Haploinsufficiency of ATP6V0C possibly underlies 16p13.3 deletions that cause microcephaly, seizures, and neurodevelopmental disorder

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Rory J Tinker
  • George J Burghel
  • Maggie Steggall


We recently contributed to the description of eight individuals with a novel condition caused by 16p13.3 microdeletions encompassing TBC1D24, ATP6V0C, and PDPK1 and resulting in epilepsy, microcephaly and neurodevelopmental problems. The phenotypic spectrum, the minimum overlapping region and the underlying disease mechanism for this disorder remain to be clarified. Here we report a 3.5‐year‐old male, with microcephaly, autism spectrum disorder and a de novo 16p13.3 microdeletion. We performed detailed in silico analysis to show that the minimum overlapping region for the condition is ~80Kb encompassing five protein coding genes. Analysis of loss of function constraint metrics, transcript‐aware evaluation of the population variants, GeVIR scores, analysis of reported pathogenic point variants, detailed review of the known functions of gene products and their animal models showed that the haploinsufficiency of ATP6V0C likely underlies the phenotype of this condition. Protein–protein interaction network, gene phenology and analysis of topologically associating domain showed that it was unlikely that the disorder has an epistatic or regulatory basis. 16p13.3 deletions encompassing ATP6V0C cause a neurodevelopmental disorder. Our results broaden the phenotypic spectrum of this disorder and clarify the likely underlying disease mechanism for the condition.

Bibliographical metadata

Original languageEnglish
JournalAmerican Journal of Medical Genetics Part A
Early online date8 Oct 2020
Publication statusE-pub ahead of print - 8 Oct 2020