Rhizomelic chondrodysplasia punctata (RCDP) is a group of disorders with overlapping clinical features including rhizomelia,
chondrodysplasia punctata, coronal clefts,
cervical dysplasia, congenital
cataracts, profound postnatal growth retardation, severe
intellectual disability, and
seizures. Mutations in PEX7, GNPAT, and AGPS, all involved in the
plasmalogen-biosynthesis pathway, have been described in individuals with RCDP. Here, we report the identification of mutations in another gene in
plasmalogen biosynthesis,
fatty acyl-CoA reductase 1 (FAR1), in two families affected by severe
intellectual disability, early-onset
epilepsy,
microcephaly, congenital
cataracts, growth retardation, and spasticity. Exome analyses revealed a homozygous in-frame indel mutation (c.495_507delinsT [p.Glu165_Pro169delinsAsp]) in two siblings from a consanguineous family and compound-heterozygous mutations (c.[787C>T];[1094A>G], p.[Arg263(∗)];[Asp365Gly]) in a third unrelated individual. FAR1 reduces
fatty acids to their respective
fatty alcohols for the
plasmalogen-biosynthesis pathway. To assess the pathogenicity of the identified mutations, we transfected human embryonic kidney 293 cells with plasmids encoding FAR1 with either wild-type or mutated constructs and extracted the
lipids from the cells. We screened the
lipids with gas chromatography and mass spectrometry and found that all three mutations abolished the
reductase activity of FAR1, given that no
fatty alcohols could be detected. We also observed reduced
plasmalogens in red blood cells in one individual to a range similar to that seen in individuals with RCDP, further supporting abolished FAR1 activity. We thus expand the spectrum of clinical features associated with defects in
plasmalogen biosynthesis to include FAR1 deficiency as a cause of syndromic severe
intellectual disability with
cataracts,
epilepsy, and growth retardation but without rhizomelia.