perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”10.21508/1027-4065-2025-70-6-95-103perinatology-2318Research ArticleОБМЕН ОПЫТОМSHARING EXPERIENCESОпыт применения полногеномного секвенирования для диагностики X-сцепленного гипофосфатемического рахита на примере двух случаевExperience of using whole genome sequencing for diagnostics of X-linked hypophosphatemic rickets on the example of two caseshttps://orcid.org/0000-0001-7894-9222БуяноваА. А.BuianovaA. A.

Буянова Анастасия Александровна — м.н.с. лаборатории клинической геномики и биоинформатики

125412, г. Москва, ул. Талдомская, д. 2 

125412, Moscow 

anastasiiabuianova97@gmail.comhttps://orcid.org/0009-0006-7876-1223РожковаА. В.RozhkovaA. V.

Рожкова Анастасия Вячеславовна — ординатор 2 года 

125412, г. Москва, ул. Талдомская, д. 2 

125412, Moscow 

https://orcid.org/0009-0007-5460-4984ПаршинаО. П.ParshinaO. P.

Паршина Ольга Павловна — ординатор 2 года 

125412, г. Москва, ул. Талдомская, д. 2 

125412, Moscow 

https://orcid.org/0009-0008-5168-535XКудакаеваА. А.KudakaevaA. A.

Кудакаева Алия Анваровна — врач-генетик, м.н.с. лаборатории клинической геномики и биоинформатики 

125412, г. Москва, ул. Талдомская, д. 2 

125412, Moscow 

https://orcid.org/0000-0003-1107-362XВасильевЕ. В.VasilyevE. V.

Васильев Евгений Витальевич — к.б.н., врач лабораторный генетик, с.н.с. лаборатории клинической геномики и биоинформатики, зав. лабораторией молекулярной и биохимической диагностики

125412, г. Москва, ул. Талдомская, д. 2 

125412, Moscow 

https://orcid.org/0000-0002-4024-5171ДанцевИ. С.DantsevI. S.

Данцев Илья Сергеевич — врач-генетик, зав. лабораторией клинической геномики и биоинформатики

125412, г. Москва, ул. Талдомская, д. 2 

125412, Moscow 

https://orcid.org/0000-0001-7146-7220НиколаеваЕ. А.NikolaevaE. A.

Николаева Екатерина Александровна — д.м.н., врач-генетик, гл.н.с. отдела клинической генетики

125412, г. Москва, ул. Талдомская, д. 2 

125412, Moscow 

Научно-исследовательский клинический институт педиатрии и детской хирургии имени академика Ю.Е. Вельтищева ФГАОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияVeltischev Research and Clinical Institute for pediatrics and pediatric surgery at the Pirogov Russian National Research Medical UniversityRussian Federation20253012202570695103Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20252025Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/2318

Х-сцепленный доминантный гипофосфатемический рахит — наиболее распространенная наследственная форма гипофосфатемического рахита, которая характеризуется нарушением функции почек, деформацией скелета и другими полиорганными осложнениями. В нашей стране с 2022 года одобрен к терапевтическому применению первый патогенетический препарат на основе моноклональных антител к фактору роста фибробластов 23 — Буросумаб. Назначение терапии требует верификации диагноза при помощи молекулярно-генетических методов. В настоящем исследовании представлены два клинических наблюдения за пациентами с Х-сцепленным доминантным гипофосфатемическим рахитом. Клинический диагноз был установлен в возрасте 7 и 12 лет на основании характерного биохимического профиля и рентгенологической картины. Однако каузативные варианты в гене PHEX (c.2147+1197A>G и chrX:22030553_22033026del) удалось выявить только после проведения полногеномного секвенирования с последующим детальным анализом данных секвенирования нового поколения.

X-linked dominant hypophosphatemic rickets is the most common inherited form of hypophosphatemic rickets, characterized by renal dysfunction, skeletal deformities, and other multi-organ complications. In Russia, since 2022, the first targeted therapy has been approved for clinical use — Burosumab, a monoclonal antibody directed against fibroblast growth factor 23. Initiation of treatment requires confirmation of the diagnosis through molecular genetic testing. This study presents two clinical case reports of patients with X-linked dominant hypophosphatemic rickets. The clinical diagnosis was established at the ages of 7 and 12 years based on a characteristic biochemical profile and radiographic findings. However, causative variants in the PHEX gene (c.2147+1197A>G and chrX:22030553_22033026del) were identified only after whole-genome sequencing, followed by detailed analysis of next-generation sequencing data.

Х-сцепленный доминантный гипофосфатемический рахитполногеномное секвенированиебуросумабX-linked dominant hypophosphatemic ricketswhole genome sequencingburosumabReferencesКуликова К.С., Тюльпаков А.Н. Гипофосфатемический рахит: патогенез, диагностика и лечение. Ожирение и метаболизм. 2018; 15(2): 46–50. DOI: 10.14341/omet9672Kulikova K.S., Tiulpakov A.N. Hypophosphatemic rickets: pathogenesis, diagnosis and treatment. Ozhirenie i metabolizm. 2018; 15(2): 46–50. (in Russ.) DOI: 10.14341/omet9672Laurent M.R., Harvengt P., Mortier G.R., Böckenhauer D. X-Linked Hypophosphatemia. 2012 Feb 9 [updated 2023 Dec 14]. In: Adam M.P., Feldman J., Mirzaa G.M., Pagon R.A., Wallace S.E., Amemiya A., editors. GeneReviews®️ [Internet]. Seattle (WA): University of Washington, Seattle; 1993– 2025. https://www.ncbi.nlm.nih.gov/books/NBK83985/# Ссылка активна на 14.07.2025Laurent M.R., Harvengt P., Mortier G.R., Böckenhauer D. X-Linked Hypophosphatemia. 2012 Feb 9 [updated 2023 Dec 14]. In: Adam M.P., Feldman J., Mirzaa G.M., Pagon R.A., Wallace S.E., Amemiya A., editors. GeneReviews®️ [Internet]. Seattle (WA): University of Washington, Seattle; 1993– 2025. https://www.ncbi.nlm.nih.gov/books/NBK83985/# \ Ссылка активна на 14.07.2025Федеральная служба государственной статистики. https://rosstat.gov.ru/folder/313/document/197667 Ссылка активна на 14.07.2025Federal State Statistics Service (in Russ) https://rosstat.gov.ru/folder/313/document/197667 \ Ссылка активна на 14.07.2025Razali N.N., Hwu T.T., Thilakavathy K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rick-ets. J Pediatr Endocrinol Metab. 2015; 28(9–10): 1009–1017. DOI: 10.1515/jpem-2014-0366Razali N.N., Hwu T.T., Thilakavathy K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rick-ets. J Pediatr Endocrinol Metab. 2015; 28(9–10): 1009–1017. DOI: 10.1515/jpem-2014-0366Thompson D.L., Sabbagh Y., Tenenhouse H.S., Roche P.C., Drezner M.K., Salisbury J.L., et al. Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. J Bone Miner Res. 2002; 17(2): 311–320. DOI: 10.1359/jbmr.2002.17.2.311Thompson D.L., Sabbagh Y., Tenenhouse H.S., Roche P.C., Drezner M.K., Salisbury J.L., et al. Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. J Bone Miner Res. 2002; 17(2): 311–320. DOI: 10.1359/jbmr.2002.17.2.311Kamenický P., Briot K., Munns C.F., Linglart A. X-linked hypophosphataemia. Lancet. 2024; 404(10455): 887–901. DOI: 10.1016/S0140-6736(24)01305-9Kamenický P., Briot K., Munns C.F., Linglart A. X-linked hypophosphataemia. Lancet. 2024; 404(10455): 887–901. DOI: 10.1016/S0140-6736(24)01305-9Haffner D., Emma F., Eastwood D.M., Duplan M.B., Bacchetta J., Schnabel D., et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019; 15(7): 435– 455. DOI: 10.1038/s41581-019-0152-5Haffner D., Emma F., Eastwood D.M., Duplan M.B., Bacchetta J., Schnabel D., et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019; 15(7): 435– 455. DOI: 10.1038/s41581-019-0152-5Imel E.A., Glorieux F.H., Whyte M.P., Munns C.F., Ward L.M., Nilsson O., et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019; 393(10189): 2416–2427. DOI: 10.1016/S0140-6736(19)30654-3Imel E.A., Glorieux F.H., Whyte M.P., Munns C.F., Ward L.M., Nilsson O., et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019; 393(10189): 2416–2427. DOI: 10.1016/S0140-6736(19)30654-3Imel E.A. Burosumab for Pediatric X-Linked Hypophosphatemia. Curr Osteoporos Rep. 2021; 19(3): 271–277. DOI: 10.1007/s11914-021-00669-9Imel E.A. Burosumab for Pediatric X-Linked Hypophosphatemia. Curr Osteoporos Rep. 2021; 19(3): 271–277. DOI: 10.1007/s11914-021-00669-9Ward L.M., Glorieux F.H., Whyte M.P., Munns C.F., Portale A.A., Högler W., et al. Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2022; 107(8): e3241-e3253. DOI: 10.1210/clinem/dgac296Ward L.M., Glorieux F.H., Whyte M.P., Munns C.F., Portale A.A., Högler W., et al. Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2022; 107(8): e3241-e3253. DOI: 10.1210/clinem/dgac296Куликова К.С., Тюльпаков А.Н. Диагностика и ведение Х-сцепленного доминантного гипофосфатемического рахита: учебно-методическое пособие. М.: Триумф, 2023: 44.Kulikova K., Tyulpakov A. Diagnosis and management of X-linked dominant hypophosphatemic rickets. Moscow: Triumf, 2023: 44 (in Russ.)Marcel M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet journal. 2011; 17(1). DOI: 10.14806/ej.17.1.200Marcel M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet journal. 2011; 17(1). DOI: 10.14806/ej.17.1.200Heng L. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Source: arXiv. 2013. DOI: 10.48550/arXiv.1303.3997Heng L. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Source: arXiv. 2013. DOI: 10.48550/arXiv.1303.3997Faust G.G., Hall I.M. SAMBLASTER: fast duplicate marking and structural variant read extraction. Bioinformatics. 2014; 30(17): 2503–2505. DOI: 10.1093/bioinformatics/btu314Faust G.G., Hall I.M. SAMBLASTER: fast duplicate marking and structural variant read extraction. Bioinformatics. 2014; 30(17): 2503–2505. DOI: 10.1093/bioinformatics/btu314“Picard Toolkit.” 2019. Broad Institute, GitHub Repository. Broad Institute. https://broadinstitute.github.io/picard/. Ссылка активна на 14.07.2025“Picard Toolkit.” 2019. Broad Institute, GitHub Repository. Broad Institute. https://broadinstitute.github.io/picard/. \ Ссылка активна на 14.07.2025Danecek P., Bonfield J.K., Liddle J., Marshall J., Ohan V., Pollard M.O., et al. Twelve years of SAMtools and BCFtools. Gigascience. 2021; 10(2): giab008. DOI: 10.1093/gigascience/giab008Danecek P., Bonfield J.K., Liddle J., Marshall J., Ohan V., Pollard M.O., et al. Twelve years of SAMtools and BCFtools. Gigascience. 2021; 10(2): giab008. DOI: 10.1093/gigascience/giab008Poplin R., Ruano-Rubio V., DePristo M.A., Fennell T.J., Carneiro M.O., Van der Auwera G.A., et al. Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv. 2017. DOI: 10.1101/201178Poplin R., Ruano-Rubio V., DePristo M.A., Fennell T.J., Carneiro M.O., Van der Auwera G.A., et al. Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv. 2017. DOI: 10.1101/201178Van der Auwera G.A., Carneiro M.O., Hartl C., Poplin R., Del Angel G., Levy-Moonshine A., et al. From FastQ Data to High-- Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Curr Protoc Bioinformatics. 2013; 43(1110): 11.10.1–11.10.33. DOI: 10.1002/0471250953.bi1110s43Van der Auwera G.A., Carneiro M.O., Hartl C., Poplin R., Del Angel G., Levy-Moonshine A., et al. From FastQ Data to High-- Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Curr Protoc Bioinformatics. 2013; 43(1110): 11.10.1–11.10.33. DOI: 10.1002/0471250953.bi1110s43McLaren W., Gil L., Hunt S.E., Riat H.S., Ritchie G.R., Thormann A., et al. The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1): 122. DOI: 10.1186/s13059-016-0974-4McLaren W., Gil L., Hunt S.E., Riat H.S., Ritchie G.R., Thormann A., et al. The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1): 122. DOI: 10.1186/s13059-016-0974-4Roller E., Ivakhno S., Lee S., Royce T., Tanner S. Canvas: versatile and scalable detection of copy number variants. Bioinformatics. 2016; 32(15): 2375–2377. DOI: 10.1093/bioinformatics/btw163Roller E., Ivakhno S., Lee S., Royce T., Tanner S. Canvas: versatile and scalable detection of copy number variants. Bioinformatics. 2016; 32(15): 2375–2377. DOI: 10.1093/bioinformatics/btw163Chen X., Schulz-Trieglaff O., Shaw R., Barnes B., Schlesinger F., Källberg M., et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016; 32(8): 1220–1222. DOI: 10.1093/bioinformatics/btv710Chen X., Schulz-Trieglaff O., Shaw R., Barnes B., Schlesinger F., Källberg M., et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016; 32(8): 1220–1222. DOI: 10.1093/bioinformatics/btv710Robinson J.T., Thorvaldsdóttir H., Winckler W., Guttman M., Lander E.S., Getz G., et al. Integrative genomics viewer. Nat Biotechnol. 2011; 29(1): 24–26. DOI: 10.1038/nbt.1754Robinson J.T., Thorvaldsdóttir H., Winckler W., Guttman M., Lander E.S., Getz G., et al. Integrative genomics viewer. Nat Biotechnol. 2011; 29(1): 24–26. DOI: 10.1038/nbt.1754Grimbly C., Ludwig K., Wu Z., Caluseriu O., Rosolowsky E., Alexander R.T., et al. X-linked hypophosphatemia caused by a deep intronic variant in PHEX identified by PCR-based RNA analysis of urine-derived cells. Bone. 2023; 176: 116839. DOI: 10.1016/j.bone.2023.116839Grimbly C., Ludwig K., Wu Z., Caluseriu O., Rosolowsky E., Alexander R.T., et al. X-linked hypophosphatemia caused by a deep intronic variant in PHEX identified by PCR-based RNA analysis of urine-derived cells. Bone. 2023; 176: 116839. DOI: 10.1016/j.bone.2023.116839Stenson P.D., Mort M., Ball E.V., Chapman M., Evans K., Azevedo L., et al. The Human Gene Mutation Database (HGMD®️): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020; 139(10): 1197–1207. DOI: 10.1007/s00439-020-02199-3Stenson P.D., Mort M., Ball E.V., Chapman M., Evans K., Azevedo L., et al. The Human Gene Mutation Database (HGMD®️): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020; 139(10): 1197–1207. DOI: 10.1007/s00439-020-02199-3Koponen L., Pekkinen M., Legebeke J., Muurinen M., Rusanen S., Hussain S. A deep intronic PHEX variant associated with X-linked hypophosphatemia in a Finnish family. JBMR Plus. 2024; 9(2): ziae169. DOI: 10.1093/jbmrpl/ziae169Koponen L., Pekkinen M., Legebeke J., Muurinen M., Rusanen S., Hussain S. A deep intronic PHEX variant associated with X-linked hypophosphatemia in a Finnish family. JBMR Plus. 2024; 9(2): ziae169. DOI: 10.1093/jbmrpl/ziae169Capelli S., Donghi V., Maruca K., Vezzoli G., Corbetta S., Brandi M.L., et al. Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets. Bone. 2015; 79: 143–149. DOI: 10.1016/j.bone.2015.05.040Capelli S., Donghi V., Maruca K., Vezzoli G., Corbetta S., Brandi M.L., et al. Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets. Bone. 2015; 79: 143–149. DOI: 10.1016/j.bone.2015.05.040Quinlan C., Guegan K., Offiah A., Neill R.O., Hiorns M.P., Ellard S., et al. Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol. 2012; 27(4): 581–588. DOI: 10.1007/s00467-011-2046-zQuinlan C., Guegan K., Offiah A., Neill R.O., Hiorns M.P., Ellard S., et al. Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol. 2012; 27(4): 581–588. DOI: 10.1007/s00467-011-2046-zBeck-Nielsen S.S., 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(7): 453–458. DOI: 10.1038/jhg.2012.56Beck-Nielsen S.S., 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(7): 453–458. DOI: 10.1038/jhg.2012.56Lin Y., Xu J., Li X., Sheng H., Su L., Wu M., et al. Novel variants and uncommon cases among southern Chinese children with X-linked hypophosphatemia. J Endocrinol Invest. 2020; 43(11): 1577–1590. DOI: 10.1007/s40618-020-01240-6Lin Y., Xu J., Li X., Sheng H., Su L., Wu M., et al. Novel variants and uncommon cases among southern Chinese children with X-linked hypophosphatemia. J Endocrinol Invest. 2020; 43(11): 1577–1590. DOI: 10.1007/s40618-020-01240-6Park P.G., Lim S.H., Lee H., Ahn Y.H., Cheong H.I., Kang H.G. Genotype and Phenotype Analysis in X-Linked Hypophosphatemia. Front Pediatr. 2021; 9: 699767. DOI: 10.3389/fped.2021.699767Park P.G., Lim S.H., Lee H., Ahn Y.H., Cheong H.I., Kang H.G. Genotype and Phenotype Analysis in X-Linked Hypophosphatemia. Front Pediatr. 2021; 9: 699767. DOI: 10.3389/fped.2021.699767Rodríguez-Rubio E., Gil-Peña H., Chocron S., Madariaga L., de la Cerda-Ojeda F., Fernández-Fernández M., et al Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population. [published correction appears in Orphanet J Rare Dis. Orphanet J Rare Dis. 2021; 16(1): 104. DOI: 10.1186/s13023-021-01729-0Rodríguez-Rubio E., Gil-Peña H., Chocron S., Madariaga L., de la Cerda-Ojeda F., Fernández-Fernández M., et al Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population. [published correction appears in Orphanet J Rare Dis. Orphanet J Rare Dis. 2021; 16(1): 104. DOI: 10.1186/s13023-021-01729-0

The authors declare that there are no conflicts of interest present.