Genetic Diagnosis Using Whole Exome Analysis in Two Cases with Malignant Infantile Osteopetrosis

  • Korcan Demir
  • Özlem Nalbantoğlu Elmas
  • Kadri Karaer
  • Hüseyin Anıl Korkmaz
  • Melek Yıldız
  • Selma Tunç
  • Behzat Özkan

J Clin Res Pediatr Endocrinol 2015;7(2):76-76


Osteopetrosis is caused by autosomal mutations occurring in nine genes (TNFRSF11A, TNFSF11, TCIRG1, CLCN7, OSTM1, SNX10, PLEKHM1, CA2, LRP5). Detecting the etiology and providing genetic counseling via individual mutation analysis of all these genes is expensive and time consuming. Whole exome sequencing is currently increasingly used given that the cost and the time needed are similar to that of single gene sequencing analysis. Here, we present two newborns, genetic evaluations of whom were made with whole exome analysis.


We examined a nine-day-old male patient who was born to non-consanguineous parents and who had bicytopenia and hypocalcaemia and a six-day-old female patient with hypocalcaemia, whose parents were first cousins and elder brother had died due to osteopetrosis. The newborns were diagnosed with malignant infantile osteopetrosis on clinical and radiological grounds. Their DNA samples were extracted from peripheral blood. Exome sequencing data generated in genotypic (India) using HiSeq 2500 sequencer were analyzed in Intergen Genetics Center.


31382 variants were detected in the first case. Among the possible genes in etiology, a novel heterozygous mutation (c.718G>A), which was predicted to be most likely a disease-causing mutation with in silico analyses, was detected in CLCN7. Another mutation was also detected using whole gene Sanger sequencing (compound heterozygous c.398_401delTTGG/c.718G>A). 32 529 variants were detected in the second case. A previously reported homozygous nonsense mutation c.2236C>T in TCIRG1 was detected and confirmed using Sanger sequencing.


Whole exome analysis is a useful method for diseases in which multiple genes play role in the etiology. It should be kept in mind when heterozygous mutations are detected in autosomal recessive diseases that exome sequencing may not evaluate 5% of coding regions and relevant gene should be reanalyzed by Sanger sequencing.

Keywords: Osteopetrosis, novel heterozygous mutation, bicytopenia, hypocalcaemia, exome sequencing