Implication of LRRC4C and DPP6 in neurodevelopmental disorders

Am J Med Genet A. 2017 Feb;173(2):395-406. doi: 10.1002/ajmg.a.38021. Epub 2016 Oct 19.


We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. © 2016 Wiley Periodicals, Inc.

Keywords: DPP6; LRRC4C; Netrin G; autism; sensory processing.

MeSH terms

  • 5' Untranslated Regions
  • Adolescent
  • Adult
  • Apraxias / diagnosis
  • Apraxias / genetics
  • Autistic Disorder / diagnosis
  • Autistic Disorder / genetics
  • Child
  • Child, Preschool
  • Chromosome Breakpoints
  • Chromosome Inversion
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics*
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Genetic Association Studies*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Karyotype
  • Male
  • Middle Aged
  • Multigene Family
  • Nerve Tissue Proteins / genetics*
  • Neurodevelopmental Disorders / diagnosis*
  • Neurodevelopmental Disorders / genetics*
  • Pedigree
  • Phenotype*
  • Potassium Channels / genetics*
  • Receptors, Cell Surface / genetics*
  • Translocation, Genetic
  • Young Adult


  • 5' Untranslated Regions
  • LRRC4C protein, human
  • Nerve Tissue Proteins
  • Potassium Channels
  • Receptors, Cell Surface
  • DPP6 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases