China
Africa
Explore chapters and articles related to this topic
Clinical Cancer Genetics
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Rosalind A. Eeles, Lisa J. Walker
Familial clustering of the same type of cancer may be due to more than one type of cancer pre-disposition gene. This is termed genetic heterogeneity. For example, familial breast cancer, in which there are clusters of >4 cases of breast cancer at <60 years of age in the same lineage, may be due to mutations in either breast cancer gene 1 or 2 (BRCA1 and BRCA2) or a panel of other breast cancer pre-disposition genes, many of which are in the DNA repair pathway. Not all such clusters can be explained by mutations in such gene panels, and we think that other breast cancer pre-disposition genes remain to be discovered.
Analyzing Complex Polygenic Traits
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Bernard R. Lauwerys, Edward K. Wakeland
Finally, both disease and genetic heterogeneity are other confounding factors that often affect the results of linkage studies. Disease heterogeneity is best illustrated in SLE in which patients may present with several combinations of symptoms (rash, arthritis, glomerulonephritis, central nervous system disease, etc) and serological findings (antibodies against dsDNA, Ro, La, etc) that usually cluster in mild versus severe forms of the disease. While both forms of SLE may represent the ends of the same disease spectrum, it is also possible that they constitute distinct disease etiologies sharing several common genetic susceptibility factors but are differentiated by specific disease-associated alleles. Dissection of the original disease into intermediate phenotypes that are used in linkage studies could overcome this problem. Similarly, healthy members of SLE multiplex families are known to be more frequently positive for the presence of antinuclear antibodies than controls. While a linkage study based on the presence or absence of disease would weaken the probability of finding genes associated with antinuclear antibody production, the use of more specific component phenotypes may enhance the power of the analysis. Finally, genetic heterogeneity indicates that multiple combinations of genes within the genome may result in identical disease phenotypes, a common feature of many genetic systems that can clearly affect the power of linkage analysis in outbred populations.
Discovery and research
Published in Peter S. Harper, The Evolution of Medical Genetics, 2019
The BRCA2 discovery points to a series of general lessons that link classical human molecular genetics with the new genomics and show how important it is that the two are not artificially separated and that workers in genomics have a firm grounding in basic genetics. First is the importance of recognising genetic heterogeneity if molecular analysis is to be accurately and effectively applied in diagnosis and prediction. An incidental result of the BRCA2 work was largely to nullify the American attempts to restrict and control patenting (see Chapter 7) which were based solely on the BRCA1 discovery. A second point of general importance is the value of accurate clinical, pathological and family studies recorded in the literature as the starting point for new molecular and genomic studies, especially if archival tissue or blood samples are available, for patients who may be long deceased. A final point, already emphasised throughout this book, is the value of clinical and laboratory researchers working closely together; this applies not only to clinical geneticists but, especially in the cancer research field, to the numerous other specialties involved.
Ocular Manifestations of Neuronal Ceroid Lipofuscinoses
Published in Seminars in Ophthalmology, 2021
Rohan Bir Singh, Prakash Gupta, Akash Kartik, Naba Farooqui, Sachi Singhal, Sukhman Shergill, Kanwar Partap Singh, Aniruddha Agarwal
Massive neuronal loss and accumulation of intracellular acidic sphingomyelinase are the predominant features in all patients. Moreover, genetic heterogeneity adds to this challenge. Urine sediment dolichol levels are elevated in both types – it’s a nonspecific but helpful finding. Neuroradiological findings in CLN-4 disease: include parieto-occipital cortical atrophy, cerebellar atrophy, hyperintense periventricular areas; and periventricular thinning and enlargement.98–100A cortical layer-specific loss of neurons has been described in layers 2 and 3 for CLN-4 disease, and EEG in the patients reveals a slow background, polyphasic spikes, and slow-wave changes.7,100,101 These changes can most reliably be confirmed by invasive brain biopsy.96 The diagnosis remains neuropathological, and despite the rarity of disease and absence of noninvasive diagnostic techniques, several criteria and guidelines are being developed by experts.89
Inherited retinal degeneration current genetics practices – a needs assessment
Published in Ophthalmic Genetics, 2020
Sydney Strait, Rebecca Loman, Lindsay Erickson, Meghan DeBenedictis
Inherited retinal degenerations (IRDs) affect approximately 1 in 3500 individuals in Europe and North America (1). IRDs are phenotypically and genetically heterogenous conditions that result in vision loss due to gradual loss of photoreceptor cell function (2). Genetic heterogeneity refers to a single phenotype caused by multiple different single genes. This can make genetic testing and clinical diagnosis for IRDs difficult for clinicians, patients, and families. However, proper diagnosis of patients with an IRD is important to understand the natural history and inheritance of the condition, and to provide information about clinical trials and possible treatment options. Furthermore, it is important to have a precise molecular diagnosis as some IRDs are due to a syndromic condition where the patient may have systemic health risks. To establish a clinical diagnosis, the American Academy of Ophthalmology (AAO) recommends clinical assessment of patients with IRDs to include thorough documentation of medical, ocular, and family history (2). Advances in genetic testing have allowed for a molecular diagnosis to be identified in over 50% of patients (3). Due to the heterogenous nature of this group of diseases with over 330 disease-causing genes identified to date, the AAO discusses the role of genetic testing as an appropriate measure to help aid in the diagnosis, prognosis, and management for this patient population (2,4,5). This begs the question: What genetics related practices are ophthalmologists and optometrists currently utilizing for patients with IRDs, and what resources could enhance current practices?
Exome sequencing identification of susceptibility genes in Chinese patients with keratoconus
Published in Ophthalmic Genetics, 2020
Liyan Xu, Kaili Yang, Qi Fan, Yuwei Gu, Bo Zhang, Chenjiu Pang, Shengwei Ren
With conspicuous genetic heterogeneity, the aetiology of KC has remained elusive. Although previous studies have identified multiple variants associated with KC (11–14,17,18), few studies concentrated on the association between rare variants and KC. ES, as a highly effective approach in discovering genes underlying multifactorial diseases, has been widely used to identify genetic factors for various complex disorders (16,25,26). In the present study, we applied ES to identify possible genetic variants in Chinese subjects with KC. With strict quality control and a series of filtering criteria, 6 SNVs (c.1168 T > C in TRANK1, c.341A>T in ERMP1, c.4346 T > C in SDK2, c.1730A>C in COL6A1, c.1138 C > T in CNBD1, c.241 C > T in KRT82) and 2 InDels (c.193_195del in NSUN5, c.1690_1698del in COL9A3) were considered as candidate variants for KC. After validated those variants by Sanger sequencing, we found the sequencing results were consistent with ES, confirming the accuracy of ES data. In addition, the candidate variants were also verified in another 100 KC individuals. We found that only c.341A>T in ERMP1 and c.193_195del in NSUN5 were found in one and two samples, respectively. The controversial results might be attributed to complex genetic heterogeneity and different disease severity. Besides, a total of 21 variants located in the amplified sequence fragments were also identified, confirming that those genes might be considered as susceptibility genes for KC.