case_images: PMC11791529_01
case_images: disease course in a patient with idiopathic CVID over a 35-year period with a novel STAT3 variant. (A) Timeline of clinical presentations observed in a patient with CVID. (B) Sanger sequencing of gDNA from P1 and their mother and father confirming a novel de novo variant in STAT3 (c. 1222T > C, p. F408L). (C) Pedigree of the family carrying the novel STAT3 VUS. (D) gnomAD minor allele frequency versus CADD score for the novel variant (P1), the adjacent DNABD GOF variants, and the SH2 GOF variant, p.Y640F. The mutation significance cutoff (99% confidence interval) is represented by the dotted line. (E) Functional domain schematic of STAT3 protein highlighting the DNABD region in which novel P1 VUS (F408L) is located. Previously validated STAT3 GOF variants (M394T, N401D, E415K/L, Y640F) are depitcted as dark green. (F) Conservation alignment and ConSurf score of DNABD amino acids from 19 representative species through evolution.
case_images: uxaf005_fig1.jpg
case_images: PMC11791529_01_uxaf005_fig1.jpg
case_images: F1
case_images: He presented with mild eczematic skin disease, urticaria, and recurrent otitis media requiring multiple grommets during his first year of life (Fig. 1A). Over the next two decades, the patient was lost to follow-up but reported minimal complications until representing at age 35 years with enteropathy and iron deficiency (Fig. 1A). F408L; Fig. 1B). The variant was absent from the proband's parents and was thus de novo (Fig. 1B and C). DNABD of STAT3 and was located near four previously reported missense variants known to be causal for STAT3 GOF Syndrome (M394T, N401D, E415L, E415K; Fig. 1E). Despite comparable biochemical properties of phenylalanine and leucine as amino acids (non-polar, identical molecular weight), the variant was private to the family, being absent from the gnomAD population database (Fig. 1D). The variant had a combined annotation-dependent depletion (CADD) score of 29.7, exceeding the gene-specific mutation significance cutoff (16.4, 99% confidence interval), and being comparable to pathogenic DNABD variants M394T, N401D, E415L, and E415K, as well as a pathogenic Src homology 2 domain variant previously reported in STAT3 GOF patients and various neoplasms (Y640F) (Fig. 1D and E). Alignment of amino acid sequences containing this novel F408L variant and known variants from representative species indicate high evolutionary conservation of the STAT3 DNABD region in vertebrates, which is supported by high ConSurf scores at these affected residues, suggesting evolutionary constraint (Fig. 1F).