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Epidemiology, etiology, and genetic aspects of reduction deficiencies of the lower limb.

ABSTRACT: Although the majority of lower limb deficiencies are of sporadic occurrence and of unknown etiology, genetic factors are involved in a significant number, with variable modes of inheritance. A better-informed public is demanding advice concerning cause and recurrence. Careful scrutiny of the medical history and family tree and attention to phenotypic details may help to delineate entities. At times, specific chromosomal tests are important, mainly when there is bilateral or multiorgan involvement or when limb deficiency is associated with developmental delay and/or mental retardation. This paper is intended to refamiliarize the orthopaedic community with basic genetic aspects regulating reduction deficiencies of the lower limbs, and to emphasize on the importance and indications of genetic counseling.

SUBMITTER: Ghanem I

PROVIDER: S-EPMC2656849 | biostudies-other | 2008 Oct

REPOSITORIES: biostudies-other

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Epidemiology, etiology, and genetic aspects of reduction deficiencies of the lower limb.

Ghanem Ismat I

Journal of children's orthopaedics 20080409 5

Although the majority of lower limb deficiencies are of sporadic occurrence and of unknown etiology, genetic factors are involved in a significant number, with variable modes of inheritance. A better-informed public is demanding advice concerning cause and recurrence. Careful scrutiny of the medical history and family tree and attention to phenotypic details may help to delineate entities. At times, specific chromosomal tests are important, mainly when there is bilateral or multiorgan involvemen ...[more]

PMID: 19308564

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Project description:Heart failure (HF) is a complex clinical syndrome defined by the inability of the heart to pump enough blood to meet the body's metabolic demands. Major causes of HF are cardiomyopathies (diseases of the myocardium associated with mechanical and/or electrical dysfunction), among which the most common form is dilated cardiomyopathy (DCM). DCM is defined by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness, which leads to progressive HF. Over 60 genes are linked to the etiology of DCM. Titin (TTN) is the largest known protein in biology, spanning half the cardiac sarcomere and, as such, is a basic structural and functional unit of striated muscles. It is essential for heart development as well as mechanical and regulatory functions of the sarcomere. Next-generation sequencing (NGS) in clinical DCM cohorts implicated truncating variants in titin (TTNtv) as major disease alleles, accounting for more than 25% of familial DCM cases, but these variants have also been identified in 2-3% of the general population, where these TTNtv blur diagnostic and clinical utility. Taking into account the published TTNtv and their association to DCM, it becomes clear that TTNtv harm the heart with position-dependent occurrence, being more harmful when present in the A-band TTN, presumably with dominant negative/gain-of-function mechanisms. However, these insights are challenged by the depiction of position-independent toxicity of TTNtv acting via haploinsufficient alleles, which are sufficient to induce cardiac pathology upon stress. In the current review, we provide an overview of TTN and discuss studies investigating various TTN mutations. We also present an overview of different mechanisms postulated or experimentally validated in the pathogenicity of TTNtv. DCM-causing genes are also discussed with respect to non-truncating mutations in the etiology of DCM. One way of understanding pathogenic variants is probably to understand the context in which they may or may not affect protein-protein interactions, changes in cell signaling, and substrate specificity. In this regard, we also provide a brief overview of TTN interactions in situ. Quantitative models in the risk assessment of TTNtv are also discussed. In summary, we highlight the importance of gene-environment interactions in the etiology of DCM and further mechanistic studies used to delineate the pathways which could be targeted in the management of DCM.

Dataset Information

Epidemiology, etiology, and genetic aspects of reduction deficiencies of the lower limb.

Publications

Epidemiology, etiology, and genetic aspects of reduction deficiencies of the lower limb.

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