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Original research
Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality
  1. Marilena Elpidorou1,
  2. Sunayna Best1,2,
  3. James A Poulter1,
  4. Verity Hartill1,2,
  5. Emma Hobson2,
  6. Eamonn Sheridan1,2,
  7. Colin A Johnson1
  1. 1Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, West Yorkshire, UK
  2. 2Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, West Yorkshire, UK
  1. Correspondence to Dr Colin A Johnson, Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS2 9JT, West Yorkshire, UK; c.johnson{at}


Background The HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype.

Methods and results We ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA.

Conclusion This study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders.

  • developmental
  • molecular genetics

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  • Twitter @MElpidorou, @jamesapoulter

  • Contributors ES and CAJ contributed equally to this manuscript by conceiving of the study, supervising the research and analysing data. ME, JAP and VH performed genetic analyses and interpreted the data. ME performed cell biology and biochemical experiments. SB and EH reviewed the clinical data. All authors contributed to drafting the manuscript and reviewed the final submission.

  • Funding This study was funded by a Sir Jules Thorn Award for Biomedical Research (JTA/09 to ES and CAJ), British Heart Foundation (Clinical Training fellowship FS/13/32/30069 to VH), Wellcome Trust (PhD Training Fellowship for Clinicians 217079/Z/19/Z to SB) and the University of Leeds.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval Members of the family were recruited following informed consent under ethical approval for molecular genetics research studies from South Yorkshire Research Ethics Committee (REC reference number 11/H1310/1). The study adhered to the tenets outlined in the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Further details and data can be obtained from the corresponding author CAJ (email:

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