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Genetics and Genetic Testing in Hypertrophic Cardiomyopathy
Published in Srilakshmi M. Adhyapak, V. Rao Parachuri, Hypertrophic Cardiomyopathy, 2020
The report generated by the testing laboratory will classify the variant identified based on their assessment of the probability that it is the cause of HCM in a given patient. This reporting framework is based on guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology. There are various tools in the public domain, such as Gnomad [20], Clinvar [21], Exac [20], and ClinGen [22], which can aid the interpretation process of the variants identified by genetic testing. The genetic testing laboratory classifies variants as follows.Benign variant;Likely benign variant;Variant of uncertain significance (VUS);Likely pathogenic variant;Pathogenic variant.
Genomic medicine in 2025–2030
Published in Ulrik Kihlbom, Mats G. Hansson, Silke Schicktanz, Ethical, Social and Psychological Impacts of Genomic Risk Communication, 2020
Martina C. Cornel, GertJan van Ommen
Different countries and different organizations might find different solutions to help citizens to keep their own data. As a general principle, individuals have a legal right to access their personal data held by governmental bodies and commercial entities and patients have a right to access their health record (Thorogood et al. 2018). With the increasing possibilities of using genomic data in risk prediction, citizens can take more responsibility for their own health by using this data. Health care thus needs to be prepared for the healthy person visiting a physician because he has a genetic variant and asking for subsequent care. Care pathways for people carrying an oncogenetic variant or cardiogenetic variant must be clear. It must also be clear which variants to interpret as relevant versus not significant. The challenges of the interpretation of Variants of Uncertain Significance (VUSs) will transcend into general medicine.
Lynch Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Andreas V. Hadjinicolaou, Mashiko Setshedi
Variations in LS phenotype, even in cases with the same germline mutation, are common. Although heterozygous mutations cause typical LS, the presence of biallelic MMR mutations is associated with constitutional mismatch repair deficiency (CMMRD) syndrome, a more severe form of disease. CMMRD is characterized by a high incidence of hematological malignancies, glioblastoma, urinary tract tumors, and neurofibromatosis typically in the pediatric age group [31,32]. Other phenotypic variations include age of onset, tumor morphology, MMR protein expression profile, and MSI stability not only between family members, but also between metachronous or even synchronous lesions in the same individual [33,34]. The variability in presentation has been ascribed to the effect of environmental factors and possibly the nature of the genes acquiring somatic mutations due to a mutator phenotype; however, this is largely speculative. This variability has led to genome-wide association studies (GWAS) that have in fact identified 20 variants. However, data from patients with mutations gave inconsistent results, failing to verify this variability and suggesting a need for further investigation [35,36]. Some variants do have functional significance, whereas the pathogenic potential of missense variants, collectively termed variants of uncertain significance (VUS) is unknown.
Oncologist-led germline genetic testing for uveal melanoma
Published in Ophthalmic Genetics, 2023
Brittany Gillies, Hatem Krema, Anning Chao, Leonardo Lando, Kirsten M. Farncombe, Marcus Butler, Filiberto Altomare, Raymond H. Kim
For the individuals identified to have variants of uncertain significance (VUS), patients were offered a genetic counselling appointment to review the results. The majority of VUS were identified in the MC1R gene (12/15), which has been recently removed from our genetic testing panels due to limited clinical utility (22). Polymorphisms in the MC1R gene are extremely common with greater than half of the general population carrying one or more variants (53). Many variants demonstrate reduced penetrance and evidence is controversial for association with cutaneous melanoma (35–37,53). Mainstreaming models differ across genetics centres in whether patients with a VUS are seen for genetic counselling or reviewed by e-consult; our process involved contacting these patients as per the preference of the ordering oncologists. This also provided a central point of contact for patients to stay in touch with, regarding variant reclassification updates in keeping with shared responsibility for re-contact (38).
Lack of evidence of association between ZNF408 variant and ROP
Published in Ophthalmic Genetics, 2023
Amit V. Mishra, Johane M. Robitaille
The identification of a missense variant alone is not proof of pathogenicity just because the gene has been associated with a disease of interest. The authors do not provide information to determine whether the variant is disease causing, as they claim, or a variant of uncertain significance (VUS). Segregation of the variant with disease, review of previous cases with a DNA change in the same codon, prevalence of the variant in relevant populations, the significance of the change at the protein level, sequence conservation analyses of the nucleotide and pathogenicity scores, functional analyses are all important considerations in determining the extent to which one may attribute causality or disease association. Failure to do so can have serious consequences. The value of genetic counselling in these situations cannot be overstated. An attempt at a segregation analysis showed that the patient’s older sister had a normal fundus exam and negative genetic testing for the ZNF408 variant. However, fluorescein angiography is important in detecting mild features of FEVR, and genetic testing and examination including angiography of the patient’s parents if abnormal would have added more weight to the final diagnosis of FEVR.
The expanding clinical and genetic spectrum of alsin-related disorders: the first cohort of Brazilian patients
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Alzira Alves De Siqueira Carvalho, Marco Antônio Troccoli Chieia, Igor Braga Farias, Acary Souza Bulle Oliveira, Wladimir Bocca Vieira De Rezende Pinto, Paulo Victor Sgobbi De Souza
In relation to pathogenic variants all were homozygous. Two apparently nonrelated Lebanese families carried the same variants. All underwent whole exome sequencing. Regarding the domain in which the variants were located, three were in the RCC1 domain, one was in MORN and one was in the VPS9 domain; however, all of the variants resulted in truncated proteins (Figure 2). Two cases (5,6) were missense variants. In relation to case 5, a Brazilian individual, the missense mutation identified (Table 2) is novel The Chr2 variant: 201.701.868 G > A (or alternatively c.4957C > T - ENST00000264276), leads to the replacement of the amino acid arginine at codon 1653 by cysteine (p.Arg1653Cys). Arginine at position 1653 is moderately conserved in the various biological species and computer programs for “in silico” prediction of pathogenicity. This variant is present in heterozygosity in only 26 out of 139,000 samples and was not previously recorded in medical literature. Thus, considering the clinical suspicion and the characteristics of the region where the variant is located, although there is a high probability that associated with the patient’s condition, according to the American recommendations College of Medical Genetics (ACMG), it is classified as a variant of uncertain significance (VUS).