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Redefining cerebral palsies as a

diverse group of neurodevelopmental
disorders with genetic aetiology
Clare L. van Eyk , Michael C. Fahey
1,2 3
& Jozef Gecz 1,2,4

Abstract Sections

Cerebral palsy is a clinical descriptor covering a diverse group of Introduction

permanent, non-degenerative disorders of motor function. Around Clinical diagnosis of cerebral

one-third of cases have now been shown to have an underlying palsy

genetic aetiology, with the genetic landscape overlapping with those What is genetic about cerebral
palsy?
of neurodevelopmental disorders including intellectual disability,
epilepsy, speech and language disorders and autism. Here we review Epigenetic and environmental
factors
the current state of genomic testing in cerebral palsy, highlighting the
Expanding phenotypes and
benefits for personalized medicine and the imperative to consider defining genotypes
aetiology during clinical diagnosis. With earlier clinical diagnosis now
Emerging mechanisms that
possible, we emphasize the opportunity for comprehensive and early underly genetic cerebral palsy
genomic testing as a crucial component of the routine diagnostic
Diagnoses of the undiagnosed
work-up in people with cerebral palsy.
Precision medicine and the
benefit of knowing

Conclusions

1
Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia. 2Robinson Research
Institute, The University of Adelaide, Adelaide, South Australia, Australia. 3Department of Paediatrics, Monash
University, Melbourne, Victoria, Australia. 4South Australian Health and Medical Research Institute, Adelaide,
South Australia, Australia. e-mail: [email protected]

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Key points Review, we discuss issues surrounding clinical diagnosis in the era of
genomics. We provide an overview of what is known about the expo-
nentially accumulating genetic causes of CP, and provide examples of
•• Currently, a clinical diagnosis of cerebral palsy (CP) is made on how this aetiological knowledge is now being used to design tailored
observation of signs and symptoms and does not consider aetiology care and precision medicine approaches for people with CP.
or pathology.
Clinical diagnosis of cerebral palsy
•• CP encompasses a clinically heterogeneous group of disorders — A historical perspective
together referred to as cerebral palsies — with at least one-third of As clinical diagnosis is made on the basis of signs and symptoms rather
cases having a genetic aetiology. than pathology or aetiology, CP incorporates a highly heterogeneous
group of movement and posture disorders. Like other NDDs, such as
•• CP has a high degree of genetic overlap with neurodevelopmental intellectual disability, epilepsy and ASDs, the causes of CP are diverse
disorders, such as intellectual disability, epilepsy and autism, and should and include both genetic and non-genetic aetiologies. To acknowledge
itself be considered, at least partly, a genetic neurodevelopmental the heterogeneity in type and degree of CP-associated disability and the
disorder. diversity of the underlying aetiologies, the collective term ‘cerebral
palsy spectrum disorder’ has been suggested4,5. The clinical definition
•• The presence of known cerebral palsy risk factors, such as of CP has been evolving over time; however, this evolution has not
prematurity and growth restriction, and the absence of other comorbid been as dynamic or proactive as in epilepsies, for example. The Inter-
neurodevelopmental phenotypes, including intellectual disability and national League Against Epilepsy 2017 Classification of the Epilepsies
epilepsy, do not rule out a genetic aetiology. incorporates aetiology in epilepsy classification, which has substantial
therapeutic implications6. As the current working definition7 (Box 1)
•• Diagnostic practice has not evolved with the fast-accumulating asserts that the defining features of CP are the permanence of the dis-
evidence for a genetic contribution to CP aetiology; the nomenclature order and the non-progressive nature of the causal brain damage or
for genetic cases and the circumstances under which a genetic abnormality, a clinical diagnosis of CP does not consider aetiology.
diagnosis should negate the CP clinical diagnosis lack consensus. Incorporating novel scientific evidence and thinking into the clini-
cal diagnosis of cerebral palsies could improve therapeutic options
•• An aetiology-driven diagnosis of CP involving a ‘genotype-first’ for many individuals living with CP. The International Cerebral Palsy
approach will bring tangible benefits to individuals with CP through Genomics Consortium was formed in 2017, in part, to address the incon-
precision medicine and improved clinical management. sistencies in diagnosis and classification of CP in comparison with
other NDDs (Fig. 1).
The current criteria for the clinical definition of CP require waiting
Introduction until the child is over 4 years of age before confirming the diagnosis7.
Cerebral palsy (CP) is a clinical descriptor rather than a distinct disorder, Although widely used by international CP registers, these criteria are
which encompasses a spectrum of non-degenerative movement disor- restrictive for use in clinical practice, where waiting until the age of
ders commonly accompanied by other neurodevelopmental disorders 4 years would preclude early and targeted interventions. Instead, CP is
(NDDs), including intellectual disability (~50%), epilepsy (~30%), speech typically diagnosed on the basis of clinical suspicion, which carries the
impairments (~60%), vision impairments (~40%) and autism spectrum risk of inconsistency owing to differences in specialty among clinicians
disorders (ASD) (~9%)1. Despite the knowledge that many of these CP making the diagnosis, and the known presence or absence of clinical
comorbidities have genetic determinants, genomic testing is currently risk factors and comorbidities8.
not part of the routine diagnostic work-up for CP in most health sys-
tems, partly owing to the continuing and pervasive misconception
that CP is always secondary to brain injury, trauma or prematurity.
Long-standing calls from epidemiologists for an aetiology-based clas-
sification system for CP2 have remained unanswered despite the obvi-
Box 1
ous benefits of this approach, partly owing to a lack of consensus on
the application of the CP clinical diagnosis itself. Cerebral palsy definition
Around 50% of people with CP have identifiable antenatal and
perinatal risk factors, and can be diagnosed as ‘at risk of CP’ at less than The main consensus criteria for cerebral palsy diagnosis7 as used by
5 months of age. The remaining 50%, who experience an uneventful cerebral palsy registers for surveillance are:
pregnancy and birth, are normally diagnosed at 5–24 months of age3. •• A disorder of movement or posture of central origin.
Early clinical diagnosis and CP-specific interventions have resulted in •• A disorder affecting motor function.
improvements to neuroplasticity and functional outcomes, reduced •• A non-progressive condition, although not necessarily
risk of complications and enhanced care-giver wellbeing3. Earlier clini- unchanging over the lifetime of an individual.
cal diagnosis offers an opportunity for earlier genetic and molecular •• A condition confirmed when the child is at least 4 years of age.
diagnosis, which can provide vast benefits including avoiding unnec- •• Where a chromosomal abnormality or syndrome is diagnosed,
essary and invasive investigations, enabling informed carrier testing the cerebral palsy diagnosis should remain if the child meets
and reproductive planning, providing prognostic information about all other consensus criteria, with the syndrome or genetic
future health needs, and in some cases, informing the use of targeted abnormality recorded.
treatments that can improve or reverse physical impairment. In this

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6th annual meeting,

3rd annual meeting, 5th annual meeting, Glasgow, Scotland,
Anaheim, USA, 4th annual meeting, Melbourne, Australia alongside the
2nd annual meeting, alongside AACPDM Toronto, Canada (virtual), alongside European Society
Zhengzhou, China and the IAACD (virtual) the AusACPDM of Human Genetics

2017 2018 2019 2020 2021 2022 2023

Formation of the ICPGC working groups: Publication of clinical Collaborative PanelApp Launch of CP Current ICPGC activities:
ICPGC (Adelaide, • Phenotype consensus statement genomic sequencing Australia CP Commons, a • Genomic data
Australia) • Bioinformatics on when to keep a CP publication gene panel v1.0 centralized resource aggregation through
• Functional genomics diagnosis where there (n = 250 trios)45 for storing clinical the CP Commons
are genetic findings21 and genomic data • Advancing the HPO
Publication reporting
for CP
Invitation for on preferences about
• Polygenic risk in CP
collaboration and genomics research of Publication of common
membership of people with CP and data elements to
ICPGC published117 their families129 standardize genomic
studies in CP10
ClinGen CP Gene
Curation Expert
Panel formed

Fig. 1 | Timeline of activities by the International Cerebral Palsy Genomics The ICPGC flagship CP Commons data portal was launched in 2022, providing
Consortium. The International Cerebral Palsy Genomics Consortium (ICPGC) a centralized resource for genomic and clinical data, and thereby enabling
is an international collaborative group formed in 2017 to pursue the common researchers to address the main outstanding questions in the field. AACPDM,
mission of accelerating progress in cerebral palsy genomic research. Through the American Academy for Cerebral Palsy and Developmental Medicine; AusACPDM,
Phenotype, Bioinformatics and Functional Genomics Working Groups, the ICPGC Australasian Academy of Cerebral Palsy and Developmental Medicine;
has focused on the key challenge of harmonizing clinical, genomic and functional CP, cerebral palsy; HPO, Human Phenotype Ontology; IAACD, International
data in cerebral palsy research, with a number of resulting publications10,21,45,117,129. Alliance of Academies of Childhood Disability.

Notable differences are also evident in how the clinical diagnosis developed, we have proposed, alongside other experts, that identify-
of CP is applied in the literature, which ranges from studies that limit ing a genetic aetiology should not preclude a clinical diagnosis of CP21.
inclusion to children with acquired static encephalopathy to those that This recommendation is in line with other NDDs, such as epilepsy6, in
include any child with a non-progressive movement disorder of central which the finding of a genetic aetiology does not negate the clinical
origin. Furthermore, genomic studies have typically not adequately diagnosis, but rather forms an integral part of disease classification
defined the criteria for inclusion9, adding further ambiguity to the field. and clinical management.
To address this issue, in 2022 the International Cerebral Palsy Genomics
Consortium Phenotype Working Group developed a set of common What is genetic about cerebral palsy?
data elements for genomic studies in CP10. In an approach known as The historical view that CP is a result of birth asphyxia has undoubtedly
reverse phenotyping, the presence of specific signs or symptoms is ret- hampered investigations into genetic or other causes of CP. Indeed,
rospectively assessed in children with a shared genetic diagnosis. Such the number of reports on genetic causes of CP in the literature are
analyses demonstrate that even children with the same highly clinically lagging behind those for other, often CP-comorbid, NDDs (Fig. 2a).
homogeneous genetic diagnosis (for example, a pathogenic variant in CP genomic studies have been primarily concentrated in high-income
the CTNNB1 gene) might be assessed differently among clinical services countries, particularly the USA, Canada, Israel and Australia, with lim-
or specialists, with some given a CP diagnosis and some not11. ited studies originating from low-income and middle-income countries
(LMICs) (Fig. 2b). Efforts such as the NESHIE (neonatal encephalopathy
Diagnosis in the era of genomics with suspected hypoxic–ischaemic encephalopathy) and CP Genet-
As the working diagnosis defines CP purely as an acquired motor disabil- ics Resource22 — a database of published genetic variants reported
ity, some clinicians advocate that a CP diagnosis should not be applied in individuals with CP and NESHIE — demonstrate a growing interest in
when a genetic aetiology has been identified8,12. In these instances, indi- assessing the genomic contribution to CP in LMICs where the rate of
viduals with genetic CP are sometimes referred to as ‘CP mimics’13–15 or NESHIE is high22.
‘CP masqueraders’16. The measurable paucity of terms relating to CP in Case reports describing genetic findings in individuals with
clinical genetics databases compared with other NDDs, such as intellec- a CP clinical diagnosis can be found in the literature as far back as
tual disability17, is therefore unsurprising. Earlier diagnosis and flagging the mid-1990s; however, the first studies reporting systematic
of ‘at risk’ infants is becoming more common3,18; growing evidence sup- genomic sequencing of people with CP were published in 2014–2015
ports the specificity and sensitivity of movement assessments19 to ena- (refs. 12,23–27). In 2020–2021, the number of genes identified with
ble earlier interventions3 and investigations into aetiology, including pathogenic variants in people with CP considerably increased, largely
genomics. Together, these factors will foreseeably result in falling rates driven by a single study in 1,526 individuals with CP, 1,345 of whom
of CP diagnosis, as genomic testing (Box 2) becomes more frequently were from a retrospective clinical laboratory referral cohort tested by
used and clinicians increasingly take a ‘genotype-first’20 approach to the commercial test provider GeneDx28 (Fig. 2a). Two meta-analyses
diagnosis. To ensure ongoing consistency with the use of CP as a clinical published in the past year have investigated the genetic diagnostic
diagnostic label until a new aetiology-inclusive classification of CP is yields for CP cohorts. The first study, including 2,419 individuals

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of small sample sizes and inconsistencies in reporting of clinical risk

Box 2 factors, studies of systematic gene–environment interactions have
not been conducted in CP. Systematic assessment of the frequency
and diversity of genetic causes across the cerebral palsies will require
Genomic testing — a primer larger, clinically unselected cohorts.
Fast-evolving evidence shows that monogenetic aetiologies asso-
•• Genomic testing is a term encompassing various technologies ciated with a clinical diagnosis of CP are highly heterogeneous. Our
used to identify genetic causes of human phenotypes. stocktake of the current literature identified more than 500 individual
•• Some technologies, such as gene panels, target specific genes genes with one or more predicted deleterious variants associated with
(usually on the basis of genotype–phenotype matching) and are CP, albeit with varying levels of supportive evidence. Application of
sometimes referred to as genetic tests. the PanelApp ‘traffic light’ criteria for gene–disease association41, for
•• Other technologies, such as exome or genome sequencing, example, identified 190 genes that were reported at least three times in
look at all known genes across the DNA of an individual or family. individuals with a clinical diagnosis of CP in the literature (see Supple-
Genome sequencing covers the whole genome, including mentary information). No single inheritance pattern was predominant
coding and non-coding regions of all genes and regions without amongst the genes identified so far (Fig. 2c); many examples of genes
known function; exome sequencing targets predominantly the associated with autosomal dominant inheritance, which mostly show
protein coding regions of genes — the exons. de novo variation in CP, have been reported, as well as X-linked and
•• Microarrays can also be used as a genomic test to assess an autosomal recessive inheritance patterns42. Further rare examples
individual’s DNA for larger genetic changes, such as gain or loss of somatic variants and mitochondrial inheritance have also been
of chromosome sections, or chromosome rearrangements, reported34,43. Identification of families likely to have a genetic aetiology
which can alter gene expression or function. for CP is complicated by the variation among inheritance patterns, as
most diagnoses will be the first in the family. This issue highlights the
importance of both broad genomic testing and appropriate genetic
counselling for families when a child is diagnosed with CP44. Because
across 15 study cohorts, found a 23% yield from exome sequencing familial CP rates are low, autosomal dominant forms are likely to be
(95% confidence interval (CI) 15–34%). A further 5% (95% CI 2–12%) under-represented in the existing list of recurrent CP genes, and rarer
diagnostic yield was gained from chromosomal microarray in five autosomal recessive forms could be over-represented. Similar to other
study cohorts including 294 individuals29. The second study, including NDDs, delineation of the full range of genetic causes of CP will require
2,612 individuals from 13 cohort studies in which exome or genome much larger cohorts, with a recent estimate of up to 7,500 trios being
sequencing only was performed, found an overall diagnostic yield of required to reach up to 91.8% saturation rate for de novo dominant
31.1% (95% CI 24.2–38.6%)30. These genetic diagnostic rates are derived causes in this mostly sporadic disorder45.
from CP cohorts from high-income countries, and therefore could be
considerably higher than in cohorts from LMICs, where the contribu- Epigenetic and environmental factors
tion of potentially preventable risk factors such as birth asphyxia and A growing number of examples of genetic variants in individuals with
neonatal infections is higher31 (Fig. 2b). CP show incomplete penetrance or variable expressivity within fami-
Most genomic studies in CP reported to date have focused on lies (Fig. 1d). For example, pathogenic variants in COL4A1/2, which
individuals with idiopathic or cryptogenic CP, in which no associated were reported in multiple CP cohorts28,33–35,46–48, are associated with
risk factors are present. This bias is partly owing to the majority of cerebrovascular disorders and are frequently inherited, with highly
cohorts being ‘convenience’ cohorts recruited through genetic or variable phenotypes even within the same family49–51. Thus, the vari-
neurology services that do not typically sequence children who have ants might represent a modifiable risk factor for CP. In line with this
other risk factors assumed to be the cause of their CP. Several studies assumption, to reduce the risk of haemorrhage, delivery by caesar-
have demonstrated an enrichment for genetic causes in individuals ean section is recommended for fetuses known to carry pathogenic
with one or a combination of other neurodevelopmental comorbidi- COL4A1/2 variants52. Furthermore, examples of monozygotic twins
ties, such as intellectual disability, epilepsy and ASD28,32. However, who are clinically discordant for CP and other NDDs despite having a
genetic causes have also been reported in individuals with a movement shared genetic cause53–56 further support the presence of modifying
disorder without additional features32–34, with a recent meta-analysis factors, including environmental and epigenetic factors.
showing that 17.6% of individuals with CP without intellectual disabil- X chromosome inactivation (XCI) variation in females is a prime
ity or developmental delay had a genetic diagnosis following exome example of an epigenetic modification that results in variable clinical
or genome sequencing30. Furthermore, several studies have found expressivity. XCI is the process during early female embryonic develop-
monogenetic causes of CP in individuals with another known CP risk ment by which one X chromosome in each cell is permanently inacti-
factor, such as prematurity, intrauterine growth restriction or intrac- vated, ensuring that genes are expressed at similar levels in XY males
ranial haemorrhage33–36; although the overall diagnostic yield has and XX females57. Given that XCI is a random process, most females are
been reported to be higher in cohorts with cryptogenic CP (42.1%) expected to have a relatively equal proportion of cells expressing each
compared with cohorts in which any individual meeting the clinical X chromosome. Deviation from this random inactivation pattern can
diagnostic criteria for CP is sequenced, regardless of their medical occur either purely owing to chance and the small pool of cells in the
history (20.7%)30. CP risk factors, including prematurity and intrau- embryo at the time of XCI or as a result of selective pressure driven by
terine growth restriction, have also been associated with maternal and a highly deleterious genetic change on one of the X chromosomes58.
fetal genetic contributions37–40, suggesting that these risk factors are Indeed, many X-linked disorders rarely or only mildly affect females,
themselves, in part, consequences of inborn genetic variation. Because as the number of cells expressing the functionally normal allele are

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generally sufficient to compensate. As females are cellular mosaics for antenatal events that persist after the original inductive event, many
X-linked variation, affected females can show a milder or even different of which have been identified as risk factors for CP, including twin-
clinical spectrum from affected males58, sometimes even resulting in a ning, congenital infection, preterm birth and intrauterine growth
female-specific disorder, as is the case of PCDH19 clustering epilepsy, restriction61–64. Some histone demethylases — KDM5A and KDM6A —
for example59. This effect can complicate the interpretation of genetic have been shown to be direct oxygen sensors, suggesting a mechanism
variation. that links in utero environment to persistent changes in epigenetic
Examples of X-linked genetic diagnoses in which CP can be a clini- profile and gene expression in the developing embryo65,66. In addition,
cal feature include KDM5C26, DDX3X28,60 and ARX28, with many affected in the past 5 years several studies have revealed distinct, identifiable
females presenting with atypical symptoms compared with males epigenetic signatures across a number of loci in genetic disorders such
with the same genetic disorder. Differences in the proportion of cells as Claes–Jensen syndrome, which results from pathogenic variation in
expressing the deleterious genetic variant are also thought to drive the epigenetic regulator KDM5C, or gene-specific DNA methylation
variable expressivity among affected females, a concept exemplified defects termed epi-variation, which result from underlying genetic
by clinical discordance observed between monozygotic twins with variation and affect gene expression67–71. Together, these observa-
X-linked disorders. A pair of female monozygotic twins described tions suggest that multiomics approaches, encompassing genomics,
in a 2021 publication provide an example of this phenomenon: the epigenomics and transcriptomics, have the potential to identify both
twins had a novel pathogenic ARX loss of function variant and both genetic and non-genetic aetiologies in CP and to aid our understanding
presented with epilepsy, intellectual disability and CP, but one twin had of the interplay among genetic and environmental factors in CP.
considerably more severe symptoms and presented with an atypical
choreoathetoid movement disorder56. Expanding phenotypes and defining genotypes
Epigenetic modifications to DNA, including DNA methylation, pro- From the available literature, we identified 190 recurrent CP genes,
vide a dynamic link between the genome and the environment. Several and of these, SPAST15,27,28,33–36,45,72–77, ATL1 (refs. 15,28,32,35,36,45,75–81),
studies support the presence of reproducible epigenetic ‘signatures’ of CACNA1A15,16,28,34,36,72,82, CTNNB1 (refs. 11,16,28,32,45,75), KCNQ2

a 1,500 b
Cumulative genes reported

Cohorts
1,000
5
4
3
500 2
1
NDD genes
CP genes
0
1980 1990 2000 2010 2020
Year

c Autosomal dominant, de novo Autosomal recessive X-linked, maternal

WT/WT WT/WT WT/VAR WT/VAR WT/Y WT/VAR

WT/WT WT/WT WT/VAR WT/WT WT/VAR VAR/VAR WT/WT WT/Y VAR/Y

e
d WT/WT WT/WT WT/WT WT/WT WT/VAR WT/WT

WT/WT WT/VAR WT/VAR WT/VAR WT/WT WT/WT WT/VAR

Fig. 2 | Genetic investigations in cerebral palsy cohorts. a, A literature review in many monozygotic twin pairs and can arise either from discordant genetic
demonstrated a measurable lag in reports of genetic causes of cerebral palsy variation arising after twinning (postzygotic variation, left pedigree), or from
(CP) compared with other neurodevelopmental disorders (NDD). b, Published the effect of other modifying factors (right pedigree). e, Incomplete penetrance
CP cohort genetic studies by country. c, Predominant inheritance patterns or intrafamilial phenotypic variability within families further support the role
described for monogenetic causes of CP are dominant largely de novo, of other modifying factors in determining clinical outcome. VAR, pathogenic
autosomal recessive and X-linked recessive. d, Clinical discordance is observed variant; WT, wild-type. NDD list generated from refs. 130,131 and SysNDD.

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(refs. 27,28,36,83,84), ATM15,33,72,85,86, PAFAH1B1/LIS1 (refs. 87,88), with recurrent CP genes, highlighting the difficulty in clinical differ-
COL4A1 (refs. 28,33–35,46–49,89–91), SPR 15,28,92,93 and GNAO1 entiation among the disorders (Fig. 3d; see Supplementary infor-
(refs. 16,33,45,72,74–76,94,95) were the most frequently reported in mation). Early onset hereditary spastic paraplegia, in particular, has
individuals who fitted the criteria for a clinical diagnosis of CP (Table 1). been acknowledged to pose diagnostic challenges: one study found
Analysis of the Human Phenotype Ontology (HPO) terms (Box 3) — a that 70% of children later diagnosed with the condition and present-
standardized set of terms for describing clinical phenotypes encoun- ing with spasticity under 3 years of age had been initially diagnosed
tered in human disease — for the 190 genes revealed enrichment for with CP77. Clinical and genetic overlap among children diagnosed with
terms relating to movement disorders and neurodevelopmental pheno- CP and those diagnosed with other movement disorders have been
types found frequently in individuals with CP (Fig. 3a). We also found a reported in multiple cohorts24,27,75. Genomic testing offers an accu-
high degree of overlap among the 190 recurrent genes and the current rate and agnostic method for diagnosing the underlying aetiology
consensus gene panels in PanelApp Australia, which apply the same of these disorders, enabling better estimation of the true frequen-
classification system we have used for CP (green list) to NDDs, including cies of each disorder and implementation of earlier and targeted
intellectual disability, epilepsy and ASD (Fig. 3b; see Supplementary therapies.
information). Notably, genes overlapping between epilepsy and CP are Speech and language disorders are a group of heterogeneous dis-
most frequently those associated with developmental and epileptic orders that, similar to CP, have been somewhat neglected in research;
encephalopathy (DEE): our analysis identified 121 of 137 overlapping thus investigation into the genetic underpinnings have only begun in
genes (Fig. 3c; see Supplementary information). This overlap supports the past few years. Of the 29 genes reported in speech and language dis-
the notion that cerebral palsies are part of the spectrum of neurode- order cohorts to date96, six are also recurrently reported in CP cohorts —
velopmental outcomes associated with DEEs, and that a CP diagnosis BCL11A, DDX3X, GNAO1, GNB1, KAT6A and POGZ16,28,33–36,43,74–76. Similar to
should not be considered as a contraindication for genetic testing in CP, speech and language disorders are frequently comorbid with other
babies presenting with neonatal seizures. NDDs, and growing evidence indicates that isolated speech and lan-
Gene panels for movement disorders, including dystonias, ataxias guage phenotypes also fall somewhere on the NDD spectrum and can
and hereditary spastic paraplegias, also have a high degree of overlap be the result of genetic variation in known NDD genes.

Table 1 | The most frequently reported genetic findings in people with a clinical diagnosis of cerebral palsy

Gene Function Relevant disease–gene associations Reported cerebral palsy type

ATL1 Dynamin-related GTPase, with a role in formation Spastic paraplegia 3A, autosomal dominant Spastic diplegic, triplegic or
of the tubular endoplasmic reticulum network and (MIM 182600); neuropathy, hereditary sensory, quadriplegic26,29,64,66
in neuronal axon elongation type ID (MIM 613708)
ATM Regulates key substrates involved in DNA repair Ataxia–telangiectasia (MIM 208900) Ataxic, dyskinetic66,75,76
and/or cell cycle control
CACNA1A Encodes α1A subunit of the multisubunit Developmental and epileptic encephalopathy, Ataxic59,71, spastic hemiplegic28
voltage-dependent calcium channel; this subunit 42 (MIM 617106)
is predominantly expressed in neuronal tissue
COL4A1 Encodes the α1 subunit of collagen type IV, an Brain small-vessel disease with or without ocular Spastic hemiplegic, diplegic or
integral component of basement membranes, anomalies (MIM 175780) quadriplegic, or choreathetoid27–29,36
forming the supporting structure and scaffolding
for epithelial tissue
CTNNB1 Encodes adherens junction protein with important Neurodevelopmental disorder with spastic Spastic diplegic11,26,71, dystonic63
roles in cell adhesion, cell signalling and diplegia and visual defects (MIM 615075)
anchoring the actin cytoskeleton
GNAO1 Encodes the α-subunit of the Go heterotrimeric Developmental and epileptic encephalopathy, Highly variable and mixed: dyskinetic,
G protein signal-transducing complex 17 (MIM 615473); neurodevelopmental disorder dystonic, spastic, quadriparesis or
with involuntary movements (MIM 617493) hemiparesis27,59,63,64,71
KCNQ2 KCNQ2 associates with KCNQ3 to form the Developmental and epileptic encephalopathy, Dystonic quadriparesis22,73
M channel, a potassium channel with a crucial 7 (MIM 613720)
role in regulation of neuronal excitability
PAFAH1B1 (LIS1) Regulates platelet-activating factor Lissencephaly, 1 (MIM 607432) Spastic quadriparesis78
SPAST Microtubule-severing protein that regulates Spastic paraplegia, 4, autosomal dominant Dystonic22,63, spastic diplegic28,71
the structure and function of the microtubule (MIM 182601)
cytoskeleton
SPR Catalyses biosynthesis of tetrahydrobiopterin, Dopa-responsive dystonia owing to sepiapterin Hypotonic, dystonic83
which is essential for production of major reductase deficiency (MIM 612716)
monoamine neurotransmitters dopamine and
serotonin in the brain
TUBB4A Encodes subunit 4A of β-tubulin; β-subunits Hypomyelinating leukodystrophy, 6 (MIM 612438); Spastic dystonic diplegic28, dystonic63
heterodimerize with α-subunits and assemble to torsion dystonia, 4, autosomal dominant
form microtubules (MIM 128101)
At least 20 individuals with a clinical diagnosis of cerebral palsy have been reported to have a pathogenic or likely pathogenic variant in each of these genes.

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Recent examples from CP cohorts suggest the presence of

both phenotypic expansion of known genetic disorders and genetic
pleiotropy, in which specific variant types or inheritance patterns
Box 3
result in specific outcomes. In 2020, a recurrent gain-of-function
variant in FBXO31, a gene historically reported and well characterized Human Phenotype Ontology
as a tumour suppressor97, was shown to cause a clinically consistent
spastic–dystonic CP syndrome in three families45,98, providing an •• The Human Phenotype Ontology (HPO), originally devised in
example of genetic pleiotropy45,98. In addition, a homozygous FBXO31 2008 (ref. 134), is a standardized vocabulary for describing
loss-of-function variant and syndromic intellectual disability was clinical phenotypes associated with human disease.
previously reported in a single family99. FBXO31 joins a growing list of •• HPO terms are derived from medical literature and databases
tumour suppressor genes with emerging roles in neurodevelopment including OMIM and DECIPHER. HPO currently contains over
(for example, USP9X, DDX3X, FBXW7, WWOX and PTEN100–105). 15,000 terms and over 200,000 annotations to human hereditary
diseases135 and is fast evolving.
Emerging mechanisms that underly genetic •• The HPO is structured into a directed acyclic graph in which
cerebral palsy terms are represented as subclasses of a parent term, with each
Our understanding of the molecular and developmental mechanisms term in the HPO describing a distinct phenotypic abnormality.
of CP is still in its infancy. Pathway analysis of the 190 recurrent CP A key feature of HPO is the ability to relate phenotype terms to
genes points to potential mechanisms that could underly the aetiol- multiple parents134.
ogy (Fig. 4 and Table 2). Key functional gene clusters include: compo- •• HPO is widely used for differential diagnostics and phenotype-
nents of the tubulin cytoskeleton and regulators of its structure and driven analysis of next-generation sequence variation data.
function; regulators of cellular metabolism; cell–cell signalling mole­ Generating HPO terms for specific disorders provides a bridge
cules; regulators of intracellular transport; chromatin modifiers; and between clinical care and genomics, aiding prioritization of
genes with key roles in the development of the nervous system. These genetic variants from genomic testing and enabling robust,
mechanisms are fundamental to the regulation of cell proliferation differential diagnosis136.
and differentiation, and although involvement of these mechanisms •• Careful phenotyping using HPO terms can enable the generation
in CP biology was identified in early genomic investigations45, they are of flexible and personalized gene panels, termed HPO-driven
not unique to CPs106–111. virtual panels, on the basis of genotype–phenotype matching
Some monogenetic causes of CP overlap with cellular pathways approaches, which can reduce the burden of incidental findings
involved in neurodevelopment and postinjury regeneration (for and variants of uncertain clinical significance.
example, CTNNB1, which encodes the β-catenin protein). High lev-
els of Wnt/β-catenin signalling are observed in oligodendrocyte pro-
genitors from white matter lesions in term infants following severe In mouse, Gpam knockout results in perturbed lipid metabolism in
hypoxic–ischaemic encephalopathy, and dysregulation of signalling astrocytes, resulting in reduced astrocyte proliferation and impaired
has been shown to result in persistent maturational arrest and failure oligodendrocyte myelination, with thinning of white matter in both the
of remyelination in a mouse model112. Other genomic studies in CP have motor cortex and prefrontal cortex103, indicating potential mechanisms
also implicated lysosome biogenesis, gap junctions, dopaminergic involved in CP pathogenesis. In the same CP gene analysis study, the
synapses, focal adhesions, cellular senescence and oestrogen signalling authors investigated the expression patterns of CP genes with and with-
in the molecular pathogenesis of CP43. Moreover, no clear pattern of out comorbid intellectual disability, and suggested that differences in
affected brain regions or cell type-specific gene expression for CP genes spatial and developmental expression patterns explain the specificity
has been identified: excitatory and inhibitory neurons, interneurons, of NDD phenotypes among genes, and could be used to predict the
astrocytes, oligodendrocytes, cerebellar granule cells, Purkinje neurons likely phenotypic spectrum associated with other CP and NDD genes43.
and microglia have all been implicated in CP pathology43. The diversity Although the existence of a ‘pure CP’ signature seems intuitive,
of spatial, and probably temporal, expression of CP genes and their caution in interpreting such findings is warranted, owing to the pres-
mechanisms of action is not surprising given that the vast majority of ence of selection biases and currently limited patient numbers. The
the recurrent CP genes are already associated with neurodevelopmental majority of patients described in the literature were recruited from
or movement disorders, and that the diagnosis of CP includes a highly clinical genetics services, with a higher level of NDD comorbidity than
heterogeneous clinical spectrum. Additional examples of novel, com- is reported in international CP registers. Unbiased whole-genome
plex NDDs are quickly emerging, with some or all cases having a move- sequencing of large, clinically unselected cohorts will be required to
ment disorder consistent with a clinical diagnosis of CP (for example, systematically identify CP-specific genes and to uncover mechanisms
SPATA5L1 (ref. 113), SLC18A2 (ref. 114), NSRP1 (ref. 115) and NRCAM116). specific to individuals with a movement disorder without other neuro­
Identification of genes that cause an isolated motor phenotype in developmental phenotypes. These analyses will have a crucial role in
the absence of additional comorbidities — CP-specific genes — could characterizing CP as either a disorder in its own right or as a clinical
reveal mechanisms of CNS development that are specific to the control feature of other complex NDDs.
of movement and posture. Only a small number of such genes have
been identified to date, including the gene encoding the mitochondrial Diagnoses of the undiagnosed
enzyme GPAM, which is nearly exclusively expressed in astrocytes Similar to other groups of rare diseases, many individuals with CP
where it catalyses synthesis of glycerolipids from saturated fatty acids. remain genetically undiagnosed after genomic sequencing, which
Compound heterozygous variants in GPAM were reported in one indi- can indicate absence of genetic aetiology, or at least absence of a mono-
vidual as a novel cause of spastic quadriplegia without comorbidity43. genic cause. However, as the interpretation of genomic sequencing data

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Review article

a HP:0001257 Spasticity
HP:0001273 Abnormal corpus callosum morphology
HP:0001276 Hypertonia Number of genes
HP:0002500 Abnormality of the cerebral white matter
HP:0010993 Abnormality of the cerebral subcortex 100
HP:0004305 Involuntary movements 120
HP:0002493 Upper motor neuron dysfunction
HP:0002167 Neurological speech impairment 140
HP:0007364 Aplasia/hypoplasia of the cerebrum 160
HP:0002977 Aplasia/hypoplasia involving the central nervous system
HP:0001252 Muscular hypotonia
HP:0011442 Abnormality of central motor function –log10(FDR)
HP:0003808 Abnormal muscle tone
HP:0002060 Abnormality of the cerebrum 40–45
HP:0001263 Global developmental delay 45–50
HP:0001250 Seizures
HP:0002060 Abnormality of forebrain morphology 50–55
HP:0001249 Intellectual disability 55–60
HP:0012758 Neurodevelopmental delay 60–65
HP:0100022 Abnormality of movement
2.5 3.0 3.5 4.0 4.5
Fold enrichment

b c d
CP 3+ ASD All epilepsy CP 3+ Dystonia
ID Epilepsy HSP Ataxia
17 7 85 111 84
CP 3+
52 1 0 23 26 21
16
784 14 0 54 54 4 10 165
704 121
17 53 2
49 1 7 11
39 88 8 3
465 11
DEEs

Fig. 3 | Genetic and clinical overlap among cerebral palsy and other disorders. monogenic epilepsy genes133, demonstrating that most overlapping genes
a, The 20 most enriched Human Phenotype Ontology (HPO) terms associated are associated with developmental and epileptic encephalopathies (DEEs).
with the 190 recurrent cerebral palsy (CP) genes derived from Curated HPO from d, Overlap among recurrent CP genes and PanelApp Australia consensus gene
ShinyGO 0.77 (ref. 132). Terms are sorted by fold enrichment with HPO database panels for movement disorders: ataxia super panel (v3.0), dystonia super panel
as background. b, Overlap among the recurrent 190 CP genes and PanelApp41 (v1.77) and hereditary spastic paraplegia (HSP) super panel (v2.51). ASD, autism
Australia consensus gene panels for neurodevelopmental disorders: intellectual spectrum disorder; FDR, false discovery rate; ID, intellectual disability. Gene lists
disabilities syndromic and non-syndromic (v0.5029), autism (v0.185) and genetic used in this figure can be found in the Supplementary Information.
epilepsy (v0.1803). c, Overlap among the 190 recurrent CP genes and curated

is limited by current knowledge of disease–gene associations, a subset approaches in comorbid disorders such as epilepsy119 and ASD120 have
of undiagnosed individuals are likely to have monogenic aetiologies demonstrated enrichment for common variants in genes associated
that are yet to be discovered. The International Cerebral Palsy Genomics with monogenetic aetiology. Furthermore, specific subtypes of these
Consortium is orchestrating systematic and collaborative re-analysis heterogeneous disorders have shown enrichment for additive common
of existing genomic data to facilitate the identification of novel genetic genetic variation, suggesting that careful phenotyping is important
causes of CP by increasing sample sizes to enhance statistical power in assessing the diversity of genetic aetiology in CP. For example, in
and incorporating new knowledge into the analysis117. Interpretation juvenile absence epilepsy, common genetic variation contributes up
of ‘cryptic’ genetic variation — variation for which functional impact to 90% of the genetic risk119.
cannot be or is poorly predicted by bioinformatic tools — is difficult,
particularly for variation that falls in non-coding regions of the genome. Precision medicine and the benefit of knowing
Multiomics approaches and laboratory assays using patient-derived A 2019 systematic literature review identified 182 reported interven-
cell lines can enable research into the effects of such variation on the tions for CP, including strategies aimed at prevention and manage-
protein or RNA118 and, in some cases, can change the interpretation of ment, with varying evidence of effectiveness121. The potential effect
pathogenicity of a genetic variant. of genetics on the inter-individual differences in effectiveness of the
Genetic investigations of CP to date have focused largely on mono- interventions has had little consideration throughout the literature.
genetic causes; however, some international efforts are now also look- However, for rehabilitation strategies, some studies have suggested a
ing at polygenic loci contributing to CP risk, including those that are contribution of common genetic variations, such as BDNF and dopa-
common, additive or individually low risk. In this model, CP is treated mine gene polymorphisms, to the variability in effectiveness. For
as a complex disorder in which heightened genetic predisposition some individuals, combining rehabilitation with medication, such as
contributes to the risk of CP in individuals with or without additional dopamine-stimulating drugs, could augment treatment outcomes122,123.
perinatal risk factors. In the absence of a genetic variant with consid- For high-risk interventions or where earlier use of an interven-
erable effect, very large sample sizes will be required to uncover the tion could substantially improve long-term outcomes, consideration
interplay between genetic and environmental risk factors. Similar of the underlying aetiology is crucial. Estimates of the proportion of

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a Semaphorin NETRIN-1 L1CAM RET

Fig. 4 | Reactome pathway
diagrams for three key
interactions signalling interactions* signalling
processes showing significant
enrichment for proteins
ANK1,2,3 encoded by recurrent cerebral
palsy genes. a, Axon guidance
EFNB
(R-HSA-422475; DOI: 10.3180/
EFNA REACT_18266.1). b, Neuronal
SEMA3A SLIT2
NTN1 NTN1 RELN system (R-HSA-112316).
c, Membrane trafficking
(R-HSA-199991). Asterisks
indicate terms within each
ARHGEF12 pathway with statistically
NCK1
FYN FARP2 FYN ANK1,2,3 significant enrichment (as listed
SRC1 FYN SRC1 SHC1 PLCG1
RND1 RAC1 PTK2 SRC1 NGEF in Table 2). ER, endoplasmic
PAK1 SRGAP GRB2
FES GRB2 KALRN RHOA FYN
CDC42 SOS1 reticulum. Reproduced from
SOS1 RAC1 ROCK
RRAS PAK1 RHOA RAC1 PAK1 reactome.org128, CC BY 4.0.
CDC42
N-WASP
LIMK1
NCAM signalling for Signalling by EPH–Ephrin REELIN signalling
neurite outgrowth ROBO receptor signalling* pathway

b Transmission across Transmission across

chemical synapses* electrical synapses

K+
Ca2+ Synaptic
vesicle

Presynaptic PTPRD
terminal K+ NRXN
Potassium
channels
Neurotransmitter

Ionotropic
receptor Metabotropic SLITRK
receptor NLGN
Postsynaptic
Protein–protein
terminal
interactions at
synapses*

GAP junction
c trafficking and
regulation*

Clathrin-mediated Recycling
endocytosis endosome

Early
ER-to-Golgi
endosome GAPs P
anterograde
transport* Late endosome
Golgi ESCRTs

RABs GTP GDP RABs

Nucleus Endosomal sorting complex

required for transport (ESCRT)

Intra-Golgi and GDP GEFs

retrograde Trans-Golgi
Golgi-to-ER network RAB regulation
traffic* vesicle of trafficking
budding* Translocation of GLUT4
to the plasma membrane*

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Review article

cases with medically actionable findings in CP cohorts vary from 12% can benefit from deep brain stimulation, which prevents admissions
to 30%15,34,74, with recommended actions including specific drug treat- to the ICU for dystonic or hyperkinetic crises74.
ments, further metabolic or imaging work-up and access to clinical A genetic diagnosis can avoid unnecessary and invasive investi-
trials. In one study, 14 of 23 participants with a molecular diagnosis gations, and enable informed carrier testing and reproductive plan-
had a treatment change following genetic diagnosis, with 13 of the ning, which can offer considerable benefits to people with CP and
14 individuals showing an improvement in symptoms as a result15. their families even in the absence of a treatment change (Box 4). Of
Current treatments are most effective in individuals with metabolic equal importance, a genetic diagnosis can also inform treatments
disorders, partly owing to the possibility of supplementing defi- that should be avoided to prevent negative outcomes. For example,
cient metabolites or removing toxic metabolites in many of these in one individual presenting with a secondary neurotransmitter defi-
individuals74. A 2014 systematic literature review identified 67 treat- ciency with a severe hyperkinetic and dyskinetic movement disorder
able inborn errors of metabolism that have been reported as either described as ‘atypical’ CP68, l-dopa therapy was reported to increase
CP mimics or presenting with CP-like symptoms according to expert dyskinetic movements, even at a low dose116. Genomic testing in this
opinion14. For 26 of these metabolic disorders, a treatment was avail- individual subsequently identified a de novo heterozygous KCNJ6 vari-
able that could reverse neurological symptoms, including CP fea- ant that was demonstrated to result in gain-of-function of the encoded
tures, but also additional cognitive, behavioural and MRI features in GRIK2 potassium channel74,116,124. This example demonstrates both
many cases14. Furthermore, individuals with not only primary but also the potential benefits of a molecular diagnosis and the importance of
secondary neurotransmitter deficiencies, caused by variants in, for characterizing the effect of genetic variation on gene function when
example, CSTB, PAK3 or TUBB4A, have been reported to respond to tar- considering treatments. Given a lack of evidence of benefit and the
geted supplementation15,74. A further group of patients with dyskinetic potential for harm, surgical procedures such as selective dorsal rhi-
movement disorders, such as GNAO1-related movement disorders, zotomy might also be contraindicated in individuals with predominant

Table 2 | Significantly enriched Reactome pathway terms identified from 190 recurrent cerebral palsy genes

Process or system Pathway Subpathway Overlap Entities in False discovery

pathway rate

Autophagy – – 11 166 2.56 × 10−3

Macroautophagy – 11 150 1.44 × 10−3

Selective autophagy – 8 89 3.19 × 10−3

Aggrephagy 6 47 3.59 × 10−3

Cell–cell communication – – 8 165 4.71 × 10−2

Chromatin organization – – 11 254 2.61 × 10−2

Chromatin-modifying enzymes – 11 254 2.61 × 10−2

Developmental biology – – 36 1356 1.40 × 10−2

Myogenesis – 4 32 2.28 × 10−2

Nervous system development – 25 621 8.02 × 10−4

Axon guidance 25 585 3.50 × 10−4

Neuronal system – – 21 490 1.44 × 10−3

Protein–protein interactions at synapses – 6 93 3.78 × 10−2

Neurexins and neuroligins 5 60 3.05 × 10−2

Transmission across chemical synapses – 15 344 7.17 × 10−3

Neurotransmitter receptors and postsynaptic 12 232 7.17 × 10−3

signal transmission

Vesicle-mediated transport – – 26 828 8.83 × 10−3

Membrane trafficking – 24 668 3.59 × 10−3

ER-to-Golgi anterograde transport 9 164 1.69 × 10−2

Gap junction trafficking and regulation 8 57 3.48 × 10−4

Intra-Golgi and retrograde Golgi-to-ER traffic 10 219 2.85 × 10−2

Trans-Golgi network vesicle budding 6 80 2.25 × 10−2

Translocation of GLUT4 to plasma membrane 7 81 7.17 × 10−3

The table lists terms showing statistically significant enrichment (false discovery rate <0.05) in the top three layers of the Reactome pathway hierarchy128. Overlap refers to the number of genes
within the term that overlap with the 190 recurrent cerebral palsy genes. ER, endoplasmic reticulum.

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Review article

Box 4

Case studies demonstrating clinical implications arising from a

genetic diagnosis in children with cerebral palsy
Case 1 nonsense-mediated mRNA decay. Early exome testing could have
A girl with cerebral palsy, microcephaly and normal brain MRI saved many years of investigations, provided an explanation to the
was referred for genetic testing at 10 years old. When she was family and reassured them about reproductive choices.
4 months old, her parents were concerned with her development
and sought medical advice but were reassured. She said her first Case 2
words at 9 months old and crawled at 14 months. At 1 year old, A now 12-year-old girl was referred for investigation of intractable
her parents sought medical attention again due to her global epilepsy occurring on the background of hemiplegic cerebral palsy.
developmental delay and microcephaly, and she was referred She was delivered at 36 weeks gestation by caesarean section
for further investigation. On examination at 1 year old, her head following spontaneous labour with Apgar scores of 9 and 9. There
circumference was below the third percentile and continued to were no perinatal issues. At 12 months of age, left hand clenched
track down from this time. She received thorough evaluations fist was noted, and walking was delayed until 20 months. The early
from neurology, paediatric and metabolic medicine departments, hand preference led to MRI, which confirmed a porencephalic
with each team conducting extensive testing, including a lumbar cyst on the right side of the brain, focal right cerebral white matter
puncture and multiple MRI scans which were normal. Her arms volume loss and evidence of prior right ventricular haemorrhage.
were flexed with a fixed flexion deformity of approximately 10° at At 2 years of age, seizures began and were refractory to sodium
her elbows. She demonstrated spastic catch and hyperreflexia valproate and benzodiazepines. Genomic testing showed a
with spread in the upper and lower limbs. At 6 years old, she heterozygous pathogenic change in COL4A1. Parental testing
had a bilateral squint requiring surgery. At 10 years old, exome showed inheritance from an unaffected parent and prompted
testing showed a de novo heterozygous ACMG class 5 variant in counselling about reproductive choices and advice regarding
CTNNB1, predicted to result in loss of protein function through smoking, blood pressure management and anticoagulant risk.

dystonia or mixed CP, and in whom the eventual genetic diagnosis of aromatic l-amino acid decarboxylase deficiency, an autosomal
of a progressive condition is made (for example, TUBB4A-related recessive disorder caused by variants in the DDC gene and frequently
disorders34,74). resulting in a clinical diagnosis of CP, have meant that gene therapy126
The increasing and persistent use of stem cell therapies in peo- is currently not available in all markets127. Genomic sequencing should
ple with CP also causes concern, given that very few individuals also be a consideration for stratifying heterogeneous CP cohorts for
would have been offered genetic testing, even prior to autologous clinical trials of new interventions.
stem cell transplant. Over 20 clinical trials of cell therapy in chil-
dren with CP, or at risk of developing CP from brain injuries such as Conclusions
hypoxic–ischaemic encephalopathy, have been reported, and more In this Review, we reflect on the complexities and shortcomings of
are ongoing125. The mechanism of action of these therapies remains the current clinical diagnosis of CP, highlighting an opportunity, if
poorly understood, and the reported therapeutic benefits are variable not an urgent need, to reassess the classification of CP in view of the
and modest. Lack of systematic genetic testing as part of the diagnos- fast-evolving knowledge of genetic aetiology. As with other neurode-
tic work-up of CP therefore not only results in lost opportunity for velopmental disabilities that are clinically comorbid and have genetic
early and targeted intervention, but also has the potential to cause overlap with CP, an aetiology-driven clinical diagnosis is essential in
harm. Similar to other genetic NDDs, offering autologous stem cell the era of precision and personalized genomic medicine. There are
transplantation to an individual with a genetic aetiology of CP, which pervasive inconsistencies in the application of the current clinical
would involve transplanting cells harbouring the genetic variant diagnosis of CP, in the choice of the genetic or genomic test to use,
back into the patient, is inconceivable, and thus prior genetic testing and in whom to test. We strongly advocate for a comprehensive
is essential. genomic test of exome or genome sequencing to be considered as
The high degree of overlap of diverse genetic aetiologies among the first-tier test for CP. We also emphasize the benefit of genomic
CP and other rare disorders, and the lack of systematic genomic test- testing of clinically unselected cohorts of individuals with a clini-
ing in clinically unselected CP cohorts, suggests that the incidence of cal diagnosis of CP to better understand the full complexity of the
some disorders is underestimated. Furthermore, these observations aetiology. Given the current knowledge of the genetic aetiology of
indicate that the clinical spectrum associated with these disorders CP and the growing clinical utility stemming from precise genetic
needs to be better understood. Improved assessment of the frequency diagnosis, not testing could be detrimental to the management of
of specific conditions is crucial for encouraging investment by pharma- these disorders.
ceutical companies, as well as ensuring that therapies are made avail-
able promptly. For example, difficulties in determining the frequency Published online: xx xx xxxx

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Review article

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The authors thank T. Kroes and D. Fornarino for their assistance with the initial curation of published maps and institutional affiliations.
cerebral palsy gene lists. J.G. is supported by NHMRC Senior Research Fellowship ID1155224
and C.L.v.E. is supported by The Hospital Research Foundation Fellowship C-MCF-48-2019. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this
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C.L.v.E. and J.G. contributed equally to discussions of the article content. C.L.v.E. researched terms of such publishing agreement and applicable law.
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Competing interests Related links

The authors declare no competing interests. Human Phenotype Ontology: https://hpo.jax.org/app/
International Cerebral Palsy Genomics Consortium CP Commons data portal:
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Supplementary information The online version contains supplementary material available at
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