Abstract
Approximately 10-15% of intellectual disability (ID) cases are caused by genetic aberrations affecting chromosome X, a condition termed X-linked ID (XLID). Examination by whole-exome sequencing of two male siblings with microcephaly and suspected XLID with an unknown genetic basis revealed that they were both hemizygous for a predicted pathogenic variant (p.Ala897Val) causing a non-synonymous substitution of an evolutionary conserved amino acid within the host cell factor C1 (HCFC1) gene. Subsequent analysis determined that this was a rare variant not identified in 100 control individuals or in online databases of control individuals. Recent studies have reported mutations affecting HCFC1 in patients with ID and dysmorphic features that are associated with defective cobalamin metabolism. Biochemical investigations did not find evidence of an association between the variant identified in the present study and cobalamin metabolic disorder. This study offers further support for mutations of HCFC1 being implicated in XLID and microcephaly, but that these are not necessarily associated with cobalamin disorder.