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  Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders

Oheim, R., Tsourdi, E., Seefried, L., Beller, G., Schubach, M., Vettorazzi, E., et al. (2022). Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders. Journal of Clinical Endocrinology and Metabolism, 107(7), e3048-e3057. doi:0.1210/clinem/dgac147.

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The Journal of Clinical Endocrinology & Metabolism_Oheim et al_2022.pdf (Verlagsversion), 465KB
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© The Author(s) 2022

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 Urheber:
Oheim, Ralf , Autor
Tsourdi , Elena , Autor
Seefried , Lothar , Autor
Beller , Gisela , Autor
Schubach , Max, Autor
Vettorazzi , Eik, Autor
Stürznickel, Julian , Autor
Rolvien , Tim, Autor
Ehmke , Nadja , Autor
Delsmann , Alena , Autor
Genest, Franca, Autor
Krüger, Ulrike , Autor
Zemojtel , Tomasz , Autor
Barvencik , Florian, Autor
Schinke , Thorsten , Autor
Jakob, Franz, Autor
Hofbauer, Lorenz C. , Autor
Mundlos, Stefan1, Autor           
Kornak, Uwe, Autor
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Schlagwörter: osteoporosis, low bone mass disorder, monogenic disorder, genetic risk score, rare genetic variant, genotype-phenotype correlation
 Zusammenfassung: Context

Many different inherited and acquired conditions can result in premature bone fragility / low bone mass disorders (LBMD).
Objective

We aimed at elucidating the impact of genetic testing on differential diagnosis of adult LBMD and at defining clinical criteria for predicting monogenic forms.
Methods

Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score <-2.0, and/or pathological fractures. After exclusion of secondary causes or unequivocal clinical/biochemical hallmarks of monogenic LBMD all participants were genotyped by targeted next-generation sequencing
Results

In total 20.8% of the participants carried rare disease-causing variants (DCV) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCV in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and four X-linked disorders. 9.7% of the participants harbored variants of unknown significance. A regression analysis revealed that the likelihood of detecting a DCV correlated with a positive family history of osteoporosis, peripheral fractures (>2), and a high normal BMI. In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD, e.g. in LRP5, were overrepresented.
Conclusion

The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield.

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Sprache(n): eng - English
 Datum: 2022-03-112022-06-26
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: DOI: 0.1210/clinem/dgac147
PMID: 35276006
 Art des Abschluß: -

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Titel: Journal of Clinical Endocrinology and Metabolism
  Andere : J. Clin. Endocrinol. Metab.
Genre der Quelle: Zeitschrift
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Affiliations:
Ort, Verlag, Ausgabe: Baltimore, Md. : Issued for the Endocrine Society by the Williams & Wilkins Co.
Seiten: - Band / Heft: 107 (7) Artikelnummer: - Start- / Endseite: e3048 - e3057 Identifikator: ISSN: 0021-972X
CoNE: https://pure.mpg.de/cone/journals/resource/110992357321228