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In a family-based whole genome sequencing study of 234 individuals from 36 pedigrees with familial classic Hodgkin lymphoma, a recurrent 5′ untranslated region (5′UTR) variant in KLHDC8B (rs387906223) was identified in 3 independent families and showed co-segregation with disease in 28 pedigrees (PMID:35977101). No protein-altering coding variants in KLHDC8B were reported, while parallel analyses uncovered risk variants in KDR, PAX5, GATA3, IRF7, EEF2KMT, and POLR1E in the same cohort.
Targeted linkage and expression studies in a kindred with nodular sclerosis cHL mapped a susceptibility locus to 3p21 but failed to detect any coding or splice variants in KLHDC8B, and expression of KLHDC8B was unaltered in Hodgkin Reed–Sternberg cell lines (PMID:29755658). This lack of functional or expression perturbation undermines a direct pathogenic role for KLHDC8B in classic Hodgkin lymphoma.
Key Take-home: A recurrent noncoding 5′UTR variant in KLHDC8B shows limited segregation but no supportive functional data, indicating insufficient evidence for clinical diagnostic application.
Gene–Disease AssociationLimitedRecurrent noncoding 5′UTR variant rs387906223 in 3 pedigrees; segregation in 28 families; no protein-altering variants described Genetic EvidenceLimitedSingle noncoding 5′UTR variant observed across multiple families without coding changes; segregation supported in 28 pedigrees Functional EvidenceLimitedNo supportive functional or expression data linking KLHDC8B to classic Hodgkin lymphoma; sequencing yielded no coding variants |