Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.22.54 (
calpain 3
)
430
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole-exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and cosegregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, and also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1 and VCP, recessive mutations in ANO5,
CAPN3
,
GAA
, LAMA2, SGCA and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses because of the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.
...
PMID:The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. 2770 73
Objective:
Inherited myopathies comprise more than 200 different individually rare disease-subtypes, but when combined together they have a high prevalence of 1 in 6,000 individuals across the world. Our goal was to determine for the first time the clinical- and gene-variant spectrum of genetic myopathies in a substantial cohort study of the Indian subcontinent.
Methods:
In this cohort study, we performed the first large clinical exome sequencing (ES) study with phenotype correlation on 207 clinically well-characterized inherited myopathy-suspected patients from the Indian subcontinent with diverse ethnicities.
Results:
Clinical-correlation driven definitive molecular diagnosis was established in 49% (101 cases; 95% CI, 42-56%) of patients with the major contributing pathogenicity in either of three genes,
GNE
(28%; GNE-myopathy),
DYSF
(25%; Dysferlinopathy), and
CAPN3
(19%; Calpainopathy). We identified 65 variant alleles comprising 37 unique variants in these three major genes. Seventy-eight percent of the
DYSF
patients were homozygous for the detected pathogenic variant, suggesting the need for carrier-testing for autosomal-recessive disorders like Dysferlinopathy that are common in India. We describe the observed clinical spectrum of myopathies including uncommon and rare subtypes in India: Sarcoglycanopathies (
SGCA/B/D/G
), Collagenopathy (
COL6A1/2/3
), Anoctaminopathy (
ANO5
), telethoninopathy (
TCAP
), Pompe-disease (
GAA
), Myoadenylate-deaminase-deficiency-myopathy (
AMPD1
), myotilinopathy (
MYOT
), laminopathy (
LMNA
), HSP40-proteinopathy (
DNAJB6
), Emery-Dreifuss-muscular-dystrophy (
EMD
), Filaminopathy (
FLNC
), TRIM32-proteinopathy (
TRIM32
), POMT1-proteinopathy (
POMT1
), and Merosin-deficiency-congenital-muscular-dystrophy-type-1 (
LAMA2
). Thirteen patients harbored pathogenic variants in >1 gene and had unusual clinical features suggesting a possible role of synergistic-heterozygosity/digenic-contribution to disease presentation and progression.
Conclusions:
Application of clinically correlated ES to myopathy diagnosis has improved our understanding of the clinical and genetic spectrum of different subtypes and their overlaps in Indian patients. This, in turn, will enhance the global gene-variant-disease databases by including data from developing countries/continents for more efficient clinically driven molecular diagnostics.
...
PMID:Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. 3325 Aug 42
Inherited muscle disorders are caused by pathogenic changes in numerous genes. Herein, we aimed to investigate the etiology of muscle disease in 24 consecutive Greek patients with myopathy suspected to be genetic in origin, based on clinical presentation and laboratory and electrophysiological findings and absence of known acquired causes of myopathy. Of these, 16 patients (8 females, median 24 years-old, range 7 to 67 years-old) were diagnosed by Whole Exome Sequencing as suffering from a specific type of inherited muscle disorder. Specifically, we have identified causative variants in 6 limb-girdle muscular dystrophy genes (6 patients;
ANO5
,
CAPN3
,
DYSF
,
ISPD
,
LAMA2
,
SGCA
), 3 metabolic myopathy genes (4 patients;
CPT2
,
ETFDH
,
GAA
), 1 congenital myotonia gene (1 patient;
CLCN1
), 1 mitochondrial myopathy gene (1 patient;
MT-TE
) and 3 other myopathy-associated genes (4 patients;
CAV3
,
LMNA
,
MYOT
). In 6 additional family members affected by myopathy, we reached genetic diagnosis following identification of a causative variant in an index patient. In our patients, genetic diagnosis ended a lengthy diagnostic process and, in the case of Multiple acyl-CoA dehydrogenase deficiency and Pompe's disease, it enabled specific treatment to be initiated. These results further expand the genotypic and phenotypic spectrum of inherited myopathies.
...
PMID:Genetic cause of heterogeneous inherited myopathies in a cohort of Greek patients. 3330 17
