LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis

Abstract

Background Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1. Case presentation A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics. Conclusions We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1.

The molecular genetics of RASopathies: An update on novel disease genes and new disorders

“… Note : References: Capri et al, 2019 , Niihori et al, 2019 , Weinstock & Sadler, 2022 ( RRAS2 ); Higgins et al, 2017 , Suzuki et al, 2019 , Motta, Sagi‐Dain, et al, 2020 , Pires et al, 2021 ( MRAS ); Yamamoto et al, 2015 , Pagnamenta et al, 2019 , Güemes et al, 2019 , Umeki et al, 2019 , Jacquinet et al, 2020 , Zhao et al, 2021 , Farncombe, Thain, Barnett‐Tapia, Sadeghian, & Kim, 2022 ( LZTR1 , dominant NS); Johnston et al, 2018 , H. Chen et al, 2019 , Perin et al, 2019 , Pagnamenta et al, 2019 , Umeki et al, 2019 , Nakagama et al, 2020 ( LZTR1 , recessive NS); Motta et al, 2021 ( SPRED2 ); Motta, Pannone, et al, 2020 ( MAPK1 ). Abbreviations: ASD, atrial septal defects; CALS, café‐au‐lait spots; D, dominant; DD, developmental delay; F, females; HCM, hypertrophic cardiomyopathy; ID, intellectual disability; M, males; MVP, mitral valve prolapse; PVS, pulmonic stenosis; R, recessive.…”

Preclinical evaluation of CRISPR-based therapies for Noonan syndrome caused by deep-intronic LZTR1 variants

“… 34 , 36 , 38 , 40 c.743G>A p.G248E dominant not detected not detected not detected – Farncombe et al. 43 c.756_758del p.N253del dominant not detected not detected not detected – Umeki et al. 40 c.859C>T p.H287Y dominant not detected not detected not detected – Yamamoto et al.…”

Familial schwannomatosis carrying LZTR1 variant p.R340X with brain tumor: A case report

“…In some cases, the clinical manifestations of NF1 may mimic those of NS, and patients with NF1 exhibit an increased incidence of benign tumors and some malignancies, including glioblastoma and glioma [ 26 ]. A recent case report described an overlap of LZTR1 -related NS with SWN and its clinical implications [ 27 ]. Although our patient had cutaneous findings, such as light-brown skin pigmentation spots, he did not present with other clinical characteristics of NF1 and NS.…”