Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

Am J Med Genet A. 2021 Mar;185(3):894-900. doi: 10.1002/ajmg.a.62025. Epub 2020 Dec 24.


Neuroligin 4 X-linked (NLGN4X) is an X-linked postsynaptic scaffolding protein, with functional role in excitatory synapsis development and maintenance, that has been associated with neuropsychiatric disorders such as intellectual disability, autism spectrum disorders (ASD), anxiety, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome. Chromosomal microarray analysis identified a paternally inherited, 445 Kb deletion on Xp22.3 that includes the entire NLGN4X in a 2.5 year old female (46,XX) with congenital hypotonia, strabismus, ASD, and increased aggressive behavioral issues. Her family history is significant for a mother with learning disabilities, a father with anxiety, major depressive disorder, and substance abuse, as well as two maternal half-brothers with developmental delays. X-inactivation studies in the proband's blood showed random X-inactivation despite the presence of an abnormal X chromosome. Furthermore, trio exome sequencing did not reveal any other deleterious variant that could explain her phenotype. Our report describes the first example of a paternally inherited NLGN4X microdeletion as the genetic etiology of ASD in a female proband, and the psychiatric phenotypes in the father. It also provides further evidence that NLGN4X is sensitive to dosage changes in females, and can contribute to a variety of psychiatric features within the same family.

Keywords: NLGN4X; X inactivation; autism; clinical exome; microarray; microdeletion.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aggression
  • Anxiety / genetics
  • Autism Spectrum Disorder / genetics
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Child Behavior Disorders / genetics
  • Child, Preschool
  • Chromosomes, Human, X / genetics*
  • Developmental Disabilities / genetics*
  • Exome Sequencing
  • Female
  • Gene Deletion*
  • Genes, X-Linked / genetics*
  • Genetic Diseases, X-Linked / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Learning Disabilities / genetics
  • Male
  • Medical History Taking
  • Microarray Analysis
  • Paternal Inheritance
  • Seizures / genetics
  • Strabismus / genetics
  • Substance-Related Disorders / genetics
  • Tourette Syndrome / genetics*
  • X Chromosome Inactivation


  • Cell Adhesion Molecules, Neuronal
  • NLGN4X protein, human