ESPE Abstracts (2022) 95 P1-21

1Department of Pediatric Endocrinology and Diabetes, Marmara University Medical School, Istanbul, Turkey; 2Department of Human Genetics, Marmara University Medical School, Istanbul, Turkey; 3Department of Pediatric Endocrinology, İstanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey

Background: Hereditary hypophosphatemia (HH), is a rare condition related to decreased renal tubular phosphate reabsorption. Although X-linked hypophosphatemia (PHEX mutation) is the most frequent cause of HH, recent advances in the next-generation sequencing (NGS) techniques enable the identification of various genetic etiologies. Our study aims to determine the molecular etiology of patients with hypophosphatemia and to identify new candidate genes.

Subjects and Methods: Forty-one patients (19 males) from 32 unrelated families were included in the molecular analyses except two cases in whom family did not give consent. Initially, the PHEX gene was sequenced, if the result was negative, MLPA (Multiplex Ligation-dependent Probe Amplification) analysis for PHEX was performed. A targeted gene panel, including all known HH genes, was carried to the patients with normal PHEX gene or isolated hypophosphatemia without any rickets findings.

Results: Genetic cause in any of the known genes was detected in 34 patients from 26 families in the study group. PHEX gene variants were identified (five novel) in 18 patients from 14 unrelated families (18/39;46%) which included 5 nonsense, 3 missense, 3 splice-site, 1 in-frame deletion, 1 deletion, and 1 duplication. Novel variants in the PHEX gene were c.1382_1391del, c.958_960del, c.1111_1112insTT. A novel exon 2 deletion and also, a novel exon 4-12 duplication of the PHEX gene were revealed by MLPA. SLC34A3 gene variants were the second most common 18% (7/39) molecular defect in our cohort. Six homozygous and one heterozygous mutations were detected including double homozygous variants (c.1335+2T>A and c.756G>A) in three patients from two families. Novel variants in SLC34A3 were c.1267G>A and c.1435del. On the SLC34A1 gene, a compound heterozygous (a novel c.457G>T and previously reported c.1484G>A) and a heterozygous (c.272_292del) variants were also detected (2;5%). The variants in FAM20C (1;2,5%), CLCN5 (1;2,5%), SLC2A2 (1;2,5%) and DMP1 (3;7,5%) genes were the other known defects detected in our cohort. The c.26del variant in the ENPP1 gene (1;2,5%) was also novel. We could not find any genetic etiology in 5 patients (5/39;%13). The evaluation of whole exome sequencing is pending for these patients.

Conclusions: The application of MLPA and NGS techniques in addition to single gene sequencing revealed a molecular etiology in 87% of our cohort. MLPA had the additive value of 5% to explain the molecular pathology. Although PHEX gene defects were the most frequent genetic cause for hyphophosphatemia, NGS demonstrate rarer molecular etiologies in the majority of the remaining patients.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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