Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.

in Genetics in medicine : official journal of the American College of Medical Genetics by Gioia Mastromoro, Claudia Santoro, Marialetizia Motta, Ugo Sorrentino, Paola Daniele, Cristina Peduto, Francesco Petrizzelli, Martina Tripodi, Valentina Pinna, Mariateresa Zanobio, Giovannina Rotundo, Emanuele Bellacchio, Francesca Lepri, Antonella Farina, Maria Cecilia D'Asdia, Francesca Piceci-Sparascio, Tommaso Biagini, Antonio Petracca, Marco Castori, Daniela Melis, Maria Accadia, Giovanna Traficante, Luigi Tarani, Paolo Fontana, Fabio Sirchia, Roberto Paparella, Aurora Currò, Francesco Benedicenti, Iris Scala, Maria Lisa Dentici, Chiara Leoni, Valentina Trevisan, Antonella Cecconi, Sandra Giustini, Antonio Pizzuti, Leonardo Salviati, Antonio Novelli, Giuseppe Zampino, Martin Zenker, Maurizio Genuardi, Maria Cristina Digilio, Laura Papi, Silverio Perrotta, Vincenzo Nigro, Elisabeth Castellanos, Tommaso Mazza, Eva Trevisson, Marco Tartaglia, Giulio Piluso, Alessandro De Luca

TLDR

  • The study found that some people with a specific gene called LZTR1 have multiple spots on their skin called café-au-lait macules. These spots are usually harmless, but they can be a sign of a rare genetic disorder called schwannomatosis or Noonan syndrome. The study found that people with a specific type of LZTR1 gene change (loss-of-function) were more likely to have these spots than the general population. The study also found that the spots in these people were different from the spots in people with schwannomatosis or Noonan syndrome. The study suggests that LZTR1 gene changes should be considered in the differential diagnosis of people with multiple café-au-lait macules.

Abstract

Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function (LoF) LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs). 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions. Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate MAPK signaling. Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.

Overview

  • The study aims to establish an association between heterozygous loss-of-function (LoF) LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs).
  • The study used RASopathy gene panel sequencing on 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions.

Comparative Analysis & Findings

  • The study found heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate MAPK signaling.

Implications and Future Directions

  • The study's findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs. The study suggests that LZTR1 variants should be considered in the differential diagnosis of individuals with multiple CaLMs. Future research should investigate the clinical and molecular characteristics of LZTR1-related CaLMs in larger cohorts and explore the potential therapeutic targets for LZTR1-related disorders.
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