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

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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.

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Case 1

The propositus was a full-term male child of an uneventful twin gestation pregnancy. Parents were healthy, nonconsanguineous white individuals, with no family history of developmental delay or cognitive deficits, seizures, autism, or mental health problems. He had a history of ventricular septal defect. Psychomotor development was severely delayed for motor skills (he sat up at 1 year and walked at 2 years) and for language. He also developed clinical features compatible with the diagnosis of

Case 2

The fraternal twin sister of the propositus was also born at full term with no medical issues. However at 6 months of age, she showed an inability to play and interact with others. She was later diagnosed with severe developmental delay and language impairment. Her clinical progress was very slow. At 7 years, she had some vocalizations, and her language was limited to 2-5 words. She had strabismus, hypotonia, and ataxia. Other symptoms included hyperventilation, stereotypies, constipation, and

Genetic Studies

Chromosomal microarray analysis was performed in our patients to identify copy number variations associated with an underlying genetic etiology.

The studies were approved by the institutional review board of St. Christopher’s Hospital. The patients had normal results for an extensive range of tests, including a detailed metabolic investigation and routine karyotyping. Genomic DNA was isolated from blood for whole-genome array single nucleotide polymorphism comparative genomic hybridization.

Discussion

Chromosomal microarray has emerged as a powerful tool to identify genomic abnormalities associated with a wide range of developmental disabilities. The frequency of disease-causing copy number variants has been described in 20%-25% of children with moderate to severe intellectual disability accompanied by malformations or dysmorphic features and in 5%-10% of cases of autism.3 It is therefore increasingly used as a first-line test in the diagnostic workup or children with autism, especially if

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