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Published on: August 15, 2019
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Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules
Gioia Mastromoro1, Claudia Santoro2, Marialetizia Motta3
1Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy.
Summary
Genetic variants in LZTR1 are linked to schwannomatosis and Noonan syndrome. This study finds these LZTR1 variants also cause isolated multiple café-au-lait macules (CaLMs), expanding known disease associations.
Area of Science:
- Genetics
- Dermatology
- Oncology
Background:
- Pathogenic LZTR1 variants are known causes of schwannomatosis and Noonan syndrome (NS).
- The genetic basis for isolated multiple café-au-lait macules (CaLMs) is not fully understood, particularly in cases negative for NF1 and SPRED1 variants.
Purpose of the Study:
- To investigate the association between heterozygous loss-of-function LZTR1 alleles and isolated multiple CaLMs.
- To characterize the clinical and molecular spectrum of LZTR1 variants in individuals with CaLMs.
Main Methods:
- RASopathy gene panel sequencing was performed on 849 participants with multiple CaLMs, excluding NF1 and SPRED1 pathogenic variants.
- Clinical data and molecular findings were collected for 125 individuals with heterozygous LZTR1 variants.
- In vitro functional assessments were conducted on selected LZTR1 variants.
Main Results:
- Heterozygous LZTR1 variants were identified in 6.0% of participants with CaLMs.
- LZTR1-related CaLMs exhibited variable presentation, sometimes with RASopathy features; schwannomas co-occurred in 2 families.
- Functional studies revealed LZTR1 variants lead to protein degradation/mislocalization and impaired MAPK signaling.
Conclusions:
- LZTR1 variants are associated with isolated multiple CaLMs, expanding the known phenotypic spectrum.
- This finding implicates LZTR1 in a broader range of conditions beyond schwannomatosis and Noonan syndrome.
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