Genomic Variants and Variations in Malformations of Cortical Development - 28/05/15

Doi : 10.1016/j.pcl.2015.03.002

Saumya S. Jamuar, MD ^a,^b,^c,^d,^e, Christopher A. Walsh, MD, PhD ^b,^c,^d,^f,^⁎
^a Department of Paediatrics, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore
^b Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA
^c Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
^d Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
^e Paediatrics Academic Programme, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore
^f Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA

^∗Corresponding author. Division of Genetics and Genomics, Boston Children’s Hospital, Center for Life Sciences 15062.2, 3 Blackfan Circle, Boston, MA 02115.

Résumé

Malformations of cortical development (MCDs) are a common cause of neurodevelopmental delay and epilepsy and are caused by disruptions in the normal development of the cerebral cortex. Several causative genes have been identified in patients with MCD. There is increasing evidence of role of de novo mutations, including those occurring post fertilization, in MCD. These somatic mutations may not be detectable by traditional methods of genetic testing performed on blood DNA. Identification of the genetic cause can help in guiding families in future pregnancies. Research has highlighted how elucidation of key molecular pathways can also allow for targeted therapeutic interventions.

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Keywords : Malformations of cortical development, Genomic variants, Somatic mutation, Microcephaly, Megalencephaly, Cortical dysplasia, Lissencephaly, Polymicrogyria

Plan

Key points

Clinical background

Embryology of cerebral cortical development

Recent advances in genetics and pathomechanism of malformations of cortical development

Overview

Microcephaly

Overgrowth-Related Disorders

Abnormal Neuronal Migration

Single Nucleotide Variants

Copy Number Variants

Current management of the disease

Investigations

Management

Future treatment approaches

	Disclosure: No conflicts of interest to declare.
	C.A. Walsh is supported by grants from the National Institute of Mental Health (R01MH083565 and 1RC2MH089952), the National Institute of Neurological Disorders and Stroke (R01NS032457, R01NS079277 and R01NS035129), the Simons Foundation, the Paul G. Allen Family Foundation, and the Manton Center for Orphan Disease Research. C.A. Walsh is an Investigator of the Howard Hughes Medical Institute.