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Genomic Informatics in the Healthcare System
Published in Salvatore Volpe, Health Informatics, 2022
Another possible explanation for the phenotypic heterogeneity among cases is epigenetic differences. Epigenetic processes such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs can alter the activity of a gene without changing the DNA sequence. To further understand and identify the detail of the heterogeneity, a strategy such as the chromatin immunoprecipitation sequencing (ChIP-Seq) or RNA-Seq can be used. Exploring factors that can account for the phenotypic variability may provide insight into the pathways involved in disease. Furthermore, the comprehensive genetic evaluation and investigation of various individuals with these conditions will likely enlighten the fields of genomic locus heterogeneity and allelic heterogeneity of the genes with a broad spectrum of detected variants.
Respiratory disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Pulmonary surfactant metabolism dysfunction, which causes the pathologic appearance of pulmonary alveolar proteinosis, is a rare autosomal recessive disorder affecting the ability of the lungs to expand after birth. There is locus heterogeneity.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Peroxisomal functions include the beta-oxidation of VLCFAs, pristanic acid and bile acid synthesis and others. PBDs are caused by a failure of protein (enzyme) import into the peroxisome, encoded by various PEX genes. A variety of gene defects can result in the same phenotype (locus heterogeneity) and yet the various phenotypes can also be allelic. In addition there are single enzyme peroxisomal disorders that can give rise to an infantile Refsum-like phenotype. All the conditions are inherited in an autosomal recessive manner.
An evaluation of setmelanotide injection for chronic weight management in adult and pediatric patients with obesity due to Bardet–Biedl syndrome
Published in Expert Opinion on Pharmacotherapy, 2023
Julia Lazareva, Sheila M. Brady, Jack A. Yanovski
Bardet–Biedl Syndrome (BBS) is a rare, multisystemic, polygenic disorder, whose cardinal clinical features include obesity, retinal degeneration, renal anomalies, polydactyly, genital anomalies, and learning difficulties [1,2], although there is high phenotypic heterogeneity [3,4]. BBS is classified as a rare autosomal recessive (though perhaps potentially oligogenic [5]) ciliopathy, having a prevalence from 1:125,000 to 160,000 in North America and Europe [6], though it may occur in 1:13,500–18,000 in isolated communities with higher rates of consanguinity [7,8]. BBS may be caused by genetic variants in a growing list of genes encoding for BBSome proteins involved in primary cilia formation and function [9,10] (Table 1). Current diagnostic criteria for BBS are the presence of either four cardinal features, or the presence of three cardinal features and at least two secondary features [11]: speech delay, strabismus, brachydactyly/syndactyly, developmental delay, ataxia/poor coordination, diabetes mellitus, dental anomalies, congenital heart disease, and anosmia/hyposmia [11] (Table 2). Due to the broad genetic locus heterogeneity of the disease, the most effective diagnostic technique is high-throughput sequencing [12]. However, not all people clinically diagnosed with BBS are found to have a clear causative gene variants.
Beyond the Usual Suspects: Expanding on Mutations and Detection for Familial Hypercholesterolemia
Published in Expert Review of Molecular Diagnostics, 2021
Shirin Ibrahim, Joep C. Defesche, John J.P. Kastelein
The availability of genetic testing for FH is rapidly expanding. For molecular diagnostic methods to be effective, they must have the ability to detect molecular and gene locus heterogeneity, to reveal a wide range of mutation types, including single nucleotide variants and both small and large-scale indels, and pay tribute to the polygenic component of FH. Advances in molecular diagnostics, for example the rapid rise of NGS, have made sequencing possible at much lower costs. This will increase the use of genetic testing. In addition, the need for genetic analysis in FH will increase, both for diagnosis and reimbursement of new therapies. Thus, cost-effective, whole-genome sequencing might soon become the clinical standard for FH diagnosis. However, this does require efforts to improve health professional and public understanding of genetic science and genomics. In addition, as the availability of genetic testing for FH expands, standardization of variant curation and maintenance of clinical databases and registries also need more support. Well-maintained and curated FH registries will help improve national standards for diagnosis and treatment.
Genetic variants associated with Hermansky-Pudlak syndrome
Published in Platelets, 2020
Melissa A. Merideth, Wendy J. Introne, Jennifer A. Wang, Kevin J. O’Brien, Marjan Huizing, Bernadette R. Gochuico
HPS displays locus heterogeneity; to date, 10 genes associated with HPS are identified (Table I). Each HPS-associated gene encodes a protein subunit of either Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, BLOC-2, BLOC-3, or the Adaptor Protein-3 (AP-3) complex [3]. These multi-subunit complexes are involved in the formation of LROs, such as delta granules in platelets and melanosomes in melanocytes [3,4]. All HPS types manifest with a bleeding diathesis and oculocutaneous albinism. Individuals with BLOC-1 (HPS types 7, 8, or 9) or BLOC-2 (HPS types 3, 5, or 6) related HPS generally exhibit mild clinical symptoms, including mild hypopigmentation. Individuals with BLOC-3 (HPS types 1 or 4) or AP-3 (HPS types 2 or 10) related HPS have more pronounced pigment defects of the skin, hair, and eyes and often have severe ancillary symptoms including progressive pulmonary fibrosis, inflammatory bowel disease, or neutropenia [2,3].