Speech and Language Disorders: Lessons from Genetics

The aim of the symposium is to explore and discuss recent advances in language genetics with a diverse and multidisciplinary audience. It will bring together leading experts from an array of fields including genomics, clinical genetics, and speech/language therapy. The symposium focuses on a range of speech and language disorders, including stuttering, dyslexia and childhood apraxia of speech, and aims to address two questions:

• What can we learn about complex speech and language disorders from genome-wide screens?
• What can rare DNA variants teach us about speech and language disorders?

Organizing committee and hosts:

Else Eising, Marscha Engelen, Marie-Christine Franken and Simon Fisher

Program

9:30 - 10:00	Registration
Part 1: What can we learn about complex speech and language disorders from genome-wide screens? Chair: Marie-Christine Franken
10:00 - 10:10	Welcome
10:10 - 10:50	Genetics of developmental stuttering and new biological perspectives Prof. Dr. Shelly Jo Kraft
10:50 - 11:30	Exploring the genetics of stuttering persistence Dr. Else Eising
Coffee/tea break
11:50 - 12:20	Recent advantages in genetic studies of language and reading traits using a multivariate approach Dr. Hayley Mountford
12:20 - 12:50	Panel discussion part 1
Lunch break
Part 2: What can rare DNA variants teach us about speech and language disorders?  Chair: Else Eising
13:30 - 14:10	Mouse models of speech disorders – unravelling mechanisms to improve diagnosis and treatment Prof. Dr. Michael Hildebrand
14:10 - 14:40	The search for rare genetic variants in stuttering: Application of trio whole exome sequencing in a cohort of individuals who stutter Ivana Dzinovic
Coffee/tea break
15:00 - 15:30	Insights from population databases: Evaluating functional consequences of rare FOXP(s) variants Dr. Barbara Molz
15:30 - 16:10	Monogenic causes for childhood apraxia of speech Prof. Dr. Angela Morgan
Refreshments
16:30 - 17:00	Panel discussion part 2

Titles and abstracts

Speaker: Prof. dr. Shelly Jo Kraft

Title: Genetics of Developmental Stuttering and New Biological Perspectives

This talk aims to highlight new genetic discoveries in developmental stuttering from a holistic perspective. The genetic complexity of stuttering is better understood when combining evidence from behavioral studies, comorbidity studies, a nd animal models. The underlying and shared biological mechanisms will be discussed, as will medical health profiling that supports broadening the recognized clinical profile of developmental stuttering across the lifespan.

 

Speaker: Dr. Else Eising

Title: Exploring the genetics of stuttering persistence

Developmental stuttering is a neurodevelopmental disorder characterized by disfluencies in speech, such as blocks, prolongations and repetitions. Stuttering generally starts early in childhood in approximately 4-8% of children, and persists into adulthood in approximately 0.8% of people. It is well established that genetic factors play a role in the development of stuttering. Large twin studies estimated the heritability of stuttering at 40% to 80%. However, it is not yet known why some children persist in their stuttering, and others don’t. One risk factor for persistent stuttering is having other family members who stutter. A pedigree analysis actually indicated that genetic factors for persistent stuttering might differ from genetic factors involved in transient stuttering. In my talk, I will show results from twin and complex trait analyses, exploring the heritability and genetic factors involved in stuttering persistence.

 

Speaker: Dr. Hayley Mountford

Title: Recent advances in genetic studies of language and reading traits using a multivariate approach

The ability to communicate through both spoken and written language are important life skills and a major route to education. Individual differences in these traits are influenced by genetic variation, with twin heritability estimates of 0.3-0.8. Until very recently, genome-wide association studies (GWAS) had only modest success in identifying the genetic variants underlying these traits, primarily due to the absence of large cohorts with suitable reading-related measures, and limited replicability between studies.

The GenLang Consortium (Eising et. al., 2022) performed meta-GWAS for word reading, nonword reading, spelling, phoneme awareness and nonword repetition, combining up to 19 cohorts (N=13,633-33,959), and identified a locus associated with word reading. The dyslexia GWAS (Doust et. al. 2023) used 23andMe, Inc. self-reported dyslexia diagnosis (51,800 cases and 1,087,070 controls), to discover 42 dyslexia associated regions.

Building on these two studies, we applied a multivariate GWAS approach (MTAG), using the high degree of shared genetics to discover additional loci for reading ability and dyslexia, increasing the effective sample size to 102,082 and 1,228,832, respectively. Polygenic scores for multivariate reading ability predicted between 2.29-3.50% of variance in reading traits in an independent sample, the National Child Development Study cohort (N = 6,410). Enrichment analysis of these regions implicates neuronally expressed genes in the developing embryonic brain, linking genetics to neurodevelopmental mechanisms. We show that by combining existing datasets to improve statistical power, these results provide novel insights into the biology of reading.

 

Speaker: Prof. dr. Michael Hildebrand

Title: Mouse models of speech disorders – unravelling mechanisms to improve diagnosis and treatment

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.

 

Speaker: Ivana Dzinovic

Title: The search for rare genetic variants in stuttering: Application of trio whole exome sequencing in a cohort of individuals who stutter

Stuttering is a motor speech disorder designated by the disruptions of speech fluency through the repetition of sounds, syllables, single or multiple words, sound prolongation, hesitation, and/or blocks. Due to its high prevalence in the general population (from ~10% among pre-school children to ~1% among adults), most genetic studies have focused on exploring the polygenic nature of stuttering. Only a few studies of large families, in which stuttering segregated across multiple generations, investigated the genetic variants of large effect and indicated that stuttering can have a monogenetic background, albeit in very rare cases. However, comprehensive systematic investigation of rare genetic causes of stuttering is still missing. Moreover, most existing studies have focused on native English speakers, thus omitting the vast linguistic heterogeneity among human populations.

We performed whole exome sequencing (WES) in a cohort of 84 trios (unaffected parents and affected offspring). Study participants were either Dutch or German native speakers. Based on the available phenotypic information, we segregated the cohort in three groups, namely persistent, ambiguous, and resolved stuttering. Our main aim was to systematically analyze the contribution of rare genetic variants with large effect, with special interest in rare de novo variants. We further prioritized variants residing in genes highly intolerant to variation, genes expressed in the brain tissue and/or known neurodevelopmental genes. We also assessed the contribution of genetic variation in genes previously associated with stuttering. Through this first large-scale WES study in a cohort of individuals who stutter, we wish to shed more light on the genetic causes of stuttering.

 

Speaker: Dr. Barbara Molz

Title: Insights from population databases: Evaluating functional consequences of rare FOXP(s) variants

Rare genetic variants in FOXP1 and FOXP2 can cause monogenic neurodevelopmental disorders with speech and language symptoms. Previous studies into these genes relied on individuals who received genetic testing because of severe symptoms. Therefore, we only have a good picture of the severe symptoms associated with causal variants in these two genes.

Here, we used the UK Biobank, a large database of nearly half a million individuals without severe disorders. We analysed whole exome sequencing data to identify rare variants in the FOXP1 and FOXP2 genes. Next, we investigated the effects of these variants on the FOXP1 and FOXP2 proteins using molecular laboratory techniques, to select the variants that damage the proteins. Lastly, using again data from the UK Biobank, we directly assessed possible phenotypic consequences of these FOXP variants.

Overall, by combining large-scale population databases with molecular laboratory assays we identified functional variants in the FOXP(s) and directly evaluated putative phenotypic consequences of carriers. This provides valuable insights into the penetrance and expressivity of FOXP variants and can help to build a more accurate representation of the phenotypic spectrum associated with the disruption of these genes.

 

Speaker: Prof. dr. Angela Morgan

Title: Monogenic causes for childhood apraxia of speech

Childhood apraxia of speech (CAS) is the prototypic severe speech disorder with an increasingly recognised genetic contribution to aetiology. In the past few years, genetic analysis of cohorts ascertained for CAS has revealed over 30 causative genes. A total of 36 pathogenic variants have been identified from 122 cases across 3 cohorts in this nascent field. Current findings suggest a remarkable one in three children have a genetic variant that explains their CAS, with significant genetic heterogeneity emerging. Around half of the candidate genes identified to date are currently supported by medium (6 genes) to strong (9 genes) evidence for the association between the specific gene of interest and CAS. Despite genetic heterogeneity; many implicated proteins functionally converge on pathways involved in chromatin modification or transcriptional regulation, opening the door to precision diagnosis and therapies. Most new candidate genes are associated with previously described neurodevelopmental conditions that include intellectual disability, autism and epilepsy; broadening the

phenotypic spectrum to a distinctly milder presentation defined by primary speech disorder in the setting of normal intellect. We have recently sequenced a further 150 trio families with a proband with CAS. The genetic yield and findings remain similar to past cohorts, although we have some new data from sex chromosome aneuploidies and an exciting new candidate gene linked to 3 cases in our new cohort. These new findings will be discussed and interpreted in light of how they align with our current knowledge of the genetic architecture of CAS and speech and language disorders more generally.