{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:54:42Z","timestamp":1791075282459,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"publisher","award":["P3-0343"],"award-info":[{"award-number":["P3-0343"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"publisher","award":["TP 20170122"],"award-info":[{"award-number":["TP 20170122"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UMCL tertiary research project","award":["P3-0343"],"award-info":[{"award-number":["P3-0343"]}]},{"name":"UMCL tertiary research project","award":["TP 20170122"],"award-info":[{"award-number":["TP 20170122"]}]},{"name":"Novo Nordisk","award":["P3-0343"],"award-info":[{"award-number":["P3-0343"]}]},{"name":"Novo Nordisk","award":["TP 20170122"],"award-info":[{"award-number":["TP 20170122"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Heterozygous variants in the NPR2 gene, which encodes the B-type natriuretic peptide receptor (NPR-B), a regulator of skeletal growth, were reported in 2\u20136% cases of idiopathic short stature (ISS). Using next-generation sequencing (NGS), we aimed to assess the frequency of NPR2 variants in our study cohort consisting of 150 children and adolescents with ISS, describe the NPR2 phenotypic spectrum with a growth pattern including birth data, and study the response to growth hormone (GH) treatment. A total of ten heterozygous pathogenic\/likely pathogenic NPR2 variants and two heterozygous NPR2 variants of uncertain significance were detected in twelve participants (frequency of causal variants: 10\/150, 6.7%). During follow-up, the NPR2 individuals presented with a growth pattern varying from low\u2013normal to significant short stature. A clinically relevant increase in BMI (a mean gain in the BMI SDS of +1.41), a characteristic previously not reported in NPR2 individuals, was observed. In total, 8.8% participants born small for their gestational age (SGA) carried the NPR2 causal variant. The response to GH treatment was variable (SDS height gain ranging from \u22120.01 to +0.74). According to the results, NPR2 variants present a frequent cause of ISS and familial short stature. Phenotyping variability in growth patterns and variable responses to GH treatment should be considered.<\/jats:p>","DOI":"10.3390\/genes13061065","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T22:17:01Z","timestamp":1655331421000},"page":"1065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Heterozygous NPR2 Variants in Idiopathic Short Stature"],"prefix":"10.3390","volume":"13","author":[{"given":"Lana","family":"Stavber","sequence":"first","affiliation":[{"name":"Clinical Institute for Special Laboratory Diagnostics, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Joao","family":"Gaia","sequence":"additional","affiliation":[{"name":"Hospital Center Vila Nova de Gaia Espinho, 4430 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5330-3983","authenticated-orcid":false,"given":"Tinka","family":"Hovnik","sequence":"additional","affiliation":[{"name":"Clinical Institute for Special Laboratory Diagnostics, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Jenko Bizjan","sequence":"additional","affiliation":[{"name":"Clinical Institute for Special Laboratory Diagnostics, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maru\u0161a","family":"Debeljak","sequence":"additional","affiliation":[{"name":"Clinical Institute for Special Laboratory Diagnostics, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-4838","authenticated-orcid":false,"given":"Jernej","family":"Kova\u010d","sequence":"additional","affiliation":[{"name":"Clinical Institute for Special Laboratory Diagnostics, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasna \u0160uput","family":"Omladi\u010d","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0273-4732","authenticated-orcid":false,"given":"Tadej","family":"Battelino","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9570-1130","authenticated-orcid":false,"given":"Primo\u017e","family":"Kotnik","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9201-2145","authenticated-orcid":false,"given":"Klemen","family":"Dov\u010d","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children\u2019s Hospital, UMC, 1000 Ljubljana, Slovenia"},{"name":"Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4210","DOI":"10.1210\/jc.2008-0509","article-title":"Consensus statement on the diagnosis and treatment of children with idiopathic short stature: A summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop","volume":"93","author":"Cohen","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1515\/jpem-2021-0332","article-title":"NPR2 gene variants in familial short stature: A single-center study","volume":"35","author":"Yuan","year":"2022","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/MOP.0000000000000653","article-title":"New developments in the genetic diagnosis of short stature","volume":"30","author":"Jee","year":"2018","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_4","first-page":"1","article-title":"Role of NPR2 mutation in idiopathic short stature: Identification of two novel mutations","volume":"8","author":"Hwang","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1210\/clinem\/dgaa842","article-title":"Clinical Characteristics of Short-Stature Patients With an NPR2 Mutation and the Therapeutic Response to rhGH","volume":"106","author":"Ke","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Plachy, L., Dusatkova, P., Maratova, K., Petruzelkova, L., Zemkova, D., Elblova, L., Kucerova, P., Toni, L., Kolouskova, S., and Snajderova, M. (2020). NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy. J. Clin. Endocrinol. Metab., 105.","DOI":"10.1210\/clinem\/dgaa037"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1210\/clinem\/dgaa491","article-title":"Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations","volume":"105","author":"Hanley","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.biocel.2018.07.004","article-title":"Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of Acromesomelic dysplasia, type Maroteaux","volume":"102","author":"Zeb","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103554","DOI":"10.1016\/j.ejmg.2018.10.006","article-title":"Novel variants in natriuretic peptide receptor 2 in unrelated patients with acromesomelic dysplasia type Maroteaux","volume":"62","author":"Iqbal","year":"2019","journal-title":"Eur. J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1210\/jc.2013-2142","article-title":"Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature","volume":"98","author":"Vasques","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ranke, M.B. (2011). Growth Hormone Deficiency: Diagnostic Principles and Practice. Diagnostics of Endocrine Function in Children and Adolescents, KARGER. Available online: https:\/\/www.karger.com\/Article\/FullText\/327405.","DOI":"10.1159\/000327405"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1109\/TMI.2008.926067","article-title":"The BoneXpert Method for Automated Determination of Skeletal Maturity","volume":"28","author":"Thodberg","year":"2009","journal-title":"IEEE Trans. Med. Imaging"},{"key":"ref_13","first-page":"45","article-title":"The LMS method for constructing normalized growth standards","volume":"44","author":"Cole","year":"1990","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1002\/aur.1345","article-title":"Rare single nucleotide polymorphisms in the regulatory regions of the superoxide dismutase genes in autism spectrum disorder","volume":"7","author":"Battelino","year":"2014","journal-title":"Autism Res."},{"key":"ref_15","unstructured":"Li, H. (2013). Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1093\/bioinformatics\/btv098","article-title":"Sambamba: Fast processing of NGS alignment formats","volume":"31","author":"Tarasov","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Poplin, R., Ruano-Rubio, V., DePristo, M.A., Fennell, Y.J., Carneiro, M.O., Ven der Auwera, G.A., Kling, D.E., Gauthier, L.D., Levy-Moonshine, A., and Roazen, D. (2018). Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv, 1\u201322.","DOI":"10.1101\/201178"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"W545","DOI":"10.1093\/nar\/gky471","article-title":"VarAFT: A variant annotation and filtration system for human next generation sequencing data","volume":"46","author":"Desvignes","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Talevich, E., Shain, A.H., Botton, T., and Bastian, B.C. (2016). CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing. PLoS Comput. Biol., 12.","DOI":"10.1371\/journal.pcbi.1004873"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1136\/jmg.2004.029538","article-title":"Splicing in action: Assessing disease causing sequence changes","volume":"42","author":"Baralle","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1086\/422013","article-title":"Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux","volume":"75","author":"Bartels","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/hmg\/dds432","article-title":"A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type","volume":"22","author":"Geister","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3389\/fendo.2021.671361","article-title":"Genetic Screening for Growth Hormone Therapy in Children Small for Gestational Age: So Much to Consider, Still Much to Discover","volume":"12","author":"Giacomozzi","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/humu.22773","article-title":"Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature","volume":"36","author":"Wang","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1210\/jc.2018-01971","article-title":"Multigene sequencing analysis of children born small for gestational age with isolated short stature","volume":"104","author":"Freire","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.cca.2016.06.045","article-title":"C-type natriuretic peptide is closely associated to obesity in Caucasian adolescents","volume":"460","author":"Cabiati","year":"2016","journal-title":"Clin. Chim. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.peptides.2013.09.013","article-title":"C-type natriuretic peptide plasma levels are reduced in obese adolescents","volume":"50","author":"Cabiati","year":"2013","journal-title":"Peptides"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-20469-z","article-title":"Adipocyte-specific expression of C-type natriuretic peptide suppresses lipid metabolism and adipocyte hypertrophy in adipose tissues in mice fed high-fat diet","volume":"8","author":"Bae","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1530\/EJE-13-0864","article-title":"Unexpected high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients","volume":"170","author":"Flechtner","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1159\/000338341","article-title":"IGF1, IGF1R and SHOX mutation analysis in short children born small for gestational age and short children with normal birth size (idiopathic short stature)","volume":"77","author":"Caliebe","year":"2012","journal-title":"Horm. Res. Paediatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1210\/er.2018-00083","article-title":"Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications","volume":"39","author":"Finken","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1515\/jpem-2016-0280","article-title":"Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2","volume":"30","author":"Vasques","year":"2017","journal-title":"J. Pediatr. Endocrinol. Metab."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1065\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:31:53Z","timestamp":1760139113000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,15]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["genes13061065"],"URL":"https:\/\/doi.org\/10.3390\/genes13061065","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,15]]}}}