Pathogenic biallelic variants in RECQL4 underlie autosomal-recessive disorders such as Rothmund–Thomson, RAPADILINO, and Baller–Gerold syndromes. Heterozygous carriers are usually asymptomatic, but isolated reports suggest immune or malignancy phenotypes in some. Likewise, FASLG loss of function is classically recessive, yet heterozygous dominant-negative effects have been reported in autoimmune lymphoproliferative syndrome (ALPS). Emerging evidence indicates that pathogenicity can arise from digenic heterozygosity, where variants in two genes that converge on related pathways together produce disease.
We describe a patient who is heterozygous for two RECQL4 variants that lie on the same allele (cis configuration)—a rare missense change c.1568G>C (p.Ser523Thr) and a truncating frameshift c.1574\_1578del (p.Cys525Serfs*11) predicted to undergo nonsense-mediated decay. In addition, the patient carries a heterozygous FASLG variant c.593G>A (p.Arg198Gln), classified as a variant of uncertain significance. Clinical features include childhood-onset recurrent sinopulmonary infections and two episodes of Campylobacter bacteremia; progressive hypogammaglobulinemia requiring immunoglobulin replacement; primary sclerosing cholangitis with portal hypertension, esophageal varices, and inflammatory colitis; marked splenomegaly and a prior diagnosis of non-Hodgkin lymphoma; and absence of poikiloderma, skeletal anomalies, or other classical RECQL4 dysmorphisms.
The genotype represents digenic heterozygosity affecting two genes implicated in lymphocyte survival: RECQL4 haploinsufficiency may impair DNA-damage repair during lymphocyte proliferation, predisposing to immunodeficiency and cancer. FASLG p.Arg198Gln, located in the extracellular TNF-homology domain, could weaken Fas-FasL–mediated activation-induced cell death, a mechanism central to immune homeostasis. Although each variant alone may be insufficient for disease, their combined impact on apoptotic regulation and genome stability offers a plausible explanation for the complex phenotype—reminiscent of reports of FAS + CASP10 or PIK3CD + PIK3R1 digenic interactions.
This case broadens the spectrum of RECQL4- and FASLG-associated disorders by highlighting a putative digenic mechanism arising from heterozygous variants in both genes. Recognizing such interactions will refine variant interpretation, guide functional testing, and improve diagnostic accuracy in atypical immune-dysregulation phenotypes.
