Hormone Research in Paediatrics
Novel Insights from Clinical Practice / Case Report
LZTR1: Genotype Expansion in Noonan SyndromeGüemes M.a,b · Martín-Rivada Á.a · Ortiz-Cabrera N.V.c · Martos-Moreno G.Á.a,b,d,e · Pozo-Román J.a,b,d,e · Argente J.a,b,d,e,faDepartments of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
bLa Princesa Research Institute, Madrid, Spain cDepartment of Clinical Genetics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain dDepartment of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain eCentro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain fIMDEA, Food Institute, CEIUAM+CSI, Madrid, Spain Keywords: RASopathyNoonan syndromeLTZR1 gene |
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Article / Publication Details
Received: June 04, 2019
Accepted: August 14, 2019
Published online: September 18, 2019
Issue release date: March 2020
Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 1
ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)
For additional information: https://www.karger.com/HRP
Abstract
Background: LZTR1 participates in RAS protein degradation, hence limiting the RAS/MAPK cascade. Pathogenic mutations in LZTR1 (MIM:600574) have been described in a few patients with Noonan syndrome (NS). Three patients with LZTR1 mutations of different genetic transmission and NS phenotype are herein characterized. Clinical Cases: Case 1 is a 5-year-old boy with NS phenotype. Sanger sequencing of PTPN11 and SOS1 identified no mutations. Whole exome sequencing (WES) detected a heterozygous missense mutation in LZTR1:c.742G>A (p.Gly248Arg) (exon 8, Kelch 4 functional domain). Bioinformatic algorithms predict a deleterious effect of this variant, previously described to cause NS. Case 2 is a 4-year-old boy with NS phenotype. Direct sequencing of 8 genes associated with NS identified no mutations. WES localized a homozygous missense mutation in LZTR1:c.2074T>C (p.Phe692Leu, exon 18). This mutation has not been reported before and is predicted to have a deleterious effect on the protein. Case 3 is an 8-year-old boy who shares NS phenotype with his mother. A multigene panel for RASopathies showed a heterozygous missense variant in LZTR1:c.730T>C (p.Ser244Pro) (exon 8; Kelch 4 functional domain) that was maternally inherited. This variant has not been previously described; however, in silico predictors classify it as deleterious. Familial segregation suggests its pathogenicity. Conclusions: The molecular approach for syndromic phenotypes associated with various genes should involve complete/updated panels or WES rather than gene-by-gene sequencing. RASopathy genetic panels should incorporate LZTR1. Patients with pathogenic mutations in LZTR1 exhibit a characteristic NS gestalt but variable cardiac, height, and neurodevelopment expressions, with recessive inheritance possibly associating with a more severe phenotype.
© 2019 S. Karger AG, Basel
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Article / Publication Details
Received: June 04, 2019
Accepted: August 14, 2019
Published online: September 18, 2019
Issue release date: March 2020
Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 1
ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)
For additional information: https://www.karger.com/HRP
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