A missense variant in the KH0-domain of FMRP downregulates the protein in a patient with the clinical hallmarks of fragile X syndrome.

The majority of patients affected by fragile X syndrome (OMIM #300624), a common inherited form of autism spectrum disorders and intellectual disability, displays a CGG triplet repeat expansion in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene promotor, resulting in hypermethylation and epigenetic silencing of the associated FMRP protein. Only a handful of missense variants have been described as causative for fragile X syndrome and only the p.Arg138Gln variant has been reported as recurrent. Here, we present a 23-year-old male subject with the clinical characteristics of fragile X syndrome who is diagnosed with the maternally inherited missense variant c.500A>C, that translates proline at amino acid residue 167 instead of glutamic acid (p.Gln167Pro), but without an FMR1 repeat expansion. Western blotting experiments demonstrated that the Gln167Pro mutant showed a remarkable reduction of FMRP expression in lymphoblastoid cell lines, paralleled by similar observations in a HEK293T overexpression system. Subsequent lymphoblastoid transcriptome analysis showed a dysregulated gene signature with significant overlap with that observed in patients with a fragile X repeat expansion. Genome-wide methylation analysis confirmed hypomethylation of the FMR1 promotor region, indicative for expression of the gene. This report suggests that the FMR1 c.500A>C (p.Gln167Pro) missense variant is causative for a fragile X syndrome phenotype with a disrupted molecular gene signature characteristic for the syndrome and illustrates the use of an ID gene panel as a complementary diagnostic tool in case of a negative CGG repeat expansion test.