Cancer genetics · 2026
Clinical spectrum of heterozygous LZTR1 variation in a schwannomatosis-clinic cohort: A descriptive study of multisystem features.
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Chaaban Mohammad Karam, Olarewaju Bukola A, Melville David, Harahsheh Ehab, Nabi Hussein Abdul, Womack Yaqqira, Chaaban Majd, Dandurand Kristina R, Carr Meghan H, Girardo Marlene, Asif Misha B, Shamoun Fadi, Dhamija Radhika, Noland Shelley S, Bendok Bernard R, Pittelkow Mark, Mrugala Maciej M, Porter Alyx B, Babovic-Vuksanovic Dusica, Hayatdavoodi Masoud, Baudhuin Linnea M, Osundiji Mayowa A
Аннотация
BACKGROUND: LZTR1-related disorders (LRDs) include schwannomatosis, Noonan syndrome, and variably expressed multisystem phenotypes, but the full clinical spectrum remains incompletely characterized. We evaluated whether adults carrying pathogenic or likely pathogenic LZTR1 variants show recurrent extracranial and central nervous system findings, while separately presenting descriptive findings from candidate VUS carriers and accounting for the limits of specialty-clinic ascertainment.
METHODS: We examined adults assessed at comprehensive schwannomatosis clinics (n = 156), including a genetically ascertained subgroup with pathogenic or likely pathogenic LZTR1 variants (n = 19) and 5 cases with candidate LZTR1 VUS. Clinical, imaging, laboratory, and genetic data were systematically reviewed and harmonized to characterize multisystem manifestations associated with LRDs.
RESULTS: Among the 19 individuals with pathogenic or likely pathogenic LZTR1 variants, recurrent manifestations included schwannomatosis (8/19), cerebral vasculopathy (7/19), congenital or peripheral vascular anomalies (8/19), neoplasia (6/19), central nervous system cystic lesions including arachnoid cysts (3/19) and perineural/Tarlov cysts (2/19), hypertrophic cardiomyopathy (2/19), and vertebral endplate abnormalities/Schmorl nodes (5/19). Because phenotype counts differ when candidate VUS carriers are included, analyses are reported using clearly specified denominators: the primary analysis is restricted to pathogenic or likely pathogenic carriers (n = 19), whereas the full clinically ascertained cohort (n = 24) is presented descriptively as a sensitivity summary. Truncating, splice, and missense variants were considered separately because the small number of missense variants and limited functional evidence preclude firm genotype-phenotype conclusions. Notably, no individual fulfilled a clinical diagnosis of Noonan syndrome.
CONCLUSION: These findings support cautious recognition of possible multisystem involvement among selected individuals with pathogenic or likely pathogenic LZTR1 variants. Candidate VUS carriers are reported descriptively but are not treated as having established deleterious alleles. Larger comparator-based studies, functional validation, and standardized surveillance data are needed before broad disease-label expansion or risk-management recommendations can be made.
METHODS: We examined adults assessed at comprehensive schwannomatosis clinics (n = 156), including a genetically ascertained subgroup with pathogenic or likely pathogenic LZTR1 variants (n = 19) and 5 cases with candidate LZTR1 VUS. Clinical, imaging, laboratory, and genetic data were systematically reviewed and harmonized to characterize multisystem manifestations associated with LRDs.
RESULTS: Among the 19 individuals with pathogenic or likely pathogenic LZTR1 variants, recurrent manifestations included schwannomatosis (8/19), cerebral vasculopathy (7/19), congenital or peripheral vascular anomalies (8/19), neoplasia (6/19), central nervous system cystic lesions including arachnoid cysts (3/19) and perineural/Tarlov cysts (2/19), hypertrophic cardiomyopathy (2/19), and vertebral endplate abnormalities/Schmorl nodes (5/19). Because phenotype counts differ when candidate VUS carriers are included, analyses are reported using clearly specified denominators: the primary analysis is restricted to pathogenic or likely pathogenic carriers (n = 19), whereas the full clinically ascertained cohort (n = 24) is presented descriptively as a sensitivity summary. Truncating, splice, and missense variants were considered separately because the small number of missense variants and limited functional evidence preclude firm genotype-phenotype conclusions. Notably, no individual fulfilled a clinical diagnosis of Noonan syndrome.
CONCLUSION: These findings support cautious recognition of possible multisystem involvement among selected individuals with pathogenic or likely pathogenic LZTR1 variants. Candidate VUS carriers are reported descriptively but are not treated as having established deleterious alleles. Larger comparator-based studies, functional validation, and standardized surveillance data are needed before broad disease-label expansion or risk-management recommendations can be made.