Fraternal Twins With Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis

• Published in: Seminars in pediatric neurology Vol. 21; no. 2; pp. 167 - 171
• Main Authors: Imitola, Jaime, MD, Walleigh, Diana, MD, Anderson, Carol E., MD, Jethva, Reena, MD, MBA, Carvalho, Karen S., MD, Legido, Agustin, MD, PhD, MBA, Khurana, Divya S., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2014
• Subjects: Autistic Disorder - diagnosis; Autistic Disorder - genetics; Autistic Disorder - physiopathology; Brain - physiopathology; Cell Adhesion Molecules, Neuronal - genetics; Child; Cognition Disorders - diagnosis; Cognition Disorders - genetics; Cognition Disorders - physiopathology; Diagnosis, Differential; Electroencephalography; Epilepsy, Absence - diagnosis; Epilepsy, Absence - genetics; Epilepsy, Absence - physiopathology; Female; Humans; Male; Microarray Analysis - methods; Nerve Tissue Proteins - genetics; Neurology; Pediatrics; Sequence Deletion; Twins, Dizygotic
• ISSN: 1071-9091; 1558-0776
• DOI: 10.1016/j.spen.2014.04.027

A 7-year-old child presented with atypical absence epilepsy. He also had autism and severe cognitive deficit. As part of his diagnostic workup, a chromosomal microarray analysis was performed, which showed novel biallelic deletions in the neurexin 1 gene ( NRXN1 ). His fraternal twin sister, who also had autism and cognitive impairment, was subsequently found to have the same biallelic deletions. Deletions included a 272-282 kb loss at band 2p16.3 in one allele and a smaller 135-174-kb loss on the second allele. Neurexin 1 (NRXN1) is a cell adhesion protein, forming a synaptic complex with neuroligin. This signals a pathway that is critical for activity-dependent synaptic transmission. Mutations in this gene have been associated with autism and neurodevelopmental delay. Although there are many reports of heterozygous mutations with variable expressivity, only 3 cases with biallelic NRXN1 mutations have been previously reported, all of which have a more severe phenotype. We report 2 siblings with biallelic deletions, both of which affect the promoter region and exons 1-5 in the α- NRXN1 isoform, which has a role in the Ca2+ -dependent release of neurotransmitters in the central nervous system. Our cases expand the phenotype of biallelic α NRXN 1 mutations and emphasize the important role of NRXN1 in autism and intellectual disability. Chromosomal microarray analysis should be the clinical standard in all specialties for first-tier genetic testing in autistic spectrum disorders.