Phenotypic Expansion of Autosomal Dominant LZTR1-Related Disorders with Special Emphasis on Adult-Onset Features

Area of Science:

• Genetics
• Molecular Biology
• Clinical Medicine

Background:

• Leucine zipper-like transcription regulator 1 (LZTR1) is a negative regulator of RAS function and MAPK signaling.
• Mutations in LZTR1 can disrupt RAS ubiquitination and protein degradation.
• Germline LZTR1 variants are associated with autosomal dominant/recessive Noonan syndrome and schwannomatosis susceptibility.

Purpose of the Study:

• To explore the genetic and phenotypic diversity of autosomal dominant LZTR1-related disorders.
• To define the clinical spectrum of LZTR1-related diseases.
• To provide updated frequencies of clinical features and highlight variability.

Main Methods:

• Literature review and compilation of published patient cohorts (51 Noonan, 123 schwannomatosis).
• Presentation of two new adult-onset cases: one with schwannomatosis and Parkinson's disease, another with Noonan syndrome, joint hypermobility, and breast cancer.
• Analysis of genetic and phenotypic data to characterize disease spectrum and variability.

Main Results:

• Autosomal dominant LZTR1 disorders exhibit extreme phenotypic variability, from mild to severe multi-systemic involvement.
• Updated frequencies of various clinical features associated with LZTR1 variants are provided.
• The study confirms LZTR1's role in diverse clinical presentations, including rare co-occurrences like Parkinson's disease.

Conclusions:

• LZTR1-related disorders present a wide spectrum of clinical manifestations.
• Understanding the mechanisms underlying phenotypic variability is crucial for precision diagnostics and therapeutics.
• Further research into LZTR1's function and associated disorders is warranted.