Expansion of the Phenotypic Spectrum and Description of Molecular Findings in a Cohort of Patients with Oculocutaneous Mosaic RASopathies

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2019 Mar 21

PMID 30891959

Citations 21

Authors

Oscar F Chacon-Camacho

Daniel Lopez-Moreno

Martha A Morales-Sanchez

Enriqueta Hofmann

Michelle Pacheco-Quito

Ilse Wieland

Vianney Cortes-Gonzalez

Cristina Villanueva-Mendoza

Martin Zenker

Juan Carlos Zenteno

Affiliations

Soon will be listed here.

Abstract

Background: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies.

Methods: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism.

Results: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids.

Conclusion: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.

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