Genetic assessment of congenital brain malformations. U. Hehr1,2, T. Rödl1, S. M. Herbst1,2, S. Schirmer1, T. Geis3, B. Kasper4, G. Schuierer5, J. Winkler6, G. Uyanik7 1) Center for Human Genetics, Regensburg, Germany; 2) Department of Human Genetics, University of Regensburg, Regensburg, Germany; 3) Department of Pediatrics, University Hospital Regensburg, Regensburg, Germany; 4) Department of Neurology, University Hospital Erlangen, Erlangen, Germany; 5) Division of Neuroradiology, University Hospital Regensburg, Regensburg, Germany; 6) Division of Molecular Neurology, University Hospital Erlangen, Erlangen, Germany; 7) Center for Medical Genetics, Hanusch Hospital, Vienna, Austria.

   Congenital brain malformations are a clinically and genetically important cause of early developmental delay, cognitive impairment and seizures. They are identified and classified based on specific structural cerebral abnormalities observed in cerebral imaging. We report our genetic results for a cohort of more than 950 independent patients with holoprosencephaly (HPE) and neuronal migration disorders (periventricular nodular heterotopia, subcortical band heterotopia, classical lissencephaly, polymicrogyria and cobblestone lissencephaly) over 13 years. Genetic testing was individually assigned considering available clinical information including family history as well as cerebral imaging. Individual testing strategies included linkage analysis for suitable families, CNV analysis by MLPA, Sanger sequencing and most recently the introduction of massive parallel sequencing, allowing the identification of the underlying genetic alterations for approximately 25% of analyzed samples. In the HPE cohort mutations were identified in SHH (16 patients), SIX3 (10), ZIC2 (14), TGIF (3), Gli2 (4). In patients with neuronal migration disorders identified mutations affected LIS1 (30), DCX (57), ARX (13), TUBA1A (5), TUBB2B (3), GPR56 (8), FLNA (32), POMT1 (16), POMGnT1 (15), FKTN (4), FKRP (7), ISPD (1), LARGE (2). Genotype phenotype correlations in particular were observed for DCX, ARX and POMT1, where truncating mutations more frequently resulted in more severe clinical manifestations. Genetic findings support the differential diagnosis, prognostic evaluation as well as genetic counseling including the option of prenatal genetic testing or even preimplantation genetic diagnosis. Our data draw special attention to autosomal dominant or X-linked genetic forms, associated with a high recurrence risk for further offspring and transmitted by apparently "healthy" parents. At closer examination a substantial proportion of heterozygous mutation carriers for X-linked conditions associated with mutations in FLNA, ARX or DCX themselves presents with a wide range of clinical manifestations, which may significantly impair social interactions as well as the perception of health and genetic risks and are currently further addressed in an ongoing study. Genome wide genetic testing strategies will further improve the number of identified genes and genetic alterations, but continue to require their critical interpretation in the context of clinical findings and cerebral imaging.

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