Identification of genetic modifiers of monogenic (bone) diseases: New tools available, but with limitations

Hul, Wim Van

doi:10.1002/jbmr.391

Cited by 5 publications

(2 citation statements)

References 10 publications

(15 reference statements)

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“…Proving which variants are actually playing as modifiers of a given condition is not a trivial issue [22]. In the present work, we restricted the analysis to coding, non-synonymous SNV with low frequency in the general population, found in genes related to bone phenotypes; however, this strategy did not identify a genotype common to all the patients, which could support the idea of an involvement in disease modulation.…”

Section: Discussionmentioning

confidence: 92%

Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis

Pangrazio

Puddu

Oppo

et al. 2014

Bone

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Autosomal Recessive Osteopetrosis is a genetic disorder characterized by increased bone density due to lack of resorption by the osteoclasts. Genetic studies have widely unraveled the molecular basis of the most severe forms, while cases of intermediate severity are more difficult to characterize, probably because of a large heterogeneity. Here, we describe the use of exome sequencing in the molecular diagnosis of 2 siblings initially thought to be affected by “intermediate osteopetrosis”, which identified a homozygous mutation in the CTSK gene. Prompted by this finding, we tested by Sanger sequencing 25 additional patients addressed to us for recessive osteopetrosis and found CTSK mutations in 4 of them. In retrospect, their clinical and radiographic features were found to be compatible with, but not typical for, Pycnodysostosis. We sought to identify modifier genes that might have played a role in the clinical manifestation of the disease in these patients, but our results were not informative. In conclusion, we underline the difficulties of differential diagnosis in some patients whose clinical appearance does not fit the classical malignant or benign picture and recommend that CTSK gene be included in the molecular diagnosis of high bone density conditions.

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Section: Discussionmentioning

confidence: 92%

Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis

Pangrazio

Puddu

Oppo

et al. 2014

Bone

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“…Additionally, other WES-prioritized variants, such as CYP1A1, were found mutated in other atypical femoral fracture cases (17,18), opening the possibility of digenic or oligogenic inheritance. It might also reflect the idea that clinical variability, observed in many monogenic diseases, can be explained by variants in modifier genes (19). The discovery of such genetic variants opens an application window into personalized medicine (20).…”

Section: Causality Of Genetic Mutations Associated With Rare Skeletal Diseases Requires Proofmentioning

confidence: 96%

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

Rauner¹,

Foessl

Formosa

et al. 2021

Front. Endocrinol.

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The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits (“endophenotypes”), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.

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Mendelian Disorders of RANKL/OPG/RANK Signaling

Whyte

2013

Genetics of Bone Biology and Skeletal Disease

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Identification of genetic modifiers of monogenic (bone) diseases: New tools available, but with limitations

Cited by 5 publications

References 10 publications

Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis

Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

Mendelian Disorders of RANKL/OPG/RANK Signaling

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