title: Exome sequencing reveals germline gain-of-functionEGFRmutation in an adult with Lhermitte-Duclos disease.
abstract: Lhermitte-Duclos disease (LDD) is a rare cerebellar disorder believed to be pathognomonic for Cowden syndrome. Presently, the only known etiology is germlinePTENmutation. We report a 41-yr-old white female diagnosed with LDD and wild-type forPTEN. Exome sequencing revealed a germline heterozygousEGFRmutation that breaks a disulfide bond in the receptor's extracellular domain, resulting in constitutive activation. Functional studies demonstrate activation of ERK/AKT signaling pathways, mimickingPTENloss-of-function downstream effects. The identification ofEGFRas a candidate LDD susceptibility gene contributes to advancement of molecular diagnosis and targeted therapy for this rare condition with limited treatment options.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Case Western Reserve University School of Medicine, Cleveland, Ohio 44195, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Colby
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Lamis
authors.initials: L
authors.lastname: Yehia
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Farshad
authors.initials: F
authors.lastname: Niazi
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: JinLian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Jessica L
authors.identifier: 0000-0001-9374-3185
authors.initials: JL
authors.lastname: Mester
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA;; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA;; CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA;; Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Charis
authors.identifier: 0000-0002-3693-5145
authors.initials: C
authors.lastname: Eng
mesh_terms: D000328:Adult; D002528:Cerebellar Neoplasms / Q000175:diagnosis; D002531:Cerebellum / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D000073659:Gain of Function Mutation / Q000235:genetics; D005729:Ganglioneuroma / Q000175:diagnosis; D020022:Genetic Predisposition to Disease; D005854:Germ Cells / Q000378:metabolism; D018095:Germ-Line Mutation / Q000235:genetics; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D015398:Signal Transduction
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: neoplasm of the nervous system