JCEM: Genetic Diagnostics in Routine Orthopaedic Evaluation of Low Bone Mass Disorders in Adults

Background: Genetic testing is increasingly integrated into diagnostic efforts across all medical disciplines due to the availability of effective next-generation sequencing-based genetic screening methods
.

This analysis method can further classify the disease, identify rare monogenic diseases, and personalize treatment

Background: Genetic testing is increasingly integrated into diagnostic efforts across all medical disciplines due to the availability of effective next-generation sequencing-based genetic screening methods

In routine clinical diagnosis, rare low bone mass disease (LBMD) in adults is primarily diagnosed by DXA and is often subsumed under the umbrella term osteoporosis, although in principle this term refers to low bone mass and microarchitectural impairment

Severe rare monogenic LBMD with congenital or infancy onset and common age-related (postmenopausal or geriatric) osteoporosis with multifactorial pathogenesis can be viewed as consecutive clinical phenotypes with many overlapping genetic and pathogenic mechanisms

Genome-wide association studies (GWAS) have identified more than 500 genetic loci containing common genetic variants affecting bone mineral density (BMD), a major risk factor for age-related osteoporosis and lifetime fracture risk

Objectives: We aimed to elucidate the impact of genetic testing on the differential diagnosis of LBMD in adults and to identify clinical criteria for predicting monogenic forms

Methods: Four clinical centers extensively recruited 394 unrelated premenopausal adult women and bone mineral density (BMD) Z-scores younger than 55 years

RESULTS: A total of 20.
8% of participants had rare disease-causing genetic variants (DCV) that cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5) , PLS3 and WNT1)
.

Furthermore, we found rare DCVs in ENPP1, LMNA, NOTCH2 and ZNF469

RESULTS: A total of 20.

Table 1 Frequency of pathogenic variants in clinically defined subgroups

 

Figure 1 Statistical analysis of clinical thresholds for predicting monogenic forms of low bone mass disease (LBMD) in adults
.

Starting with the entire cohort of n=394, classifications were subjected to regression tree analysis showing clinical thresholds determining the frequency of pathogenic variants (DCVs)

Figure 1 Statistical analysis of clinical thresholds for predicting monogenic forms of low bone mass disease (LBMD) in adults

Figure 2 The role of common BMD-associated and rare deleterious variants in individuals with LBMD without a single gene pathogenic variant
.

(A) BMD predicted by Genetic Risk Score (GRS) relative to healthy controls in LBMD without DCV (LBMD nod cv; 312), LBMD with DCV (LBMD DCV; n=82), 1KG EUR control cohort (1KG EUR; n=503), and individuals with high BMD (high BMD; n=56)

Figure 2 The role of common BMD-associated and rare deleterious variants in individuals with LBMD without a single gene pathogenic variant
.
(A) BMD predicted by Genetic Risk Score (GRS) relative to healthy controls in LBMD without DCV (LBMD nod cv; 312), LBMD with DCV (LBMD DCV; n=82), 1KG EUR control cohort (1KG EUR; n=503), and individuals with high BMD (high BMD; n=56)
.
(B) Receiver operating characteristic (ROC) curves of genetic risk score (GRS) for common variants associated with bone mineral density
.
GRS of LBMD individuals without DCV compared to 1KG EUR (red) and high BMD (blue)
.
AUC = area under the curve
.
An AUC of 0.
5 (dashed line) indicates random assignment
.
Full allocation using GRS will be achieved at an AUC of 1.
0
.
(C) The frequency of SNP rs4988321, one of the strongest BMD-affecting common variants in LRP5, was significantly increased in LBMD noDCV compared to controls (*p<0.
05, **p<0.
01)
.

Conclusions: The overlapping spectrum of monogenic adult LBMD can be easily disentangled by genetic testing, and the proposed clinical criteria can help maximize diagnostic yield
.

Conclusions: The overlapping spectrum of monogenic adult LBMD can be easily disentangled by genetic testing, and the proposed clinical criteria can help maximize diagnostic yield
.

Original source: Oheim R, Tsourdi E, Seefried L, et al.
Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders.
J Clin Endocrinol Metab 2022 Mar 11

Original source: Oheim R, Tsourdi E, Seefried L, et al.
Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders.
J Clin Endocrinol Metab 2022 Mar 11 Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders.
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