Article In Brief
Researchers discover 10 novel genes for childhood apraxia of speech that demonstrate it is a sporadic monogenic disorder arising from a de novo mutation, and is extremely genetically heterogenous.
The discovery of 10 new genes for childhood apraxia of speech (CAS) implicate broad and complex developmental pathways in this disorder, according to a new study published online on April 28 in Neurology.
The study combined whole genome-wide sequencing and microarray data with highly detailed phenotyping, allowing the researchers to conclude that CAS is most commonly a sporadic monogenic disorder arising from a de novo mutation, and is extremely genetically heterogenous.
“These findings form a gateway into this disorder,” said Dianne Newbury, PhD, of Oxford Brookes University in Oxford, UK, who was not involved in the study. “I think there is a lot of power in this approach to begin to identify causal relationships” between gene variants and phenotype.
CAS is characterized by three core features, explained study author Angela Morgan, PhD, professor of speech pathology at the University of Melbourne, Australia, where she leads the Speech and Language group at the Murdoch Children's Research Institute.
These features include inconsistent errors on consonants and vowels, lengthened and disrupted transitions between sounds and syllables, and inappropriate stress and intonation. Unlike many milder speech impairments, children generally do not “grow out of” CAS, and it is often a source of lifelong disability, Dr. Morgan told Neurology Today.
Work in the past 20 years has indicated that these common features may be due to a multitude of underlying etiologies. Especially significant was the discovery in 2001 that variants in the transcription factor FOXP2 caused some cases of CAS, said study co-author Michael Hildebrand, PhD, associate professor of medicine and head of the Translational Neurogenetics Laboratory at the University of Melbourne. Further work showed that downstream targets of FOXP2 were responsible for some other cases, Dr. Hildebrand said.
But this small cluster of genes accounted for only a minority of all cases. Subsequent gene discoveries accounted for only a small handful more until 2019, when a whole-genome sequencing study of 19 individuals with CAS turned up likely genetic causes in eight American children. This work was led by Dr. Simon Fisher (also a co-author on the present study) at the Max Planck Institute in Nijmegen, The Netherlands, and Drs. Morgan and Hildebrand both contributed to that study.
The Largest Cohort to Date
Those results led Drs. Morgan and Hildebrand to design an expanded new study of 34 children with CAS, the largest cohort to date. Dr. Morgan established the diagnosis and comprehensive phenotyping, including multiple standard tests of oral language function and a review of detailed medical records. In addition to the core features of CAS, a handful of children had mild dysmorphic features, as well as attention deficits, autism spectrum disorder, and a variety of non-neurologic medical issues.
Dr. Hildebrand led the genotyping effort, which included sequencing of either one or both parents in addition to the child with CAS, in order to determine if any variant was inherited from a parent or arose or de novo during early development. Gene variants were subjected to rigorous exclusion filtering, including ruling out variants found in unaffected parents, and were then characterized based on the likelihood of effect on the encoded protein, specifically whether the variant likely caused a loss of function. Individuals carrying FOXP2 variants were excluded by prior screening.
The sequencing effort identified nine “high confidence” variants, all de novo and all dominant, meaning disruption of just one copy of the gene was sufficient to cause CAS. In addition, there was one compound heterozygote recessive variant where both copies of the gene were disrupted, and one of uncertain inheritance. Ten of these were sequence variants; in one child, a copy number variant was detected on chromosomal microarray that appeared to be causative. One of the genes (SETBP1) had turned up in the 2019 CAS study. Overall, a diagnostic gene variant was detected in about one-third (11 of 34) of children in the study.
Eight of the 10 sequence variants were in transcription factors, which made sense, Dr. Hildebrand said, since transcription factors are responsible for controlling the expression of hundreds of other genes during neural development of brain regions critical for speech function, and so might be expected to have profound and far-reaching effects when disrupted.
“This is a highly plausible network of genes” to cause CAS, he said.
The team then looked for co-localization of the genes they identified and found that multiple pairs of these genes were co-expressed in brain tissue much more commonly than would be expected by random due to chance, “suggesting they may be part of a common pathway involved in CAS,” said Dr. Hildebrand. That conclusion was further strengthened by expanding the co-expression analysis to those genes found in the 2019 whole-genome study of CAS.
Many of the genes from that study were found to be co-expressed with the genes in the current study. “We think there are likely to be other genes downstream from these that may also be implicated in CAS,” Dr. Hildebrand added, a similar phenomenon to that already established for FOXP2.
An Unknown Mechanism
The mechanism through which these gene variants cause CAS is still unknown, Dr. Morgan said. Many of the genes are involved in DNA binding, and others are involved in a G-protein complex, but much work remains to be done to determine how loss of these gene pathways leads to the speech impairment.
“It has been very hard to determine exactly at which level of speech production the apraxia is having its effect,” she said, although it is considered to be predominantly a motor problem, with difficulty at the point of executing the motor plan to create speech. Most individuals with CAS also have delayed development of gross and fine motor skills, she added, further supporting that idea. Discovery of these new genes may lead to animal models to further explore the underlying mechanisms.
For now, one of the most important messages arising from these results is for the families of children with CAS. “When a child neurologist sees a child with a severe disorder of speech, and particularly where that is the main parental concern, it is appropriate to consider that there may be a genetic etiology. The core message to the family is that the condition doesn't have to be inherited.”
“This is really important for genetic counseling,” Dr. Hildebrand added,” “so the family knows that if they have another child, the probability of that child carrying this same disorder is very low. If we can tell them it is not something they passed on, that is very powerful in relieving the sense of guilt a parent may feel over their child's condition.”
“This is a very interesting paper,” commented Dr. Newbury of Oxford Brookes University, where she is senior lecturer in the department of biological and medical sciences. “It pulls together a lot of areas of research, and it is really exciting to begin to see these links appearing” between the findings of different research groups. One strength of the study was that the children in it “were very well characterized, and from that we can see how heterogenous a condition this is, and how much this disorder overlaps with other forms of developmental disorder.”
The high percentage of causative genes that were transcription factors was a bit surprising, she said, but it makes sense given that the effect of such genes on proper development is known to be highly dosage-sensitive.
Genes that cause CAS don't appear to have much in common with at least one inherited form of another speech disorder, stuttering. Hashim Raza, PhD, assistant professor in the child language doctoral program at the University of Kansas in Lawrence, has studied families with this disorder and found multiple genes, all of which are involved in the lysosomal pathway and intracellular trafficking, apparently far removed from the broad effects of developmental transcription factors. Genes suggested in language impairment, however, are also targets of transcription factors implicated in CAS, he noted. This suggests molecular targets in speech and language disorders may have shared gene pathways.
However, Dr. Raza noted, “We should expect there to be a broad spectrum of genes that lead to speech problems, because the speech production process is not as simple as previously thought.”
While developing animal models for study of human speech difficulties is challenging, he added, it is not impossible. Mouse models for stuttering based on his findings look at the patterns of vocalizations in mice that correspond to the disrupted patterns seen in human stuttering; a similar approach might be used to develop models of CAS, he suggested. In addition, larger genetic studies are needed to confirm the genes identified here.
“The way forward is to develop functional studies using CAS candidate genes, to identify gene pathways and identify the specific effects of these gene variants,” he said, which can lead to developing validated models and, perhaps, strategies for interventions to improve speech in affected individuals.
Drs. Hildebrand, Newbury, and Raza had no relevant disclosures.