A Homozygous CPSF1 Variant Causes Congenital Cataract, Intellectual Disability and Hyperphagia

The cleavage and polyadenylation specific factor 1 (CPSF1) gene encodes a subunit of the cleavage and polyadenylation specificity factor (CPSF), a multi-protein complex essential for mRNA 3' end processing. The role of CPSF1 in retinal function and eye development has been demonstrated using zebrafish models and heterozygous variants in CPSF1 have been reported in early-onset high myopia (MIM: 618827). Here, we present a patient with bilateral congenital cataracts and intellectual disability with a novel homozygous missense variant (c.3817G>C; p.Asp1273His) in CPSF1. This amino acid change is predicted to change the protein structure with likely damaging effect. Proteomic results in white blood cells revealed increased CPSF1 protein abundance and dysregulated proteins in pathways linked to cellular signalling processes, protein degradation, and exosome biology. To our knowledge, this is the first report of recessive CPSF1-related disease in humans presenting as a case with congenital cataracts, intellectual disability, and hyperphagia.