ESPE Abstracts

Aim: Osteopetrosis is caused by autosomal mutations occurring in nine genes (TNFRSF11A, TNFSF11, TCIRG1, CLCN7, OSTM1, SNX10, PLEKHM1, CA2, and LRP5). Detecting the aetiology and providing genetic counselling 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, two newborns, genetic evaluations of whom were made with whole exome analyses, are presented.

Methods: A 9-day-old male case, who was born to nonconsanguineous parents, with bicytopenia and hypocalcaemia and a 6-day-old female patient with hypocalcaemia, whose parents are first cousins and elder brother had died due to osteopetrosis, were studied. They 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 HiSDefault 2500 sequencer were analysed in İntergen Genetics Center.

Results: 31 382 variants were detected in the first case. Among the possible genes in aetiology, 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.

Conclusion: Whole exome analysis is a useful method for diseases in which multiple genes play role in the aetiology. 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 reanalysed by Sanger sequencing.