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Am J Med Genet B Neuropsychiatr Genet. 2018 Sep;177(6):589-595. doi: 10.1002/ajmg.b.32673. Epub 2018 Aug 4.

A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three-generation Chinese family.

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Dongguan Maternal and Child Health Care Hospital, Dongguan, People's Republic of China.
Dongguan Institute of Reproductive and Genetic Research, Dongguan, People's Republic of China.
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Fengcheng No.1 High School, Liaoning, People's Republic of China.
Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China.
Division of Genetics and Genomics, Boston Children's Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts.


Members of the neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3) encode important components of synaptic function implicated in autism and other neurodevelopmental/neuropsychiatric disorders. Loss of function variants have been reported predominantly in NRXN1, with fewer such variants detected in NRXN2 and NRXN3. Evidence for segregating NRNX3 variants has particularly been lacking. Here, we report identification by chromosomal microarray analysis of a rare exonic deletion affecting the NRXN3 alpha isoform in a three-generation Chinese family. The proband, a 7-year-old boy, presented with motor and language delay and met the clinical diagnostic criteria for autism. He also presented with moderate intellectual disability, attention-deficit hyperactivity disorder and facial dysmorphic features. The mother and maternal grandfather, both deletion carriers, presented with variable degrees of language and communication difficulties, as well as neuropsychiatric problems such as schizophrenia and temper tantrums. A compilation of sporadic cases with deletions involving part or all of NRXN3 revealed that 9 of 23 individuals (39%) displayed features of autism. The evidence for cosegregation in our family further supports a role for NRXN3 in autism and neurodevelopmental/neuropsychiatric disorders but demonstrates intrafamily variable expressivity due to this NRXN3 deletion, with schizophrenia and facial dysmorphism being potential novel features of NRXN3 haploinsufficiency.


NRXN3; autism; intrafamily expressivity; intragenic deletion

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