Fourteen de novo loss-of-function variants in RFX7were identified, including four frameshift variants, five stop gain variants, one in-frame deletion, and two missense variants.
RFX7exhibits intolerance to loss-of-function variation in human population databases (gnomAD, pLI scores = 1.00). All variants were absent from gnomAD except for RFX7p.Pro964_Thr965del, which is detected at a very low frequency in gnomAD v2.1.1 (AF 0.00007677) leading us to formally classify it as a variant of uncertain significance. The fact that the majority of variants identified are predicted to cause outright protein truncation or gene deletion strongly supports a loss-of-function / haploinsufficiency model.
RFXtranscription factors are defined by a conserved, specialized winged-helix type DNA binding domain (DBD) that recognize the X-box motif. RFX7 variants did not exhibit clustering to specific functional domains.
RFX7has been reported to have relatively high expression in human cortex. Single-cell transcriptomes from developing and adult human cortex revealed that in developing human cortex, RFX7is most highly expressed in interneurons from the medial ganglionic eminence, and in adult cortex RFX7was highly expressed in both inhibitory and excitatory neurons. These expression profiles suggest that RFXdeleterious variants may lead to our observed neurodevelopmental phenotypes by altering the development or function of neurons.
RFX7