LZTR1 – Schwannomatosis

Schwannomatosis is a rare tumor predisposition syndrome characterized by multiple benign peripheral nerve sheath tumors without bilateral vestibular schwannomas. Germline loss-of-function (LoF) variants in LZTR1 (HGNC:6742) have been established as a definitive cause of schwannomatosis following the initial discovery of LZTR1 mutations in 16/20 familial cases lacking SMARCB1 alterations (2014) (PMID:24362817).

LZTR1-related schwannomatosis follows an autosomal dominant inheritance pattern with incomplete penetrance. Multiple case reports and series document constitutional LZTR1 variants in sporadic and familial settings, including unilateral vestibular schwannoma in a teenager carrying c.791+1G>A (p.Arg264Ter) and familial aggregation in siblings with c.1018C>T (p.Arg340Ter) (PMID:28295212; PMID:38983105). Segregation analyses demonstrate LZTR1 mutations co-segregating with schwannomatosis in at least 4 affected relatives across independent pedigrees (PMID:26848914).

Large cohort studies reveal a spectrum of LoF LZTR1 variants—nonsense, frameshift, canonical splice-site, and deep-intronic mutations—comprising 64 pathogenic/likely pathogenic alleles in 359 probands (17.8%) compared with 0.36% in gnomAD controls (p < 0.0001) (PMID:35391499). Recurrent mutations include c.1018C>T (p.Arg340Ter), a truncating variant observed in multiple unrelated families.

Functional studies support haploinsufficiency as the mechanism of pathogenicity. LZTR1 acts as a substrate adaptor for CUL3-based ubiquitin ligase complexes, promoting polyubiquitination and proteasomal degradation of RAS GTPases, with loss of LZTR1 leading to RAS/MAPK hyperactivation in cell lines and in vivo models (PMID:31337872). In zebrafish, lztr1 knockout recapitulates RASopathy-linked cardiac and vascular phenotypes, underscoring functional concordance with human disease (PMID:31883238).

No significant conflicting evidence has been reported; although incomplete penetrance and modifier effects exist, the accumulation of LoF variants, segregation data, and mechanistic insight consolidate LZTR1 as a definitive schwannomatosis gene. Routine genetic testing for LZTR1 variants is warranted in individuals with multiple schwannomas, unilateral vestibular tumors, or familial aggregation.

Key Take-home: Germline pathogenic LZTR1 variants are a definitive cause of schwannomatosis, justifying inclusion of LZTR1 in diagnostic panels and guiding patient surveillance and management.

References

• Nature Genetics • 2014 • Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas PMID:24362817
• Human Mutation • 2022 • Comparison of the frequency of loss-of-function LZTR1 variants between schwannomatosis patients and the general population PMID:35391499
• Clinical Genetics • 2017 • Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager PMID:28295212
• Molecular Genetics and Metabolism Reports • 2024 • Familial schwannomatosis carrying LZTR1 variant p.Arg340Ter with brain tumor: A case report PMID:38983105
• Cell Death and Differentiation • 2020 • LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases PMID:31337872
• Molecular Genetics & Genomic Medicine • 2020 • Noonan syndrome–associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish PMID:31883238

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