Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia:Novel Mutations in PHEX and SLC34A3

Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood

Clinical and laboratory characteristics of children with de novo or inherited <i>PHEX</i> mutations.

<p>Clinical and laboratory characteristics of children with de novo or inherited <i>PHEX</i> mutations.</p

Characterization of a large deletion of <i>PHEX</i> in patient V-3.

<p>(A) Genechip cytogenetics array results. The top is showing weighted log2 ratios plot showing a normal copy number state for the X chromosome. The deletion is indicated by a dark bar and enclosed in the black lines. More than 70 SNP probes are present in the deleted region and indicated by an arrow. (B) Schematic representation of 179,880 bp deletion of <i>PHEX</i> and <i>ZNF645</i>. The 5’ breakpoint is located in the intron 15 of <i>PHEX</i> and 7 kb from exon 15. The 3’ breakpoint point is 103 kb from <i>ZNF645</i>, resulting in the deletion of exon 16–22 of PHEX and entire <i>ZNF645</i>. The 5’ and 3’ undeleted nucleotide sequences are highlightted in bold. Deletion analysis is based on GRCh37/hg19. (C) Electropherogram of the breaking point. The DNA fragment was amplified by PCR using primers flanking the 5’ and 3’ deletion point. The breakpoint is indicated by an arrow.</p

Summary of clinical and laboratory findings in patients with hereditary hypophosphatemia.

<p>Summary of clinical and laboratory findings in patients with hereditary hypophosphatemia.</p

<i>In silico</i> prediction of single nucleotide variations in the <i>PHEX</i> gene.

<p><i>In silico</i> prediction of single nucleotide variations in the <i>PHEX</i> gene.</p

Sequence analysis of <i>PHEX</i> in patients with hereditary hypophosphatemia.

<p>(A) Five novel <i>PHEX</i> mutations. c.983_987dupCTACC (patient II-3 and her mother) and c.436+1G>T (patient IX-3 and his mother) are inherited mutations from mother; c.1586+2T>G (patinet IV-3), c.1206delA (patient XV-3), and c.1217G>T (patientVI-3) are de novo mutations not present in parents. The c.1586+2T>G results in exon 14 skipping. (B) Six previously reported <i>PHEX</i> mutations. c.1645C>T, c. 187+1G>T, and c.2104C>T are de novo mutations. c.1601C>T, c.2239C>T, and c.1404+1del G are inherited mutations transmitted from mother. Mutation is indicated by an arrow.</p

Sequence analysis of <i>SLC34A3</i> in a patient with hereditary hypophosphatemia.

<p>A novel heterozygous mutation c.1639-1652del14 is present in the mother, patient, and his sister. A novel heterozygous splice donor site mutation c.1335+2T>A is present in the father, patient, and his sister. Compound heterozygous <i>SLC34A3</i> mutations are carried by both patient and his sister. Mutation is indicated by an arrow.</p

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3

Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood