Genomics and Pharmacogenomics

Introduction: Hypophosphatemic rickets, characterized by hypophosphatemia and defective bone mineralization, is predominantly inherited as an X-linked dominant condition caused by inactivating PHEX mutations. Autosomal dominant and recessive forms due to mutations in FGF23, DMP1, ENPPI, and SLC34A3 respectively are also documented. Aim: To identify mutations in cases with familial hypophosphatemic rickets (FHR) and their family members. Patients and Methods: The three FHR patients (probands) were born out of non-consanguineous marriages. In the family I, the patient and her mother were affected, in family II, the patient, her brother, and mother were affected while family III had two sisters, their father and paternal uncle affected. Clinical and family history was documented and 5ml blood drawn for DNA extraction. PHEX exons were screened by direct sequencing and result analyzed using in silico tools. Whole Exome Sequencing (WES) was done to find involvement of genes responsible for intra-familial variability seen in the affected members, and validation of mutations was done by Sanger sequencing. Results: The patients had short stature, limb deformities, and low serum phosphate. PHEX screening revealed three mutations in three patients and their affected family members, of which one was novel missense (c.2048T>A) and two reported nonsense and missense (c.871C>T; c.1601C>T) mutations respectively. Two families presented with intra-familial variability in disease phenotype. The paternal uncle of family III had dental anomalies and mother of the family I had short stature. WES was done for the family I, and family III probands, father and paternal uncle. Results revealed a novel PHEX mutation G>C in exon 21 in the family I proband, which was absent in her mother but did not reveal any additional mutations, other than c.1601C>T in family III. Conclusion: This study reports two novel PHEX mutations and also suggests that PHEX may be mainly responsible for FHR in India.