Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
-
Ihsan Turan
,
Sevcan Erdem
,
Leman Damla Kotan
,
Semine Ozdemir Dilek
,
Mehmet Tastan
Abstract
Objectives
Hereditary Hypophosphatemic Rickets (HHR) is a heterogeneous group of disorders characterized by hypophosphatemia. Although the X-linked dominant HHR is the most common form, the genetic etiology of HHR is variable. Recently, developed next-generation sequencing techniques may provide opportunities for making HHR diagnosis in a timely and efficient way.
Methods
We investigated clinical and genetic features for 18 consecutive probands and their 17 affected family members with HHR. All patient’s clinical and biochemical data were collected. We first analyzed a single gene with Next-generation sequencing if the patients have a strong clue for an individual gene. For the remaining cases, a Hypophosphatemic Rickets gene panel, including all known HHR genes by Next-generation sequencing, was employed.
Results
We were able to diagnosis all of the consecutive 35 patients in our tertiary care center. We detected nine novel and 10 previously described variants in PHEX (9; 50%), SLC34A3 (3; 17%), ENPP1 (3; 17%), SLC34A1 (1; 5%), CLCN5 (1; 5%), and DMP1 (1; 5%).
Conclusions
To delineate the etiology of HHR cases in a cost and time-efficient manner, we propose single gene analysis by next-generation sequencing if findings of patients indicate a strong clue for an individual gene. If that analysis is negative or for all other cases, a Next-generation Sequence gene panel, which includes all known HHR genes, should be employed.
Acknowledgments
We are grateful to Fatma Dereli (Intergene Genetic Center, Ankara) and Dr. Esra Giray, MD (Koc University, Istanbul).
-
Research funding: This research did not receive any specific grant.
-
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Competing interests: The authors have no conflict of interest to disclose.
-
Informed consent: All the participants or their legal guardians provided written informed consents.
-
Ethical approval: The Ethics Committee of the Cukurova University Faculty of Medicine approved this study.
References
1. Carpenter, TO. The expanding family of hypophosphatemic syndromes. J Bone Miner Metabol 2012;30:1–9. https://doi.org/10.1007/s00774-011-0340-2.Search in Google Scholar
2. Linglart, A, Biosse-Duplan, M, Briot, K, Chaussain, C, Esterle, L, Guillaume-Czitrom, S, et al.. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect 2014;3:R13–30. https://doi.org/10.1530/ec-13-0103.Search in Google Scholar
3. Carpenter, TO, Shaw, NJ, Portale, AA, Ward, LM, Abrams, SA, Pettifor, JM. Rickets. Nat Rev Dis Primers 2017;3:17101. https://doi.org/10.1038/nrdp.2017.101.Search in Google Scholar
4. Razali, NN, Hwu, TT, Thilakavathy, K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets. J Pediatr Endocrinol Metab 2015;28:1009–17. https://doi.org/10.1515/jpem-2014-0366.Search in Google Scholar
5. Stenson, PD, Ball, EV, Mort, M, Phillips, AD, Shaw, K, Cooper, DN. The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformatics 2012;39:1–13.10.1002/0471250953.bi0113s39Search in Google Scholar PubMed
6. Consortium, A. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000;26:345–8. https://doi.org/10.1038/81664.Search in Google Scholar
7. Lorenz-Depiereux, B, Bastepe, M, Benet-Pages, A, Amyere, M, Wagenstaller, J, Muller-Barth, U, et al.. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 2006;38:1248–50. https://doi.org/10.1038/ng1868.Search in Google Scholar
8. Levy-Litan, V, Hershkovitz, E, Avizov, L, Leventhal, N, Bercovich, D, Chalifa-Caspi, V, et al.. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 2010;86:273–8. https://doi.org/10.1016/j.ajhg.2010.01.010.Search in Google Scholar
9. Lorenz-Depiereux, B, Schnabel, D, Tiosano, D, Hausler, G, Strom, TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet 2010;86:267–72. https://doi.org/10.1016/j.ajhg.2010.01.006.Search in Google Scholar
10. Feng, JQ, Ward, LM, Liu, S, Lu, Y, Xie, Y, Yuan, B, et al.. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006;38:1310–5. https://doi.org/10.1038/ng1905.Search in Google Scholar
11. Haffner, D, Emma, F, Eastwood, DM, Duplan, MB, Bacchetta, J, Schnabel, D, et al.. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019;15:435–55. https://doi.org/10.1038/s41581-019-0152-5.Search in Google Scholar
12. Ruppe, MD. X-linked hypophosphatemia. In: Adam, MP, Ardinger, HH, Pagon, RA, Wallace, SE, Bean, LJH, Stephens, K, editors, et al.. GeneReviews((R)). Seattle (WA): University of Washington; 2017.Search in Google Scholar
13. Neyzi, O, Bundak, R, Gokcay, G, Gunoz, H, Furman, A, Darendeliler, F, et al.. Reference values for weight, height, head circumference, and body mass index in Turkish children. J Clin Res Pediatr Endocrinol 2015;7:280–93. https://doi.org/10.4274/jcrpe.2183.Search in Google Scholar
14. Stenson, PD, Ball, EV, Mort, M, Phillips, AD, Shiel, JA, Thomas, NS, et al.. Human gene mutation database (HGMD): 2003 update. Hum Mutat 2003;21:577–81. https://doi.org/10.1002/humu.10212.Search in Google Scholar
15. Fokkema, IF, Taschner, PE, Schaafsma, GC, Celli, J, Laros, JF, den Dunnen, JT. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat 2011;32:557–63. https://doi.org/10.1002/humu.21438.Search in Google Scholar
16. Lek, M, Karczewski, KJ, Minikel, EV, Samocha, KE, Banks, E, Fennell, T, et al.. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536:285–91. https://doi.org/10.1038/nature19057.Search in Google Scholar
17. Richards, S, Aziz, N, Bale, S, Bick, D, Das, S, Gastier-Foster, J, et al.. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.Search in Google Scholar
18. Kopanos, C, Tsiolkas, V, Kouris, A, Chapple, CE, Albarca Aguilera, M, Meyer, R, et al.. VarSome: the human genomic variant search engine. Bioinformatics 2019;35:1978–80. https://doi.org/10.1093/bioinformatics/bty897.Search in Google Scholar
19. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1–150.Search in Google Scholar
20. Siklar, Z, Turan, S, Bereket, A, Bas, F, Guran, T, Akberzade, A, et al.. Nationwide Turkish cohort study of hypophosphatemic rickets. J Clin Res Pediatr Endocrinol 2020;12:150–9.10.4274/jcrpe.galenos.2019.2019.0098Search in Google Scholar PubMed PubMed Central
21. Beck-Nielsen, SS, Brixen, K, Gram, J, Brusgaard, K. Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet 2012;57:453–8. https://doi.org/10.1038/jhg.2012.56.Search in Google Scholar
22. Filisetti, D, Ostermann, G, von Bredow, M, Strom, T, Filler, G, Ehrich, J, et al.. Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues. Eur J Hum Genet 1999;7:615–9. https://doi.org/10.1038/sj.ejhg.5200341.Search in Google Scholar
23. Kotwal, A, Ferrer, A, Kumar, R, Singh, RJ, Murthy, V, Schultz-Rogers, L, et al.. Clinical and biochemical phenotypes in a family with ENPP1 mutations. J Bone Miner Res 2020;35:662–70. https://doi.org/10.1002/jbmr.3938.Search in Google Scholar
24. Farrow, EG, Davis, SI, Ward, LM, Summers, LJ, Bubbear, JS, Keen, R, et al.. Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets. Bone 2009;44:287–94. https://doi.org/10.1016/j.bone.2008.10.040.Search in Google Scholar
25. Demir, K, Yildiz, M, Bahat, H, Goldman, M, Hassan, N, Tzur, S, et al.. Clinical heterogeneity and phenotypic expansion of NaPi-IIa-associated disease. J Clin Endocrinol Metab 2017;102:4604–14. https://doi.org/10.1210/jc.2017-01592.Search in Google Scholar
26. Online Mendelian Inheritance in Man, OMIM®. Baltimore, MD: Johns Hopkins University; 2008. MIM Number: 612286 [Internet]. Available from: https://omim.org/.Search in Google Scholar
27. Proesmans, WC, Fabry, G, Marchal, GJ, Gillis, PL, Bouillon, R. Autosomal dominant hypophosphataemia with elevated serum 1,25 dihydroxyvitamin D and hypercalciuria. Pediatr Nephrol 1987;1:479–84. https://doi.org/10.1007/bf00849257.Search in Google Scholar
28. Johns Hopkins University B, MD. Online Mendelian Inheritance in Man, OMIM®. [updated MIM Number: {241530}: {02/14/2006}]. Available from: https://omim.org/.Search in Google Scholar
29. Lorenz-Depiereux, B, Benet-Pages, A, Eckstein, G, Tenenbaum-Rakover, Y, Wagenstaller, J, Tiosano, D, et al.. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet 2006;78:193–201. https://doi.org/10.1086/499410.Search in Google Scholar
30. Payne, RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem 1998;35:201–6. https://doi.org/10.1177/000456329803500203.Search in Google Scholar
31. Lockitch, G, Halstead, AC, Albersheim, S, MacCallum, C, Quigley, G. Age- and sex-specific pediatric reference intervals for biochemistry analytes as measured with the Ektachem-700 analyzer. Clin Chem 1988;34:1622–5. https://doi.org/10.1093/clinchem/34.8.1622.Search in Google Scholar
32. Rowe, PS, Oudet, CL, Francis, F, Sinding, C, Pannetier, S, Econs, MJ, et al.. Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). Hum Mol Genet 1997;6:539–49. https://doi.org/10.1093/hmg/6.4.539.Search in Google Scholar
33. Holm, IA, Huang, X, Kunkel, LM. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am J Hum Genet 1997;60:790–7.Search in Google Scholar
34. Francis, F, Strom, TM, Hennig, S, Boddrich, A, Lorenz, B, Brandau, O, et al.. Genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets. Genome Res 1997;7:573–85. https://doi.org/10.1101/gr.7.6.573.Search in Google Scholar
35. Ichikawa, S, Sorenson, AH, Imel, EA, Friedman, NE, Gertner, JM, Econs, MJ. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab 2006;91:4022–7. https://doi.org/10.1210/jc.2005-2840.Search in Google Scholar
36. Acar, S, BinEssa, HA, Demir, K, Al-Rijjal, RA, Zou, M, Catli, G, et al.. Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: novel mutations in PHEX and SLC34A3. PloS One 2018;13:e0193388. https://doi.org/10.1371/journal.pone.0193388.Search in Google Scholar
37. Areses-Trapote, R, Lopez-Garcia, JA, Ubetagoyena-Arrieta, M, Eizaguirre, A, Saez-Villaverde, R. Hereditary hypophosphatemic rickets with hypercalciuria: case report. Nefrologia 2012;32:529–34. https://doi.org/10.3265/Nefrologia.pre2012.Apr.11321.Search in Google Scholar
38. Schlingmann, KP, Ruminska, J, Kaufmann, M, Dursun, I, Patti, M, Kranz, B, et al.. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol 2016;27:604–14. https://doi.org/10.1681/asn.2014101025.Search in Google Scholar
39. Nitschke, Y, Baujat, G, Botschen, U, Wittkampf, T, du Moulin, M, Stella, J, et al.. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 2012;90:25–39. https://doi.org/10.1016/j.ajhg.2011.11.020.Search in Google Scholar
40. Lloyd, SE, Pearce, SH, Fisher, SE, Steinmeyer, K, Schwappach, B, Scheinman, SJ, et al.. A common molecular basis for three inherited kidney stone diseases. Nature 1996;379:445–9. https://doi.org/10.1038/379445a0.Search in Google Scholar
© 2021 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Covid19 pandemic and pediatric endocrinology and metabolism—Are we through with it?
- Original Articles
- Invisible burden of COVID-19: enzyme replacement therapy disruptions
- Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia)
- Etiologies, profile patterns and characteristics of children with short stature in Jordan
- Sexual maturity assessment in Indian children—a study from western India
- Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study
- Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis
- Prevalence and MRI findings of incidentally detected pituitary non-enhancing lesion on brain MRI in children
- Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents
- Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
- Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents
- Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes
- Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia
- Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
- Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
- Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
- Case Reports
- Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
- Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication
- Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide
- Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature
Articles in the same Issue
- Frontmatter
- Editorial
- Covid19 pandemic and pediatric endocrinology and metabolism—Are we through with it?
- Original Articles
- Invisible burden of COVID-19: enzyme replacement therapy disruptions
- Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia)
- Etiologies, profile patterns and characteristics of children with short stature in Jordan
- Sexual maturity assessment in Indian children—a study from western India
- Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study
- Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis
- Prevalence and MRI findings of incidentally detected pituitary non-enhancing lesion on brain MRI in children
- Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents
- Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
- Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents
- Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes
- Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia
- Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
- Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
- Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
- Case Reports
- Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
- Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication
- Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide
- Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature
