Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

Hum Genomics. 2021 Feb 8;15(1):11. doi: 10.1186/s40246-021-00309-4.


Background: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations.

Methods: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs).

Results: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient.

Conclusions: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

Keywords: CNV; Cerebral palsy; Dystonia; Epilepsy; Neuromotor delay; Variome.

Publication types

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

MeSH terms

  • Cerebral Palsy / genetics
  • Cerebral Palsy / pathology
  • Child
  • DNA Copy Number Variations / genetics*
  • Developmental Disabilities / epidemiology
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / pathology
  • Dystonia / genetics
  • Dystonia / pathology
  • Epilepsy / genetics
  • Epilepsy / pathology
  • Exons / genetics
  • Gene Duplication / genetics
  • Genetic Predisposition to Disease*
  • Humans
  • KCNQ2 Potassium Channel / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Mutation / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Seizures / genetics
  • Seizures / pathology
  • Synaptic Transmission / genetics


  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • Membrane Proteins