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Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare congenital disorder classically characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis. Germline  PTEN  mutations have been reported in up to 60% of BRRS patients. The remaining cases are of unknown genetic etiology. We exome-sequenced 35 unrelated  PTEN- wildtype patients with classic presentation of BRRS and identified  TTN  germline missense variants in 12/35 (34%) patients.  TTN  encodes TITIN, a key structural and functional muscle protein. Exome and  TTN- targeted sequencing in an additional unrelated series of 231 BRRS-like patients revealed 37 (16%) additional patients with germline  TTN  variants. All variants were predicted to be deleterious and equally distributed between the A-band and I-band protein domains. Rare  TTN  variants (MAF ≤ 0.0001) are enriched in classic BRRS patients compared to BRRS-like (OR = 2.7, 95% CI 1.21-5.94,  p  = 1.6 × 10 -2 ) and multiple population controls (OR = 2.2, 95% CI 1.01-4.20,  p  = 4.7 × 10 -2 ). Germline  TTN  mutations of different genotypes, inheritance patterns, and protein domain enrichment have been identified in multiple cardiac and/or skeletal muscular disorders. Functional interrogation of I-band variant p.Cys5096Arg identified in one of our classic BRRS patients, using CRISPR-Cas9 genome-edited cell lines, reveals an increased growth and lack of contact inhibition phenotype associated with increased levels of or phosphorylation of focal adhesion kinase (FAK) in mutant cells. These findings suggest that TITIN could play a role in overgrowth-relevant pathways and phenotypes. In summary, our observations suggest  TTN  as a candidate predisposing gene in classic  PTEN- wildtype BRRS patients, perhaps suggesting this syndrome join the growing list of Titinopathies.

Germline TTN variants are enriched in PTEN-wildtype Bannayan–Riley–Ruvalcaba syndrome