Submission Details

HEPHL1 was first reported in relation to autosomal dominant iron overload in 2015 (McDonald CM et al., PMID: PMID: 26151776) the p.Asp136Val variant mentioned in this study is found in 101 alleles including 1 homozygous in gnomAD V4 making it’s role unclear in the proband described. Biallelic *HEPHL1 *variants were later associated with a phenotype of pilli torti and developmental delay (Sharma P et al., PMID: 31125343). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism using the evidence provided by these papers. Therefore, the following disease entities have been lumped into one disease entities pili torti-developmental delay-neurological abnormalities syndrome. Two variants (one missense and one in-frame del, that have been reported in one probands in one publications (Sharma P et al., PMID: 31125343) are included in this curation. The mechanism of pathogenicity appears to be loss of function as both published variants reported resulted in non-detectable conversion of Fe (II) to Fe (III) indicating that that both mutants were catalytically inactive in the assay (Sharma P et al., PMID: 31125343). This gene-disease relationship is also supported by mouse models where Hephl1 knockout mouse model exhibited short, curled whiskers that was not found in Heterozygous mice (Zp+/-) models (Sharma P et al., PMID: 31125343). No additional neurological phenotypes were tested in these animal models according to the publication. In summary, there is limited evidence supporting the relationship between HEPHL1 and autosomal recessive pili torti-developmental delay-neurological abnormalities syndrome. This classification was approved by the ClinGen IEM GCEP on the meeting date February 14 (SOP Version 11).