Genetic Testing in Childhood Apraxia of Speech

Genetic Testing in Childhood Apraxia of Speech

PUBLISHED 2018 | BY  PROFESSOR ANGELA MORGAN BSpPath (Aud Hons), MURDOCH CHILDREN’S RESEARCH INSTITUTE & UNIVERSITY OF MELBOURNE, MELBOURNE, AUSTRALIA

 

Is childhood apraxia of speech genetic?

The cause for childhood apraxia of speech (CAS) has remained unknown since the condition was first described in the 1950s. In many cases, the suspected cause is due to a complex interaction between a child’s genetic and brain makeup, and their environmental influences. We have a lot to learn about the brain and environmental links with CAS, but we have gained genetic insights in the past decade since the discovery of FOXP2; the first gene associated with CAS (Lai et al., 2001; and for recent review of FOXP2 and CAS see Morgan et al., 2017). The discovery that mutations or variants in FOXP2 caused a rare and severe form of CAS, catalysed the study of further genes for apraxia.

More than 15 years after the FOXP2 discovery, new genetic technologies now enable rapid and relatively cost-efficient genetic testing. This technology has led to the discovery of further gene pathways associated with CAS. Today we understand that CAS may be related to changes in single genes, such as FOXP2, or they may be associated with copy number variations (CNVs). CNVs are essentially small or large deletions or duplications of sections of our chromosomes. All humans carry CNVs. For many of us, these CNVs will not be related to any obvious physical or health problems. For some of us, these CNVs do cause health or medical conditions, including CAS (for further reading see Morgan & Webster, 2018). By contrast, single gene mutations are where just one gene on a chromosome is interrupted or mutated and linked to CAS.

Genetic diagnoses indicate need to embrace the complexity of CAS and associated diagnoses

Mutations in FOXP2 are generally associated with quite a ‘pure’ profile of CAS (Morgan et al., 2017) in the absence of other neurodevelopmental difficulties or diagnoses. By contrast, new gene pathways linked to CAS, discovered after FOXP2, have also been associated with other neurodevelopmental disorders such as intellectual disability, global developmental delays, epilepsy, autism or attention deficit hyperactivity disorder (Eising et al., 2018, for recent review see for review see Morgan & Webster, 2018). That is, few of the new genes or copy number variant syndromes identified, have been associated only with CAS in isolation. Rather, these genes appear to be associated with the early development of brain regions that may also be associated with other neurodevelopmental conditions. That is, these genes are not ‘CAS-specific’. Increasingly, informed by genetic research, we realise 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 & 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 clinician 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.

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, ie., 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 a CAS associated with a genetic diagnosis.

What are the steps forward if I do want to pursue genetic testing?

As a first step, we suggest talking to your general paediatrician to see whether they feel a comparative genomic hybridisation microarray should be performed. This is the first level of genetic testing typically pursued and it will detect CNVs. However this form of microarray testing is not able to look at a single gene level (i.e., does not test for FOXP2 mutations or other single gene mutations). 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, contact Apraxia Kids and they may be able to put you in touch with the researchers.

 

REFERENCES

  1. 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. (2018). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry. Feb 20. doi: 10.1038/s41380-018-0020-x. [Epub ahead of print].
  2. Lai CSFisher SEHurst JAVargha-Khadem FMonaco AP. (2001). A forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413(6855):519-23.
  3. Morgan AT, Scheffer I, Fisher S, Hildebrand M. (2017). FOXP2 related speech and language disorder. NIH Gene Reviews. https://www.ncbi.nlm.nih.gov/books/NBK368474/
  4. 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.

Genetic Testing in Childhood Apraxia of Speech

PUBLISHED 2018 | BY  PROFESSOR ANGELA MORGAN BSpPath (Aud Hons), MURDOCH CHILDREN’S RESEARCH INSTITUTE & UNIVERSITY OF MELBOURNE, MELBOURNE, AUSTRALIA

 

Is childhood apraxia of speech genetic?

The cause for childhood apraxia of speech (CAS) has remained unknown since the condition was first described in the 1950s. In many cases, the suspected cause is due to a complex interaction between a child’s genetic and brain makeup, and their environmental influences. We have a lot to learn about the brain and environmental links with CAS, but we have gained genetic insights in the past decade since the discovery of FOXP2; the first gene associated with CAS (Lai et al., 2001; and for recent review of FOXP2 and CAS see Morgan et al., 2017). The discovery that mutations or variants in FOXP2 caused a rare and severe form of CAS, catalysed the study of further genes for apraxia.

More than 15 years after the FOXP2 discovery, new genetic technologies now enable rapid and relatively cost-efficient genetic testing. This technology has led to the discovery of further gene pathways associated with CAS. Today we understand that CAS may be related to changes in single genes, such as FOXP2, or they may be associated with copy number variations (CNVs). CNVs are essentially small or large deletions or duplications of sections of our chromosomes. All humans carry CNVs. For many of us, these CNVs will not be related to any obvious physical or health problems. For some of us, these CNVs do cause health or medical conditions, including CAS (for further reading see Morgan & Webster, 2018). By contrast, single gene mutations are where just one gene on a chromosome is interrupted or mutated and linked to CAS.

Genetic diagnoses indicate need to embrace the complexity of CAS and associated diagnoses

Mutations in FOXP2 are generally associated with quite a ‘pure’ profile of CAS (Morgan et al., 2017) in the absence of other neurodevelopmental difficulties or diagnoses. By contrast, new gene pathways linked to CAS, discovered after FOXP2, have also been associated with other neurodevelopmental disorders such as intellectual disability, global developmental delays, epilepsy, autism or attention deficit hyperactivity disorder (Eising et al., 2018, for recent review see for review see Morgan & Webster, 2018). That is, few of the new genes or copy number variant syndromes identified, have been associated only with CAS in isolation. Rather, these genes appear to be associated with the early development of brain regions that may also be associated with other neurodevelopmental conditions. That is, these genes are not ‘CAS-specific’. Increasingly, informed by genetic research, we realise 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 & 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 clinician 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.

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, ie., 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 a CAS associated with a genetic diagnosis.

What are the steps forward if I do want to pursue genetic testing?

As a first step, we suggest talking to your general paediatrician to see whether they feel a comparative genomic hybridisation microarray should be performed. This is the first level of genetic testing typically pursued and it will detect CNVs. However this form of microarray testing is not able to look at a single gene level (i.e., does not test for FOXP2 mutations or other single gene mutations). 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, contact Apraxia Kids and they may be able to put you in touch with the researchers.

 

REFERENCES

  1. 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. (2018). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry. Feb 20. doi: 10.1038/s41380-018-0020-x. [Epub ahead of print].
  2. Lai CSFisher SEHurst JAVargha-Khadem FMonaco AP. (2001). A forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413(6855):519-23.
  3. Morgan AT, Scheffer I, Fisher S, Hildebrand M. (2017). FOXP2 related speech and language disorder. NIH Gene Reviews. https://www.ncbi.nlm.nih.gov/books/NBK368474/
  4. 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.


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