{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:54:25Z","timestamp":1793382865989,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T00:00:00Z","timestamp":1657756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Nearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of <jats:italic>COL1A1<\/jats:italic> and <jats:italic>COL1A2<\/jats:italic> genes, of which <jats:italic>de novo<\/jats:italic> mutations cover a large proportion, whereas their characteristics remain to be elucidated. This study aims to compare the differences in clinical and genetic characteristics of <jats:italic>de novo<\/jats:italic> and inherited <jats:italic>COL1A1\/COL1A2<\/jats:italic> mutations of OI, assess the average paternal and maternal age at conception in <jats:italic>de novo<\/jats:italic> mutations, and research the rate of nonpenetrance in inherited mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>A retrospective comparison between <jats:italic>de novo<\/jats:italic> and inherited mutations was performed among 135 OI probands with <jats:italic>COL1A1\/COL1A2<\/jats:italic> mutations. Mutational analyses of all probands and their family members were completed by Sanger sequencing. A new clinical scoring system was developed to assess the clinical severity of OI quantitatively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 51 probands (37.78%) with <jats:italic>de novo<\/jats:italic> mutations and 84 probands (62.22%) with inherited mutations were grouped by the results of the parental gene verification. The proportion of clinical type III (<jats:italic>P<\/jats:italic>&amp;lt;0.001) and clinical scores (<jats:italic>P<\/jats:italic>&amp;lt;0.001) were significantly higher in <jats:italic>de novo<\/jats:italic> mutations. Missense mutations covered a slightly higher proportion of <jats:italic>de novo COL1A1<\/jats:italic> mutations (46.34%) compared with inherited <jats:italic>COL1A1<\/jats:italic> mutations (33.33%), however, lacking a significant difference (<jats:italic>P<\/jats:italic>=0.1923). The mean BMD Z\/T-score at the lumbar spine in <jats:italic>de novo<\/jats:italic> mutations was -2.3 \u00b1 1.5, lower than inherited mutations (-1.7 \u00b1 1.8), but lacking statistical significance (<jats:italic>P<\/jats:italic>=0.0742). There was no significant difference between the two groups in OI-related phenotypes (like fracture frequency, blue sclera, and hearing loss) and biochemical indexes. In <jats:italic>de novo<\/jats:italic> mutations, the average paternal and maternal age at conception was 29.2 (<jats:italic>P<\/jats:italic>&amp;lt;0.05) and 26.8 (<jats:italic>P<\/jats:italic>&amp;lt;0.0001), respectively, which were significantly younger than the average gestational age of the population. Additionally, 98.04% of pedigrees (50\/51) with <jats:italic>de novo<\/jats:italic> mutations were spontaneous conception. The rate of nonpenetrance of parents with pathogenic variants in the inherited mutation group was 25.64% (20\/78).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data revealed that the proportion of clinical type III and clinical scores were significantly higher in <jats:italic>de novo<\/jats:italic> mutations than in inherited mutations, demonstrating that <jats:italic>de novo<\/jats:italic> mutations are more damaging because they have not undergone purifying selection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.935905","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T05:40:21Z","timestamp":1657777221000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1\/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis 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