FIG 3.

Biallelic ZNFX1 variants lead to the loss of protein expression in response to stimulation by intracellular nucleic acids. A, The pedigrees of the 8 families. Patients carrying homozygous or compound heterozygous deleterious variants in ZNFX1 are indicated by solid symbols. Healthy individuals carrying heterozygous variants are indicated by dotted symbols. Affected persons with an unknown genotype are indicated by open red symbols, whereas unaffected individuals are indicated by open diamonds. Circles indicate females, and squares indicate males. Slashes over symbols indicate deceased patients. N/A (meaning not available) indicates that sequencing was not performed. B, Predicted domains and identified variants in the ZNFX1 amino acid sequence. The 11 deleterious variants identified are indicated by arrows. The domain homologous to the RNA helicase Aquarius (Protein Data Bank identifier 4PJ3) is highlighted in orange, with an insert shown in yellow. C, A ribbon diagram of a homology model of ZNFX1 (183-1255), based on the structural template RNA helicase Aquarius (Protein Data Bank identifier 4PJ3) is shown. Locations of the 4 missense variants within this domain are shown as teal spheres in the present study. D, A protein immunoblot for ZNFX1 in dermal fibroblasts from a healthy donor (control [CTRL]) and from P5.1, P3.2, and P2.1 under resting conditions and 24 hours after transfection with the nucleic acids poly(dA:dT) or poly(I:C). β-Actin was used as a loading control.