Poster Presentation 41st Lorne Genome Conference 2020

Diagnostic outcomes of the Australian genomics brain malformations flagship (#162)

Daniz Kooshavar 1 2 , Kate Riney 3 , Christopher Barnett 4 , Jonathon Silberstein 5 , Rani Sachdev 6 , Shekeeb S Mohammad 7 , Kathryn North 1 8 , Tiffany Boughtwood 1 8 , Paul J Lockhart 1 2 , Richard J Leventer 1 2 9
  1. Murdoch Children's Research Institute (MCRI), Parkville, VIC, Australia
  2. Department of Paediatrics, The University of Melbourne,, Melbourne, Victoria, Australia
  3. Neuroscience Unit, Queensland Children’s Hospital, Brisbane, Queensland, Australia
  4. SA Clinical Genetics Service, Women's and Children's Hospital, Adelaide, South Australia, Australia
  5. Department of Neurology, Princess Margaret Hospital, Perth, Western Australia, Australia
  6. Department of Medical Genetics, Sydney Children’s Hospital, Sydney, New South Wales, Australia
  7. Department of Neurology, Westmead Hospital, Sydney, New South Wales, Australia
  8. Australian Genomics Health Alliance, Melbourne, Victoria, Australia
  9. The Royal Children's Hospital, Melbourne, Victoria, Australia

Malformations of brain development represent a large group of conditions resulting from disturbances in brain development, examples include lissencephaly and cortical dysplasia. Whilst individually rare, collectively brain malformations are a major cause of disability, foetal loss, cerebral palsy and epilepsy.

This cohort project aimed to determine the genetic diagnostic yield in MCD patients using clinical whole exome sequencing (WES). We performed a nation-wide multi-centre cohort study as part of the Australian Genomics Health Alliance. Patients were selected based on stringent inclusion criteria regarding age, clinical features, and prior genetic testing. The sequence data analysis was restricted to clinically relevant genes. Pathogenic/likely pathogenic mutations were identified and reported according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) standards and guidelines.

Genetic causes were identified in 40/100 (40%) patients: 7/40 (17.5%) had a mutation in TUB1A1; 2/40 (5%) in DCX, 2/40 (5%) in TUBB2B, 2/40 (5%) in DYNC1H1, 2/40 (5%) in FLNA, 2/40 (5%) in FOXG1; and the remaining 23/40 (57.5%) had a mutation in one of the following genes ACTB, AHI1, CASK, CHMP1A, COL4A1, DCHS1, DEPDC5, DHCR7, KIF1A, KIF1BP, MKRN3, NIPBL, NPRL3, NSDHL, PARN, PIGG, POMGNT1, SON, TMEM237, TSC2, TSEN54, and ZBTB18.

This study reached a genetic diagnostic rate of 40%, which is consistent with previous studies. Using WES for genetic diagnosis of MCDs is an efficient method to address the high genetic heterogeneity of the disease. Nevertheless, although genetic causes are thought to underlie the majority of MCDs there is still a large number of patients with no genetic diagnosis. A limitation of this study was restricted analysis to genes known to be associated with brain malformations. Continued investigations in the research setting are being performed to identify potential novel genes associated with brain malformations.