Autosomal recessive Emery–Dreifuss muscular dystrophy caused by a novel mutation (R225Q) in the lamin A/C gene identified by exome sequencing

Jiménez‐Escrig, Adriano; Gobernado, Isabel; García-Villanueva, Mercedes; Sánchez-Herranz, Antonio

doi:10.1002/mus.22324

Cited by 37 publications

(23 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have provided evidence for the high diagnostic yield of exome sequencing [44-46]. Using ES as a screening test can increase the diagnostic yield of a clinical evaluation in a cost-effective fashion and decrease the time to diagnosis [2-4,47,48]. If used properly, PhenoVar can help address many of the challenges associated with integrating genomic technologies into clinical practice (see “Challenges of integrating ES in clinic” subsection).…”

Section: Discussionmentioning

confidence: 99%

PhenoVar: a phenotype-driven approach in clinical genomics for the diagnosis of polymalformative syndromes

et al. 2014

View full text Add to dashboard Cite

BackgroundWe propose a phenotype-driven analysis of encrypted exome data to facilitate the widespread implementation of exome sequencing as a clinical genetic screening test.Twenty test-patients with varied syndromes were selected from the literature. For each patient, the mutation, phenotypic data, and genetic diagnosis were available. Next, control exome-files, each modified to include one of these twenty mutations, were assigned to the corresponding test-patients. These data were used by a geneticist blinded to the diagnoses to test the efficiency of our software, PhenoVar. The score assigned by PhenoVar to any genetic diagnosis listed in OMIM (Online Mendelian Inheritance in Man) took into consideration both the patient’s phenotype and all variations present in the corresponding exome. The physician did not have access to the individual mutations. PhenoVar filtered the search using a cut-off phenotypic match threshold to prevent undesired discovery of incidental findings and ranked the OMIM entries according to diagnostic score.ResultsWhen assigning the same weight to all variants in the exome, PhenoVar predicted the correct diagnosis in 10/20 patients, while in 15/20 the correct diagnosis was among the 4 highest ranked diagnoses. When assigning a higher weight to variants known, or bioinformatically predicted, to cause disease, PhenoVar’s yield increased to 14/20 (18/20 in top 4). No incidental findings were identified using our cut-off phenotypic threshold.ConclusionThe phenotype-driven approach described could render widespread use of ES more practical, ethical and clinically useful. The implications about novel disease identification, advancement of complex diseases and personalized medicine are discussed.

show abstract

Section: Discussionmentioning

confidence: 99%

PhenoVar: a phenotype-driven approach in clinical genomics for the diagnosis of polymalformative syndromes

et al. 2014

View full text Add to dashboard Cite

show abstract

“…There are two major types of Emery Dreifuss muscular dystrophy (EDMD): X-linked (X-EDMD or EDMD1) and autosomal EDMD (AD-EDMD or EDMD2), which can occur in a dominant or very rare recessive form (128, 247). EDMD is characterized by progressive skeletal muscle wasting, contractures of major tendons and cardiac conduction defects (65).…”

Section: Nuclear Envelopathiesmentioning

confidence: 99%

Diseases of the Nucleoskeleton

Holaska

2016

Comprehensive Physiology

View full text Add to dashboard Cite

The nucleus is separated from the cytosol by the nuclear envelope, which is a double lipid bilayer composed of the outer nuclear membrane and the inner nuclear membrane. The intermediate filament proteins lamin A, lamin B, and lamin C form a network underlying the inner nuclear membrane. This proteinaceous network provides the nucleus with its strength, rigidity, and elasticity. Positioned within the inner nuclear membrane are more than 150 inner nuclear membrane proteins, many of which interact directly with lamins and require lamins for their inner nuclear membrane localization. Inner nuclear membrane proteins and the nuclear lamins define the nuclear lamina. These inner nuclear membrane proteins have tissue-specific expression and diverse functions including regulating cytoskeletal organization, nuclear architecture, cell cycle dynamics, and genomic organization. Loss or mutations in lamins and inner nuclear membrane proteins cause a wide spectrum of diseases. Here, I will review the functions of the well-studied nuclear lamina proteins and the diseases associated with loss or mutations in these proteins. © 2016 American Physiological Society.

show abstract

“…With this approach, anonymized exome sequencing data from a great number of consenting individuals will likely be available and help us advance our knowledge of clinical application of genomic technologies. At a clinical level, on top of enabling earlier diagnosis [39], I-MPOS will aid in the refinement of the phenotype of known syndromes. For example, in conventional approaches only patients who fit very closely all or almost all characteristics of a described genetic syndrome are tested for the genes involved.…”

Section: Discussionmentioning

confidence: 99%

Patient-controlled encrypted genomic data: an approach to advance clinical genomics

Trakadis

2012

BMC Med Genomics

View full text Add to dashboard Cite

BackgroundThe revolution in DNA sequencing technologies over the past decade has made it feasible to sequence an individual’s whole genome at a relatively low cost. The potential value of the information generated by genomic technologies for medicine and society is enormous. However, in order for exome sequencing, and eventually whole genome sequencing, to be implemented clinically, a number of major challenges need to be overcome. For instance, obtaining meaningful informed-consent, managing incidental findings and the great volume of data generated (including multiple findings with uncertain clinical significance), re-interpreting the genomic data and providing additional counselling to patients as genetic knowledge evolves are issues that need to be addressed. It appears that medical genetics is shifting from the present “phenotype-first” medical model to a “data-first” model which leads to multiple complexities.DiscussionThis manuscript discusses the different challenges associated with integrating genomic technologies into clinical practice and describes a “phenotype-first” approach, namely, “Individualized Mutation-weighed Phenotype Search”, and its benefits. The proposed approach allows for a more efficient prioritization of the genes to be tested in a clinical lab based on both the patient’s phenotype and his/her entire genomic data. It simplifies “informed-consent” for clinical use of genomic technologies and helps to protect the patient’s autonomy and privacy. Overall, this approach could potentially render widespread use of genomic technologies, in the immediate future, practical, ethical and clinically useful.SummaryThe “Individualized Mutation-weighed Phenotype Search” approach allows for an incremental integration of genomic technologies into clinical practice. It ensures that we do not over-medicalize genomic data but, rather, continue our current medical model which is based on serving the patient’s concerns. Service should not be solely driven by technology but rather by the medical needs and the extent to which a technology can be safely and effectively utilized.

show abstract

Autosomal recessive Emery–Dreifuss muscular dystrophy caused by a novel mutation (R225Q) in the lamin A/C gene identified by exome sequencing

Abstract: This technique will be preferred for studying patients with muscular dystrophy in the coming years.

Cited by 37 publications

References 24 publications

PhenoVar: a phenotype-driven approach in clinical genomics for the diagnosis of polymalformative syndromes

PhenoVar: a phenotype-driven approach in clinical genomics for the diagnosis of polymalformative syndromes

Diseases of the Nucleoskeleton

Patient-controlled encrypted genomic data: an approach to advance clinical genomics

Contact Info

Product

Resources

About