Around one third of children with CAS have a genetic cause for their condition [Hildebrand et al., 2020]. New genetic technologies now enable rapid and relatively cost-efficient genetic testing. This has led to the discovery of many new genetic conditions associated with CAS. Today we understand that CAS may be related to:
(i)Single gene variants or alterations in genes, such as FOXP2, GRIN2A, CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, UPF2, ZNF142, CHD3, SETD1A, WDR5, KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2 [Lai et al., 2001; Turner et al., 2015; Eising et al., 2018; Hildebrand et al., 2020; Morgan et al., 2021]. This is where just one gene on a chromosome is altered [den Hoed & Fisher, 2020]. Some gene variants are passed down through families (inherited). Importantly however, de novo variation seems more common in children with CAS – this is where a gene variant has occurred in a child in the family for the first time rather than being inherited [Hildebrand et al., 2020].
(ii)Copy number variations (CNVs). CNVs are essentially small or large deletions, duplications or rearrangements of sections of our chromosomes (the structures by which our DNA is stored). That is, CNVs include larger alterations that include more than a single gene. All humans carry CNVs. For many, these CNVs will not be related to any obvious physical or health problems. For some, these CNVs do cause health or medical conditions, including CAS (for further reading see Morgan & Webster, 2018; Eising et al., 2019; Hildebrand et al., 2020). It is currently unknown why some CNVs are associated with difficulties, but others are not. One hypothesis is that the size of the CNV affects their impact; another hypothesis is that the specific section of DNA that is changed is important. Children with single gene or CNV conditions typically experience one or more co-occurring neurodevelopmental features including gross and fine motor difficulties, ADHD, ASD, epilepsy, intellectual disability or learning difficulties. Examples include 16p11.2 deletion condition [Mei et al., 2018] and 17q21.31 microdeletion (also known as Koolen de Vries Syndrome [Morgan et al., 2018]).
(iii)Other genetic syndromes. CAS can sometimes occur as part of a broader genetic (e.g. Fragile X, Down syndrome, Klinefelter syndrome, Noonan’s syndrome), metabolic (e.g. galactosaemia), or mitochondrial disorder. Metabolic and mitochondrial disorders are also typically genetic conditions, and children with these conditions also typically experience co-occurring neurodevelopmental disorders as well as additional health concerns. There are quite a few disorders in which CAS can arise, but that does not mean that all children with these disorders also have CAS. For example, not all children with Klinefelter Syndrome have a speech problem and when they do, only some have CAS. Similarly, many children with galactosemia have a speech problem, and out of those children, only some have CAS.
There are some complications associated with the detection of CNVs through genetic testing. A particular CNV may be associated with different clinical conditions. For example, a duplication of a particular section of a chromosome could be associated with cognitive impairment, autism spectrum disorder, and/or schizophrenia. What accounts for the variation in the condition or symptoms (phenotype) the person has is also still unclear. Another complication is that a CNV may be detected and yet be irrelevant to the child’s condition.
Genetic diagnoses indicate need to embrace the complexity of CAS and associated diagnoses
Most genetic causes for CAS are associated with other neurodevelopmental conditions such as gross and fine motor impairments, learning difficulties or intellectual disability, global developmental delays, epilepsy, autism spectrum disorder or attention deficit hyperactivity disorder (Hildebrand et al., 2020). That is, few genes or copy number variant syndromes are associated with CAS in isolation. Rather, these gene pathways are responsible for supporting early brain development and when the pathways are altered, they may be associated with CAS and broader neurodevelopmental conditions. Increasingly, informed in part by genetic research, we realize that CAS is often accompanied by other neurodevelopmental conditions and when this is the case, it has been suggested that genetic testing should be pursued (Morgan et al., 2021; Morgan & Webster, 2018)
Why would I pursue a genetic diagnosis for my child with CAS?
Diagnosis. The primary purpose of genetic testing is to determine whether there is a genetic cause for CAS. Provision of a genetic diagnosis and understanding more about the cause of CAS is helpful to some families who have been on a diagnostic journey to try and understand why their child has CAS.
Prognosis. Some genetic diagnoses are well studied and are known to be associated with other health or neurodevelopmental conditions, or are known to have more or less severe symptom presentations and better or poorer long-term communication outcomes. This knowledge allows the family and treating health professionals to be better informed and provide support tailored to this knowledge.
Future family planning. Third, in some cases, the results provide information on recurrence risk. That is, to understand the chances of further children having the same condition. This would be determined by the type of genetic change, if any, detected via testing. Some genetic variants are de novo – they first appear in the child affected by the condition (in this case, CAS). Other genetic variants are inherited – they are passed on from one, or both, of the child’s parents. The chance of recurrence is dependent on these properties, among others.
Guiding interventions. Into the future, specific treatments targeting gene pathways, such as drugs, may become available. Yet, this sort of targeted therapy is thought to be many decades away at this time. Hence for the moment, a genetic diagnosis will not alter your child’s management of CAS, let alone any other educational or therapeutic programs. Although one could argue that having a genetic diagnosis means your child’s CAS is less tractable, i.e., more challenging to resolve with therapy. Hence one may suggest that more intensive therapy is required in the early years to try and make the optimal gains possible for a child with CAS associated with a genetic diagnosis.
Support. Some genetic diagnoses have a related support group to connect, advocate for, and educate individuals living with these conditions and their families. Some families may find it helpful to connect with others who have a similar lived experience, or to access more specific resources and services related to their genetic diagnosis, if available.
What are the steps forward if I do want to pursue genetic testing?
As a first step, we suggest talking to your general pediatrician to see whether they feel a comparative genomic hybridisation microarray (also known as a chromosomal microarray, molecular karyotype, or SNP microarray) should be performed. This is the first level of genetic testing typically pursued and it will detect small extra or missing sections of DNA, such as CNVs. However, this form of microarray testing is not able to look at specific single genes (i.e., does not test for FOXP2 variants or other single gene changes). Microarrays work by comparing a sample of the individual’s DNA (commonly collected via blood, or sometimes saliva) to a reference set of DNA – it then detects differences between the two DNA sequences. These differences (or variations) are often in the form of CNVs. As mentioned above, these CNVs may be related to a health or medical condition (such as CAS), or may be benign or unrelated to CAS.
At the moment, single gene testing is really still in the domain of researchers until we have enough research and evidence to show direct causative links between CAS and the many new single genes identified in the research literature. There are a number of research programs currently offering genetic testing for children with CAS. For further information about these studies, please look at current research studies here or contact Apraxia Kids and they may be able to put you in touch with the relevant research groups.
- den Hoed J, Fisher SE. (2020). Genetic pathways involved in human speech disorders. Current Opinions in Genetics & Development, 65:103-111.
- Eising E, Carrion-Castillo A, Vino A, Strand EA, Jakielski KJ, Scerri TS, Hildebrand MS, Webster R, Ma A, Mazoyer B, Frankcs C, Bahlo M, Scheffer IE, Morgan AT, Shriberg LD, Fisher SE. (2019). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry, 24(7):1065-1078.
- Hildebrand MS, Jackson VE, Scerri TS, Van Reyk O, Coleman M, Braden RO, Turner S, Rigbye KA, Boys A, Barton S, Webster R, Fahey M, Saunders K, Parry-Fielder B, Paxton G, Hayman M, Coman D, Goel H, Baxter A, Ma A, Davis N, Reilly S, Delatycki M, Liégeois FJ, Connelly A, Gecz J, Fisher SE, Amor DJ, Scheffer IE, Bahlo M, Morgan AT. (2020). Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation. Neurology, 94(20):e2148-e2167.
- Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. (2001). A forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413(6855):519-23.
- Mei C, Morgan A. (2011). Incidence of mutism, dysarthria and dysphagia associated with childhood posterior fossa tumour. Childs Nervous System, 27(7):1129-36.
- Morgan AT, Haaften LV, van Hulst K, Edley C, Mei C, Tan TY, Amor D, Fisher SE, Koolen DA. (2018). Early speech development in Koolen de Vries syndrome limited by oral praxis and hypotonia. European Journal of Human Genetics, 26(1):75-84.
- Liegeois F, Mei C, Pigdon L, Lee K, Stojanowski B, Mackay M, Morgan A. (2019). Speech and Language Impairments After Childhood Arterial Ischemic Stroke: Does Hemisphere Matter? European Journal of Child Neurology, 92:55-59.
- Morgan AT, Braden R, Wong MMK, Colin E, Amor D, Liegeois F, Srivastava S, Vogel A, Bizaoui V, Ranguin K, Fisher SE, van Bon BW. (2021). Speech and language deficits are central to SETBP1 haploinsufficiency disorder. European Journal of Human Genetics. doi: 10.1038/s41431-021-00894-x. [Epub ahead of print].
- Morgan AT, Masterton R, Pigdon L, Connelly A, Liégeois F. (2013). Functional magnetic resonance imaging of chronic dysarthric speech after childhood brain injury: Reliance on a left-hemisphere compensatory network. Brain, 136(Pt 2):646-657.
- Morgan AT, Webster R. (2018). Aetiology of childhood apraxia of speech: A clinical practice update for paediatricians. Journal of Paediatrics and Child Health, 54(10):1090-1095.
- Turner SJ, Mayes AK, Verhoeven A, Mandelstam SA, Morgan AT, Scheffer IE. (2015). GRIN2A: An aptly named gene for speech dysfunction. Neurology, 84(6):586-593.
By Professor Angela Morgan PhD, BSpPath (Aud Hons), and Mariana Lauretta MSpPath, BBiomed, Murdoch Children’s Research Institute & University of Melbourne, Melbourne Australia with original contributions by Heidi Feldman, MD, PhD