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Both gain- and loss-of-function mutations have recently implicated  HCFC1  in neurodevelopmental disorders. Here, we extend our previous  HCFC1  over-expression studies by employing short hairpin RNA to reduce the expression of  Hcfc1  in embryonic neural cells. We show that in contrast to over-expression, loss of Hcfc1 favoured proliferation of neural progenitor cells at the expense of differentiation and promoted axonal growth of post-mitotic neurons. To further support the involvement of  HCFC1  in neurological disorders, we report two novel  HCFC1  missense variants found in individuals with intellectual disability (ID). One of these variants, together with three previously reported  HCFC1  missense variants of unknown pathogenicity, were functionally assessed using multiple cell-based assays. We show that three out of the four variants tested result in a partial loss of HCFC1 function. While over-expression of the wild-type  HCFC1  caused reduction in HEK293T cell proliferation and axonal growth of neurons, these effects were alleviated upon over-expression of three of the four  HCFC1  variants tested. One of these partial loss-of-function variants disrupted a nuclear localization sequence and the resulting protein displayed reduced ability to localize to the cell nucleus. The other two variants displayed negative effects on the expression of the HCFC1 target gene  MMACHC,  which is responsible for the metabolism of cobalamin, suggesting that these individuals may also be susceptible to cobalamin deficiency. Together, our work identifies plausible cellular consequences of missense  HCFC1  variants and identifies likely and relevant disease mechanisms that converge on embryonic stages of brain development.

HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain