title: Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis.
abstract: Autosomal Recessive Osteopetrosis is a genetic disorder characterized by increased bone density due to lack of resorption by the osteoclasts. Genetic studies have widely unraveled the molecular basis of the most severe forms, while cases of intermediate severity are more difficult to characterize, probably because of a large heterogeneity. Here, we describe the use of exome sequencing in the molecular diagnosis of 2 siblings initially thought to be affected by "intermediate osteopetrosis", which identified a homozygous mutation in the CTSK gene. Prompted by this finding, we tested by Sanger sequencing 25 additional patients addressed to us for recessive osteopetrosis and found CTSK mutations in 4 of them. In retrospect, their clinical and radiographic features were found to be compatible with, but not typical for, Pycnodysostosis. We sought to identify modifier genes that might have played a role in the clinical manifestation of the disease in these patients, but our results were not informative. In conclusion, we underline the difficulties of differential diagnosis in some patients whose clinical appearance does not fit the classical malignant or benign picture and recommend that CTSK gene be included in the molecular diagnosis of high bone density conditions.
authors.affiliation: UOS/IRGB, Milan Unit, CNR, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pangrazio
authors.affiliation: CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Italy; IRGB-CNR, Cittadella Universitaria di Monserrato, Cagliari, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Puddu
authors.affiliation: CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Oppo
authors.affiliation: CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Valentini
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Zammataro
authors.affiliation: Great Ormond Street Children's Hospital, London, United Kingdom.
authors.forename: Ashok
authors.initials: A
authors.lastname: Vellodi
authors.affiliation: Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Gener
authors.affiliation: Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Llano-Rivas
authors.affiliation: National Institute of Child Health, Karachi, Pakistan.
authors.forename: Jamal
authors.initials: J
authors.lastname: Raza
authors.affiliation: National Institute of Child Health, Karachi, Pakistan.
authors.forename: Irum
authors.initials: I
authors.lastname: Atta
authors.affiliation: UOS/IRGB, Milan Unit, CNR, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.affiliation: Department of Pediatrics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.affiliation: UOS/IRGB, Milan Unit, CNR, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.affiliation: UOS/IRGB, Milan Unit, CNR, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Italy. Electronic address: cristina.sobacchi@humanitasresearch.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sobacchi
mesh_terms: D056657:Cathepsin K / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010022:Osteopetrosis / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics*; D011859:Radiography; D055815:Young Adult
chemical_list: C534130:CTSK protein, human; D056657:Cathepsin K
keywords: CTSK; Differential diagnosis; Exome sequencing; Sclerosing bone disorder; Therapy