RT Journal Article SR Electronic T1 Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2020-106873 DO 10.1136/jmedgenet-2020-106873 A1 Marilena Elpidorou A1 Sunayna Best A1 James A Poulter A1 Verity Hartill A1 Emma Hobson A1 Eamonn Sheridan A1 Colin A Johnson YR 2020 UL http://jmg.bmj.com/content/early/2020/06/22/jmedgenet-2020-106873.abstract AB 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.