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Bone. 2014 Feb;59:122-6. doi: 10.1016/j.bone.2013.11.014. Epub 2013 Nov 20.

Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis.

Author information

1
UOS/IRGB, Milan Unit, CNR, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Italy.
2
CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Italy; IRGB-CNR, Cittadella Universitaria di Monserrato, Cagliari, Italy.
3
CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Italy.
4
Humanitas Clinical and Research Center, Rozzano, Italy.
5
Great Ormond Street Children's Hospital, London, United Kingdom.
6
Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain.
7
National Institute of Child Health, Karachi, Pakistan.
8
Department of Pediatrics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
9
UOS/IRGB, Milan Unit, CNR, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Italy. Electronic address: cristina.sobacchi@humanitasresearch.it.

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.

KEYWORDS:

CTSK; Differential diagnosis; Exome sequencing; Sclerosing bone disorder; Therapy

PMID:
24269275
PMCID:
PMC3885796
DOI:
10.1016/j.bone.2013.11.014
[Indexed for MEDLINE]
Free PMC Article

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