{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:02:16Z","timestamp":1753869736056,"version":"3.41.2"},"reference-count":17,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T00:00:00Z","timestamp":1579737600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP17ek0109281"],"award-info":[{"award-number":["JP17ek0109281"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Achondroplasia (ACH), the most common form of short\u2010limbed skeletal dysplasia, is caused by gain\u2010of\u2010function mutations in the fibroblast growth factor receptor 3 (<jats:italic>FGFR3<\/jats:italic>) gene. More than 97% of patients result from a heterozygous p.G380R mutation in the <jats:italic>FGFR3<\/jats:italic> gene. We present here a child who had two de novo variants in the <jats:italic>FGFR3<\/jats:italic> on the same allele, a common p.G380R mutation and a novel p.S378N variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A 3\u2010year\u2010old Japanese girl born from non\u2010consanguineous healthy parents showed more severe clinical and radiological phenotypes than classic ACH, including severe short\u2010limbed short stature with marked ossification defects in the metaphysis and epiphysis, hydrocephalus and cervicomedullary compression due to foramen magnum stenosis, prolonged pulmonary hypoplasia, and significant delay in the gross motor development. Genomic DNA was extracted from the proband and whole\u2010exome sequencing was performed. The variants were subsequently confirmed by Sanger sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mutation analysis demonstrated that the proband had p.S378N (c.1133G&gt;A) and p.G380R (c.1138G&gt;A) variants in the <jats:italic>FGFR3<\/jats:italic> gene. Both variants were not detected in her parents and therefore considered de novo. An allele\u2010specific PCR was developed in order to determine whether these mutations were on the same allele (cis) or on different alleles (trans). The c.1138G&gt;A mutation was found in the PCR product generated with the primer for the mutant 1133A, but it was not detected in the product with the wild\u2010type 1133G, confirming that p.S378N and p.G380R variants were located on the same allele (cis).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the second case who had two <jats:italic>FGFR3<\/jats:italic> variants in the transmembrane domain on the same allele. The p.S378N variant may provide an additive effect on the activating receptor with the p.G380R mutation and alter the protein function, which could be responsible for the severe phenotype of the present case.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1148","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T01:53:21Z","timestamp":1579830801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Severe achondroplasia due to two de novo variants in the transmembrane domain of <i>FGFR3<\/i> on the same allele: A case report"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7284-7428","authenticated-orcid":false,"given":"Tadashi","family":"Nagata","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Nagoya University Graduate School of Medicine Nagoya 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