SMARCA4 – Familial Rhabdoid Tumor Predisposition Syndrome

Germline heterozygous loss-of-function variants in SMARCA4 predispose to autosomal dominant familial rhabdoid tumor predisposition syndrome, characterized by early-onset malignant rhabdoid tumors often arising in the kidney or central nervous system before age 3. Two sisters harboring a SMARCA4 nonsense mutation, c.3565C>T (p.Arg1189Ter), exhibited germline mutation and somatic loss of the wild-type allele by uniparental disomy in their tumors, demonstrating tumor suppressor activity (PMID:20137775). Although rare compared to SMARCB1, SMARCA4 germline variants have been implicated in RTPS2, with preliminary recommendations for surveillance analogous to RTPS1 (PMID:28620006). The mechanism involves haploinsufficiency and subsequent somatic inactivation of the second allele, consistent with a two-hit model. No conflicting reports have been documented, but the limited number of families underscores the need for additional case series and segregation analyses. Key take-home: Testing for SMARCA4 germline mutations should be considered in SMARCB1-negative familial rhabdoid tumor cases to guide genetic counseling and surveillance.

References

• American Journal of Human Genetics • 2010 • Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. PMID:20137775
• Clinical Cancer Research • 2017 • Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. PMID:28620006

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