Elsevier

Bone

Volume 59, February 2014, Pages 122-126
Bone

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

https://doi.org/10.1016/j.bone.2013.11.014Get rights and content
Under a Creative Commons license
open access

Highlights

  • Whole exome sequencing was applied to 2 patients with “intermediate osteopetrosis” and negative mutation screening in ARO genes.

  • We identified CTSK gene mutations in these as well as in additional patients referred with “intermediate osteopetrosis”.

  • We investigate the role of modifier genes possibly impacting on the clinical manifestation of the disease in these patients.

  • We recommend that CTSK gene analysis be included in the molecular workup of high bone density conditions.

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

Exome sequencing
CTSK
Sclerosing bone disorder
Differential diagnosis
Therapy

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