A Novel de novo Frameshift Mutation in the BCL11A Gene in a Patient with Intellectual Disability Syndrome and Epilepsy

Authors

Georg Christoph Korenke ¹, Björn Schulte ^{2 3}, Saskia Biskup ^{2 3}, John Neidhardt ^{4 5 6 7}, Marta Owczarek-Lipska ⁴

Department of Neuropediatrics, University Children’s Hospital, Klinikum Oldenburg, Oldenburg, Germany.
Praxis für Humangenetik, Tübingen, Germany.
Center for Genomics and Transcriptomics, CeGaT GmbH, Tübingen, Germany.
Human Genetics, Faculty VI – School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.
Research Center Neurosensory Science, University of Oldenburg, Oldenburg, Germany.
Joint Research Training Group of the Faculty VI – School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany, and University Medical Center Groningen, Groningen, The Netherlands.
Junior Research Group, Genetics of Childhood Brain Malformations, Faculty VI – School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.

Intellectual disability syndrome (IDS) associated with a hereditary persistence of fetal haemoglobin (HbF), also known as Dias-Logan syndrome, is commonly characterised by psychomotor developmental delay, intelectual disability, language delay, strabismus, thin upper lip, abnormalities of external ears, microcephaly, downslanting palpebral fissures. Sporadically, autism spectrum disorders and blue sclerae in infancy have been reported in IDS. Rarely, IDS-affected patients present with epilepsy and/or epileptic syndromes. It has been shown that a haploinsufficiency of the B cell leukaemia/lymphoma 11A gene (BCL11A) is responsible for IDS. Herein, we identified a novel de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene in a boy affected with IDS. Interestingly, this heterozygous loss-of-function BCL11A mutation was also associated with a generalised idiopathic epilepsy and severe language delay observed in the patient. Moreover, our study showed that the combination of molecular genetic analyses with the monitoring of HbF was essential to make the final diagnosis of Dias-Logan syndrome. Because our patient suffered from well-controlled epilepsy, we propose to include the BCL11A gene in routinely used molecular genetic epilepsy-related gene panels. Additionally, many of the clinical features of IDS overlap with symptoms observed in patients with suspected alcohol spectrum disorders. Therefore, we also suggest monitoring HbF levels in patients with these syndromes to further facilitate clinical diagnosis.