TY - JOUR
T1 - Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis
AU - Pangrazio, Alessandra
AU - Puddu, Alessandro
AU - Oppo, Manuela
AU - Valentini, Maria
AU - Zammataro, Luca
AU - Vellodi, Ashok
AU - Gener, Blanca
AU - Llano-Rivas, Isabel
AU - Raza, Jamal
AU - Atta, Irum
AU - Vezzoni, Paolo
AU - Superti-Furga, Andrea
AU - Villa, Anna
AU - Sobacchi, Cristina
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - CTSK
KW - Differential diagnosis
KW - Exome sequencing
KW - Sclerosing bone disorder
KW - Therapy
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U2 - 10.1016/j.bone.2013.11.014
DO - 10.1016/j.bone.2013.11.014
M3 - Article
C2 - 24269275
AN - SCOPUS:84889560860
VL - 59
SP - 122
EP - 126
JO - Bone
JF - Bone
SN - 8756-3282
ER -