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NLGN2 Haploinsufficiency Causes a Distinctive Neurobehavioral Phenotype Characterized By Anxiety, Autism, Intellectual Disability, and Obesity
Objectives: Investigation of the molecular basis of a distinctive neurobehavioral phenotype in a 14-year-old Caucasian male.
Methods: The proband exhibited global developmental delay since early infancy. He was diagnosed with PDD-NOS at age 3 years but later his phenotype has been dominated by short attention span, severe anxiety and obsessive-compulsive behaviors. His other problems included hypotonia, some dysmorphic features, macrocephaly and obesity, which was associated with hyperphagia, food-seeking behavior, and diet-related obsession. His previous work-up has been negative and included chromosomal microarray analysis, molecular testing for fragile X syndrome, and methylation studies for Prader Willi syndrome. Exome sequencing was performed using Agilent Clinical Research Exome kit and Illumina HiSeq 2000 100 bp paired-end reads. GeneDx's XomeAnalyzer was used to evaluate sequence changes between the proband, parental samples and reference. Sanger sequencing was used to confirm positive exome findings.
Results: Exome sequencing revealed a heterozygous de novo variant in NLGN2designated as c.441C>A (p.Y147X; p.Tyr147Ter), which has not been reported previously as a disease causing mutation nor as a benign polymorphism. It is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Conclusions: This is the first report of a truncating variant in NLGN2 that recapitulates the anxiety phenotype in mice. We provide evidence that the de-novo loss-of-function variant in our proband is pathogenic. Our data add to the accumulating evidence implicating synaptic proteins in the etiologies of a spectrum of neurodevelopmental phenotypes and demonstrate the power of exome sequencing in psychogenetics. The genetic data may have implications for the treatment of the psychological findings in our proband.