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

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 -