Poster Presentation 41st Lorne Genome Conference 2020

Transcriptional dysregulation underlies severe childhood speech disorder (#125)

Matthew Coleman 1 , Michael S Hildebrand 1 , Victoria E Jackson 2 , Thomas S Scerri 2 , Olivia Van Reyk 3 , Ruth Braden 3 , Samantha Turner 3 , Kristin A Rigbye 1 , Amber Boys 4 , Sarah Barton 3 , Richard Webster 5 , Michael Fahey 6 , Kerryn Saunders 6 , Bronwyn Parry-Fielder 7 , Georgia Paxton 7 , Michael Hayman 7 , David Coman 8 , Himanshu Goel 9 , Anne Baxter 9 , Alan Ma 10 , Noni Davis 11 , SHeena Reilly 3 , Martin Delatycki 4 , Frederique J Liegeois 12 , Alan Connelly 13 , Jozef Gecz 14 , Simon E Fisher 15 , David J Amor 7 , Ingrid E Scheffer 1 , Melanie Bahlo 2 , Angela T Morgan 3
  1. Department of Medicine, University of Melbourne, Heidelberg, VIC, Australia
  2. Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. Speech and Language, Murdoch Children's Research Institute, Parkville, VIC
  4. Victorian Clinical Genetics Services, Parkville, VIC, Australia
  5. Department of Neurology, The Children's Hospital Westmead, Westmead, NSW, Australia
  6. Department of Paediatrics, Monash University, Clayton, VIC, Australia
  7. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
  8. The Wesley Hospital, Auchenflower, QLD, Australia
  9. Hunter Genetics, John Hunter Hospital, New Lambton Heights, NSW, Australia
  10. Clinical Genetics, The Children's Hospital Westmead, Westmead, NSW, Australia
  11. Melbourne Children's Clinic, Melbourne, VIC, Australia
  12. UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  13. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
  14. Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
  15. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands

Determining the genetic basis of speech and language disorders provides insight into the neurobiology of human communication. Despite intensive investigation, the molecular aetiology of speech disorder remains unexplained in most children. We investigated a cohort of 34 children with suspected severe childhood speech disorder. After detailed phenotypic profiling, 32 had a confirmed diagnosis of childhood apraxia of speech (CAS) and two had severe phonological disorder, as well as a range of co-occurring neurodevelopmental features. We sequenced whole genomes or exomes of these 34 children on a research basis, and clinical microarray analysis was conducted for 15. In 11/34 (32%) of probands, we identified a pathogenic single nucleotide (n = 10) or copy number (n = 1) variant in novel genes or loci for CAS that have been implicated in neurodevelopmental disorders: CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142, and the 5q14.3q21.1 locus. In nine of these probands the variants were confirmed de novo by screening parental DNA. Seven of these genes encode proteins critical for regulation of gene transcription. In parallel collaborative work found pathogenic variants in additional families with severe childhood speech disorder in DDX3X, SETBP1, UPF2, and ZNF142. In one proband, we identified a large mosaic deletion at 5q14.3q21.1 that included two genes (CHD1, NR2F1) linked to neurodevelopmental disorders. We performed gene co-expression analyses on these genes and identified at least one distinct network of regulatory genes emerging from our molecular screening of CAS. Our findings underscore the importance of transcriptional regulation during speech development.