Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders
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Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders. / Oheim, Ralf; Tsourdi, Elena; Seefried, Lothar; Beller, Gisela; Schubach, Max; Vettorazzi, Eik; Stürznickel, Julian; Rolvien, Tim; Ehmke, Nadja; Delsmann, Alena; Genest, Franca; Krüger, Ulrike; Zemojtel, Tomasz; Barvencik, Florian; Schinke, Thorsten; Jakob, Franz; Hofbauer, Lorenz C; Mundlos, Stefan; Kornak, Uwe.
in: J CLIN ENDOCR METAB, Jahrgang 107, Nr. 7, 16.06.2022, S. e3048-e3057.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders
AU - Oheim, Ralf
AU - Tsourdi, Elena
AU - Seefried, Lothar
AU - Beller, Gisela
AU - Schubach, Max
AU - Vettorazzi, Eik
AU - Stürznickel, Julian
AU - Rolvien, Tim
AU - Ehmke, Nadja
AU - Delsmann, Alena
AU - Genest, Franca
AU - Krüger, Ulrike
AU - Zemojtel, Tomasz
AU - Barvencik, Florian
AU - Schinke, Thorsten
AU - Jakob, Franz
AU - Hofbauer, Lorenz C
AU - Mundlos, Stefan
AU - Kornak, Uwe
PY - 2022/6/16
Y1 - 2022/6/16
N2 - CONTEXT: Many different inherited and acquired conditions can result in premature bone fragility/low bone mass disorders (LBMDs).OBJECTIVE: We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs 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 LBMDs, all participants were genotyped by targeted next-generation sequencing.RESULTS: In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 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 body mass index (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 (eg, 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.
AB - CONTEXT: Many different inherited and acquired conditions can result in premature bone fragility/low bone mass disorders (LBMDs).OBJECTIVE: We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs 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 LBMDs, all participants were genotyped by targeted next-generation sequencing.RESULTS: In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 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 body mass index (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 (eg, 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.
U2 - 10.1210/clinem/dgac147
DO - 10.1210/clinem/dgac147
M3 - SCORING: Journal article
C2 - 35276006
VL - 107
SP - e3048-e3057
JO - J CLIN ENDOCR METAB
JF - J CLIN ENDOCR METAB
SN - 0021-972X
IS - 7
ER -