Clinical and genetic profiles of grey matter heterotopia – report of 28 patients

Background: Heterotopia are rare brain malformations with a heterogenous clinical picture ranging from asymptomatic to severe epilepsy and developmental delay/intellectual disability (DD/ID). We report on the results of a study on genetic etiology of heterotopia in a Romanian pediatric population.

Materials and methods: 28 patients with heterotopia were included in this study. Phenotypic evaluation included a general clinical exam completed with neurologic, psychiatric, and psychologic evaluations, brain MRI and electroencephalograms. Genetic investigations included array based comparative genomic hybridization, and classical and next generation sequencing (WES).

Results and discussion: Brain MRI revealed subcortical band heterotopia in 2 patients, periventricular nodular heterotopia in 20 patients, and nodular subcortical heterotopia in 6 cases. Most patients were referred for epilepsy with or without DD/ID. Two genomic imbalances were identified, a duplication of 22q11.2 and a deletion of 7q35 which includes CNTNAP2 gene. A pathogenic frameshift mutation in DCX gene in a girl with band heterotopia; another patient with a complex phenotype has a pathogenic mutation in PIK3CA gene and a compound heterozygous mutation in VPS13D gene. Our study brings new data on the clinical features and epilepsy phenotypes. Both genomic inbalances and gene mutations were detected in our patient group. Brain imaging and genetic studies were instrumental in the diagnostic and patient care algorithm.

Acknowledgments: for technical support with WES to Medical Genetics Center CRH Craiova. Grants: This work was supported by grants of the Romanian National Authority for Scientific Research Innovation, CCCDI-UEFISCDI, Projects number 87/2019 and 88/2019, COFUND-ERANET E-RARE 3-HETER-OMICS-2, within PNCDI III.