Phenotypic spectrum of NRXN1 mono- and bi-allelic deficiency: A systematic review

Clin Genet. 2020 Jan;97(1):125-137. doi: 10.1111/cge.13537. Epub 2019 May 7.


Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes (NRXN1-3), each yielding a longer alpha (α) and a shorter beta (β) transcript. Deletions spanning the promoter and the initial exons of the NRXN1 gene, located in chromosome 2p16.3, are associated with a variety of neurodevelopmental, psychiatric, neurological and neuropsychological phenotypes. We have performed a systematic review to define (a) the clinical phenotypes most associated with mono-allelic exonic NRXN1 deletions, and (b) the phenotypic features of NRXN1 bi-allelic deficiency due to compound heterozygous deletions/mutations. Clinically, three major conclusions can be drawn: (a) incomplete penetrance and pleiotropy do not allow reliable predictions of clinical outcome following prenatal detection of mono-allelic exonic NRXN1 deletions. Newborn carriers should undergo periodic neuro-behavioral observations for the timely detection of warning signs and the prescription of early behavioral intervention; (b) the presence of additional independent genetic risk factors should always be sought, as they may influence prognosis; (c) children with exonic NRXN1 deletions displaying early-onset, severe psychomotor delay in the context of a Pitt-Hopkins-like syndrome 2 phenotype, should undergo DNA sequencing of the spared NRXN1 allele in search for mutations or very small insertions/deletions.

Keywords: Pitt-Hopkins-like syndrome 2; autism spectrum disorder; compound heterozygosity; developmental delay; neurexin 1; schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Calcium-Binding Proteins / deficiency
  • Calcium-Binding Proteins / genetics*
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Genetic Predisposition to Disease*
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Mental Disorders / genetics
  • Mental Disorders / pathology
  • Mutation
  • Nervous System Diseases / genetics
  • Nervous System Diseases / pathology
  • Neural Cell Adhesion Molecules / deficiency
  • Neural Cell Adhesion Molecules / genetics*
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / pathology
  • Phenotype


  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal
  • NRXN1 protein, human
  • Neural Cell Adhesion Molecules