Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?

Hundreds of variants in autosomal genes associated with the limb girdle muscular dystrophies (LGMDs) have been reported as being causative. However, in most cases the proof of pathogenicity derives from their non-occurrence in hundreds of healthy controls and/or from segregation studies in small fam...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2016-01, Vol.24 (1), p.73-77
Main Authors: Di Fruscio, Giuseppina, Garofalo, Arcomaria, Mutarelli, Margherita, Savarese, Marco, Nigro, Vincenzo
Format: Article
Language:English
Subjects:
Age of Onset
Alleles
Congenital diseases
Cytoskeletal Proteins - genetics
Databases, Genetic
Dystrophin-Associated Proteins - genetics
Dystrophy
Exome
Female
Gene Frequency
Genes
Genes, Dominant
Genes, Recessive
Genetic diversity
Genetic variance
Genetic Variation
Genetics
Genomics
Heredity
Humans
Male
Muscular Dystrophies, Limb-Girdle - diagnosis
Muscular Dystrophies, Limb-Girdle - genetics
Muscular Dystrophies, Limb-Girdle - pathology
Muscular dystrophy
Mutation
Nerve Tissue Proteins - genetics
Nuclear Matrix-Associated Proteins - genetics
Pathogenicity
Penetrance
Point mutation
Population
Proteins
Variation
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Summary:Hundreds of variants in autosomal genes associated with the limb girdle muscular dystrophies (LGMDs) have been reported as being causative. However, in most cases the proof of pathogenicity derives from their non-occurrence in hundreds of healthy controls and/or from segregation studies in small families. The limited statistics of the genetic variations in the general population may hamper a correct interpretation of the effect of variants on the protein. To clarify the meaning of low-frequency variants in LGMD genes, we have selected all variants described as causative in the Leiden Open Variation Database and the Human Gene Mutation Database. We have systematically searched for their frequency in the NHLBI GO Exome Sequencing Project (ESP) and in our internal database. Surprisingly, the ESP contains about 4% of the variants previously associated with a dominant inheritance and about 9% of those associated with a recessive inheritance. The putative disease alleles are much more frequent than those estimated considering the disease prevalence. In conclusion, we hypothesize that a number of disease-associated variants are non-pathogenic and that other variations are not fully penetrant, even if they affect the protein function, suggesting a more complex genetic mechanisms for such heterogeneous disorders.
ISSN:1018-4813
1476-5438
DOI:10.1038/ejhg.2015.76