Here we provide the first comprehensive characterisation of speech and language in CDK13-related disorder. With the addition of 33 novel cases to the existing 60 cases in the literature, we also provide a description of over a third of all published cases of CDK13-related disorder to date.
Speech production was substantially more impaired when compared to other communication domains, such as social communication. Speech disorder was the most prevalent phenotypic feature, where CAS was dominant (63.6%) and considerably more prevalent than general population diagnostic frequencies (0.1%) (35, 36). CAS frequently co-occurred with other speech sound disorders. Despite this frequency of CAS, only one participant was receiving a CAS specific intervention. This lack of recognition of CAS may be hindering opportunities for more targeted therapy with negative implications for longer-term outcomes. Development of speech was generally protracted, with most participants using AAC to support their communication needs while speech developed. Some participants remained minimally verbal or had severely impaired speech intelligibility, requiring AAC aides into adolescence. Comprehensive AAC supports are required so that individuals can meet all their communication needs where speech cannot.
Historically, speech/language and delay/disorder have been used to describe the features observed in CDK13-related disorder. Our systematic characterisation of speech and language is critical for the provision of tailored interventions. Our findings suggest access to AAC in the early years, with ongoing support for AAC into adolescence if needed, is of paramount importance to optimise communication outcomes. Typically developing children are immersed in their language system from birth and say their first words around 12 months of age. A child with CDK13-related disorder should be exposed to both verbal language and AAC before their first birthday to allow for optimal learning opportunities with a trained speech pathologist (37). AAC is not used as a replacement for verbal development, but rather it is known to support verbal development (38) and particularly support growth of expressive vocabulary and grammar (39). Once a child begins talking, speech therapy focusing on AAC should be supplemented alongside interventions tailored to the child’s speech and language presentation. AAC should continue to be implemented if the child cannot be understood by different people across most possible communication settings (eg. school, home, with friends) to meet all of their communication needs. Consequently, AAC systems that can execute a range of communication functions should be considered. A combination of AAC systems can be used, such as KWS and a high-tech graphic AAC (40).
The most common speech disorder in this group, CAS, disrupts motor planning and programming for speech. In line with this speech motor involvement, fine and gross motor impairment were also widespread. The frequency of co-occurring motor disorders implicates an underlying mechanism of disordered movement planning abilities in CDK13-related disorder. Evidence for the motor involvement in CDK13-related disorder is consistent with neurobiological evidence showing high CDK13 expression in the cerebellum which is responsible for physical movement, executive functioning and language ability (41, 42). Cognitive and linguistic impairments further involve cerebellum function and in our cohort almost half of those with MRI findings had hypoplasia of the corpus callosum. Callosal aberrations have also been implicated in speech sound disorder (43), suggesting further investigation into the corpus callosum’s role CDK13-related disorder.
Six female participants had average expressive and/or receptive language skills. These participants provide examples that speech and language disorders may dissociate, as all of this group still had speech disorders. All participants with moderate to severe social behavioural impairment also had similarly impaired language skills. There were participants with average social behaviour and impaired language ability. Hence, impaired social behaviour was associated with impaired language skills, but not vice versa. Further, it is important to recognise that speech and language impairment can be present in the absence of ID, with linguistic behaviours having their own biologically driven neurological pathways, (44).
Receptive language was a relative strength when compared to expressive language ability. In genetic conditions with a high prevalence of CAS systematically characterised to date, this dissociation between receptive and expressive language skills has not been seen (16, 17). This suggests that receptive language may be a strength for individuals with CDK13-related disorder, at least relative to other genetic conditions involving CAS that are understood at this time.
Moderate ID generally corresponded with moderate to severely impaired language skills. However, three participants with very low to average FSIQ had moderate to severely impaired language skills. Consequently, intellectual and language ability are typically congruent, but can be distinct from one another in some individuals.
The incidence of ID was less in this cohort than previously reported (14), with around one quarter of assessed participants having borderline to average FSIQ. However, this cohort may be biased, as caregivers may only self-refer to a speech and language study for children with stronger language and intellectual ability. Additionally, previous literature largely characterises individuals drawn from ID cohorts, so here we broaden the phenotype of CDK13-related disorder with the inclusion of individuals without ID.
The occurrence of other neurodevelopmental conditions such as autism and ADHD was consistent with previously published cases (14). However, most participants with moderate to severe social behaviour impairment did not have a clinical diagnosis of autism. This indicates that rates of autism may be higher still in individuals with pathogenic CDK13 variants. For the first time, sensory processing disorder was identified as a commonly occurring feature of CDK13-related disorder, with over one-quarter of the cohort affected. However, sensory processing disorder and autism are difficult to differentially diagnose, especially on a background of intellectual and language impairment, and sensory processing disorder is not considered a DSM-V diagnosis (30, 45). The range of co-occurring neurodevelopmental conditions highlights the importance of systematic neuropsychological assessment, to provide optimal, individualised support.
With regards to genotype-phenotype correlations, there was little evidence to indicate that genetic variants were closely associated with specific phenotypes. Of the 17 participants who shared the same variant, considerable heterogeneity emerged in intellectual, language, speech, and medical presentations.
The health and medical profile in CDK13-related disorder was expanded here with our addition of 33 novel cases to the literature. Feeding problems had a significant impact in infancy and early childhood. Similarly, renal, urogenital, and musculoskeletal malformations, and vision impairment were more common than cardiac malformations in our cohort who, as noted earlier, may have been a more biased group. Cryptorchidism was present in our cohort (38% of males), having been recently described in individuals with pathogenic CDK13 variants (14).
We are the first to characterise sleep disturbances in CDK13-related disorder, highlighting prevalent insomnia features. Sleep quality and duration can negatively impact receptive and expressive language skills (46). Additionally, we are the first to systematically characterise feeding difficulties in young children with CDK13-related disorder.
Rouxel & colleagues (14) linked anxiety with CDK13-related disorder in 50% of their cohort (all > 7 years). Anxiety disorder was also present in our cohort, although less prevalent (17.5%, all > 8 years bar one 5-year-old). The median age of Rouxel et al.’s cohort was markedly older (median age = 12 years) than our cohort (median age = 7 years). The experience of living with speech and language disorder can place individuals at risk of developing anxiety (47, 48). Hence, without additional in-depth and longitudinal research, it is difficult to implicate CDK13 as causative for anxiety. The prevalence of anxiety in CDK13-related disorder could be attributed to co-morbid speech and language impairments.
Neuropsychological assessments are recommended to assess cognitive abilities, given the incidence of ID and other neurodevelopmental conditions. Likewise, occupational and physiotherapy are warranted as fine and gross motor impairment was ubiquitous. Lastly, speech pathology services should be sought to implement AAC in early childhood, and then provide targeted speech and language therapy (e.g., evidence-based CAS therapy) when verbal speech develops.
In conclusion, we characterise speech and language in CDK13-related disorder and identify CAS as a common feature. Until this study, CAS had only been described in one individual (ID 27) in the literature (13, 14). Specific speech and language diagnoses reflect the neurobiological underpinnings and associated linguistic implications of a disorder. The profile of speech, language and ID, on the background of significant health disorders, emphasises the importance of comprehensive, multidisciplinary assessment and intervention for individuals with CDK13-related disorder.