i.e neonatal asphyxia or prematurity).

CP is a clinically diverse condition, in which no one person presents with the same condition. We are not saying that genetics is the only cause of CP, but it is a cause that we can readily define.

Genetics is not the only cause of CP, but it is a cause that we can readily define.

 

And as with research on other neurodevelopmental conditions, genetic insights have the potential to provide a context for understanding the pathways that lead to CP when they go awry. Not only is this important to enhance our knowledge base of CP neurobiology, but is paramount for counselling, surveillance, early detection and the possible development of targeted preventative and therapeutic strategies.

1 Rosenbaum et al. (2007). “A report: the definition and classification of cerebral palsy April 2006.” Developmental Medicine and Child Neurology Supplemental. 109:8-14

2 Abou Jamra et al. (2011). “Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.” American Journal of Human Genetics 88(6): 788.

3 Bauer et al. (2012). “Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47).” Neurogenetics 13(1): 73.

4 Moreno-De-Luca et al. (2011). “Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability.” Journal of Medical Genetics 48(2): 141-144.

5 Najmabadi et al. (2011). “Deep sequencing reveals 50 novel genes for recessive cognitive disorders”. Nature478(7367): 57.

6 Verkerk, A. J. M. H., et al. (2009). “Mutation in the AP4M1 Gene Provides a Model for Neuroaxonal Injury in Cerebral Palsy.” American Journal of Human Genetics 85(1): 40.

7 Kruer et al. (2013). “Mutations in γ adducin are associated with inherited cerebral palsy.” Annals of Neurology 74(6): 805.

8 Lynex et al. (2004). “Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders.” BMC Neurology 4(1): 20.

9 McHale et al. (1999). “A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25.” American Journal of Human Genetics 64(2): 526.

10 Lerer et al. (2005). “Deletion of the ANKRD15 gene at 9p24.3 causes parent-of-origin-dependent inheritance of familial cerebral palsy.” Human Molecular Genetics 14(24): 3911.

11 McMichael et al. (2014). Rare copy number variation in cerebral palsy. EJHG, 22:40-45

12 Oskoui, M., et al. (2015). “Clinically relevant copy number variations detected in cerebral palsy.” Nature communications 6: 7949.

13 Segel, R., et al. (2015). “Copy number variations in cryptogenic cerebral palsy.” Neurology 84(16): 1660-1668.

14 Zarrei, M., et al. (2017). “De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy.” Genetics in Medicine.

15 McMichael, G., et al. (2015). “Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.” Molecular Psychiatry 20(2): 176-182.

16 Schnekenberg, R. P., et al. (2015). “De novo point mutations in patients diagnosed with ataxic cerebral palsy.” Brain: A Journal of Neurology 138(Pt 7): 1817-1832.

17 Srivastava, S., et al. (2014). “Clinical whole exome sequencing in child neurology practice.” Annals of Neurology 76(4): 473-483.