HELLS was first reported in relation to autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome 4 in 2015 (Thijssen et al., PMID: 26216346). This condition is characterized by recurrent infection, dysmorphic facial features, developmental delay, cytogenetic abnormalities on chromosomes 1,9, and 16, and hypomethylation of alpha satellite regions. Six variants (frameshift, in frame deletion, missense, nonsense, and splice site) have been reported in five probands in two publications (PMIDs: 26216346, 30511102). Variants segregated with disease in two families. Heterozygous parents and siblings were unaffected. The mechanism of pathogenicity appears to be loss of function.
This gene-disease association is also supported by biochemical function, GTEx bulk tissue expression showing that HELLS is greatly expressed in EBV transformed lymphocytes and other highly proliferative tissues such as the testis, and a co-immunoprecipitation assay demonstrated that HELLS interacts with CDCA7, which is associated with ICF type 3 (PMIDs:23715323, 36012581, 30307408). Additionally, the gene-disease relationship is supported by several cell culture and animal models, including a conditional mouse model which showed that knocked out LSH (mouse orthologue of HELLS) recapitulated a core immunological phenotype of reduced Ig levels (PMID: 32727902). Other cell culture models demonstrated that knock down HELLS recapitulated phenotypes of centromeric hypomethylation (PMID:26216346), while another model suggests HELLS may effect NHEJ, which may reflect a deficiency in class switch recombination observed in patients (PMID:32727902). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This classification was originally approved by the ClinGen SCID-CID GCEP on 4/20/2023. This gene-disease relationship was re-evaluated on 4/16/2025. As a result of this re-evaluation, no new evidence was identified and the classification did not change (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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