Diagnostic outcomes of the australian genomics brain malformations flagship

Abstract

Malformations of brain development (MBD) represent a large group of conditions resulting from disturbances in brain formation during pregnancy While individually rare, collectively MBD are a major cause of disability, cerebral palsy and epilepsy. This cohort project aimed to determine the genetic diagnostic yield in MBD patients using singleton 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. Pathogenic/likely pathogenic variants identified in clinically relevant genes were reported according to the American College of Medical Genetics standards and guidelines. Genetic causes were identified in 38/102 (37.2%) patients: 8/38 (21%) had Pathogenic/likely pathogenic variants in TUB1A1; 2/38 (5.3%) in DCX, 2/38 (5.3%) in TUBB2B, 2/38 (5.3%) in DYNC1H1, 2/38 (5.3%) in FLNA, 2/38 (5.3%) in FOXG1; and the remaining 20/38 (52.6%) had Pathogenic/likely pathogenic variants(s) in one of the following genes: ACTB, AHI1, CASK, CEP85L, CHMP1A, COL4A1, DCHS1, DEPDC5, DHCR7, KIF1A, KIF1BP, NIPBL, NSDHL, PIGG, POMGNT1, SON, TMEM237, TSEN54, TUBB2A, and ZBTB18. This study reached a genetic diagnostic rate of 37.2%, which is consistent with previous smaller studies. We confirmed that using WES for genetic diagnosis of MBD is an efficient method to address the high genetic heterogeneity of these disorders. It is likely that trio WES could potentially yield a greater diagnostic rate. Benefits for patients with a genetic diagnosis included ending the diagnostic odyssey and improved prognostic and reproductive counseling.L6351862972021-06-10 <br />