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)
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
