Genetic analysis of osteopetrosis in Pakistani families identifies novel and known sequence variants

BMC Med Genomics. 2021 Nov 9;14(1):264. doi: 10.1186/s12920-021-01117-4.


Osteopetrosis is a genetically heterogenous, fatal bone disorder characterized by increased bone density. Globally, various genetic causes are reported for osteopetrosis with all forms of inheritance patterns. A precise molecular diagnosis is necessary for prognosis and for prescribing treatment paradigms in osteopetrosis. Here we report on thirteen individuals diagnosed with infantile malignant osteopetrosis coming from ten unrelated Pakistani families; nine of whom are consanguineous. We performed whole exome sequencing and Sanger sequencing in all families and identified homozygous variants in genes previously reported for autosomal recessive inheritance of osteopetrosis. All the identified variants are expected to affect the stability or length of gene products except one nonsynonymous missense variant. TCIRG1 was found as a candidate causal gene in majority of the families. We report six novel variants; four in TCIRG1 and one each in CLCN7 and OSTM1. Our combined findings will be helpful in molecular diagnosis and genetic counselling of patients with osteopetrosis particularly in populations with high consanguinity.

Keywords: Autosomal recessive osteopetrosis; Disease variants; Genetic diagnosis; TCIRG1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chloride Channels / genetics
  • Exome Sequencing
  • Female
  • Homozygote
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Mutation, Missense
  • Osteopetrosis / genetics*
  • Pakistan
  • Pedigree
  • Ubiquitin-Protein Ligases / genetics
  • Vacuolar Proton-Translocating ATPases / genetics


  • CLCN7 protein, human
  • Chloride Channels
  • Membrane Proteins
  • OSTM1 protein, human
  • TCIRG1 protein, human
  • Ubiquitin-Protein Ligases
  • Vacuolar Proton-Translocating ATPases