title: Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.
abstract: 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 272-282kb 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 Ca(2+)-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.
authors.affiliation: Division of Neuroimmunology and Multiple Sclerosis, Department of Neurology and Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH.
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.affiliation: Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Diana
authors.initials: D
authors.lastname: Walleigh
authors.affiliation: Section of Genetics, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Carol E
authors.initials: CE
authors.lastname: Anderson
authors.affiliation: Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA; Section of Genetics, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Reena
authors.initials: R
authors.lastname: Jethva
authors.affiliation: Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Carvalho
authors.affiliation: Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Agustin
authors.initials: A
authors.lastname: Legido
authors.affiliation: Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA. Electronic address: divya.khurana@drexelmed.edu.
authors.forename: Divya S
authors.initials: DS
authors.lastname: Khurana
mesh_terms: D001321:Autistic Disorder / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002648:Child; D003072:Cognition Disorders / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D003937:Diagnosis, Differential; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D046228:Microarray Analysis / Q000379:methods*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D017384:Sequence Deletion; D014429:Twins, Dizygotic
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules