Submission Details

The HCFC1 gene is located on chromosome Xq28 and encodes the host cell-factor 1, a transcriptional co-regulator protein implicated in the control of the cell cycle. HCFC1 was first reported in relation to X-linked intellectual disability (ID) in 2012 (PMID: 23000143). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Cases from twenty-one families were curated; most of the identified HCFC1 variants are missense changes, with 9 missense variants, one 5’UTR variant, and one splice variant resulting in an in-frame exonic deletion reported (PMIDs: 23000143, 24011988, 25740848, 26893841, 28363510, and 33517344). Most individuals inherited the HCFC1 variant from an unaffected mother, with only one de novo case scored. Most reported cases were males but mildly affected females have been described in one family with a splice variant (PMID: 33517344). Affected males present with either methylmalonic acidemia and hyperhomocysteinemia, type cblX, a severe metabolic disorder associated with ID; or with ID with mild or absent metabolic abnormalities. There is a tentative genotype-phenotype correlation in which the metabolic form is associated with HCFC1 missense variants in the conserved kelch domain and the non-metabolic phenotype is associated with HCFC1 variants outside the kelch domain, in domains important for protein interactions, heterodimerization, and nuclear localization (PMID: 33517344). This gene-disease association is supported by functional alteration in both non-patient and patient cells, demonstrating that HCFC1 binds to the MMACHC promoter, which may underlie the metabolic phenotype in severely affected patients (PMIDs: 24011988, 25281006). A zebrafish knockdown model results in craniofacial defects that can be rescued by co-injection of human HCFC1 or MMACHC (PMID: 25281006). Conditional knockout of HCFC1 in the ventral telencephalon in mouse showed reduced Nkx2.1-derived neurons and glia due to increased cell death, defects of the anterior commissure and corpus callosum, and alteration in cortical lamination (PMID: 31207118). In summary, HCFC1 is definitively associated with X-linked ID. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. Please note, due to a known issue in which the Gene Curation Interface is capping the total number of points allotted for missense variants at 7 points (not yet reflective of the change in scoring in SOP version 8), the total number of points for genetic evidence is not reflecting the true amount, which is the maximum of 12 points. This curation was approved by the ID/Autism Gene Curation Expert Panel on 3/17/21 (SOP Version 8).