The Genetic Risk of a Couple Aiming to Conceive
Carlos Simón, Carmen Rubio in Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
The protein-coding regions are defined as exons, and code for 21,000 genes in the human genome. This constitutes 1.5% of the genome. At least 5,000 Mendelian disorders are exonic in origin (1) The other 98.5% of the genome contains non-coding DNA, believed to be responsible for gene regulation. Non-coding regions (introns) may separate coding genes or be interspersed among exons of a clinically significant gene. At a single genetic locus, many different nuclear mutations may arise. In compound heterozygosity, two different alleles may show different base mutations, each deleterious. Causative mutant alleles influencing a single phenotype may exist in two different genetic loci (mixed heterozygosity). It follows that both genes are necessary for a normal phenotype.
Molecular Genetic Diagnosis of Human Malignant Hyperthermia
S. Tsuyoshi Ohnishi, Tomoko Ohnishi in Malignant Hyperthermia, 1994
Markers reflect allelic variation at a given locus. Ideally they exhibit a high degree of heteromorphism (many variants) and heterozygosity (each variant proportionally represented) in the general population so that alleles at a specific locus differ between each of a parent’s two chromosomes and are different from those present on the other parent’s chromosome at the same locus. Only by knowing which parent has transmitted the marker is it possible to know whether a specific marker allele and the disease gene are associated on the same chromosome or on opposite members of a homologous pair. In this way the phase of a marker is assigned. In general, markers have multiple alleles thereby increasing the likelihood of identifying the two parental chromosomes at a specific locus and discriminating between the two chromosomes of an affected individual. A marker linked to a disease phenotype in one family may be found in an individual from a second family without implying the presence of the disease. Only by investigation of the family taken as a whole can linkage data be interpreted. In the ideal setting for linkage analysis, expression of the disease is well defined, diagnosis is unequivocal with a standardized test, penetrance is high (everyone with the mutant allele can be diagnosed), there is clear-cut evidence of parent to child transmission, at least three living relatives from three generations are affected, and multiple families bearing close similarity have been identified.
Introductory Remarks
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Chromosomal amplification/repetition refers to the presence of extra piece from another chromosome that leads to multiple copies of all chromosomal regions and increases the dosage of the genes located within. Chromosomal deletion refers to loss of large chromosomal regions including certain genes (with interstitial deletion being defined as an intra-chromosomal deletion that removes a segment of DNA from a single chromosome and thus apposes previously distant genes, and loss of heterozygosity being loss of one allele, either by a deletion or a genetic recombination event, in an organism with two different alleles). Chromosomal translocation refers to interchange of genetic parts from nonhomologous chromosomes, and chromosomal inversion refers to reversion of the orientation of a chromosomal segment [6].
Rucaparib for the treatment of ovarian cancer
Published in Expert Opinion on Orphan Drugs, 2018
Sunu Lazar Cyriac, Katherine Karakasis, Amit M. Oza
LOH is a commonly observed genomic aberration in many cancers and results from inactivation of a tumor suppressor gene. Heterozygosity is a common phenomenon occurring in alleleic pairs of genes because of change in single base pairs in one allele (single nucleotide polymorphisms or SNPs) with usually no significant functional impairment [65]. Additionally, when the DNA repair mechanism is defective it can lead to loss of one parental copy of an already heterozygous gene region leading to LOH. LOH does not imply return to homozygosity. Various mechanisms like nondysjunction, recombination between homologous or nonhomologous genes, deletions or gene conversions can lead to LOH [66]. LOH can occur in different chromosomes and can also be quantified. LOH might manifest as a complete loss of chromosomes or some might affect only part of the chromosomes. LOH has got a high degree of specificity with different cancers and is a helpful aid for diagnosis, prognosis, and predicting treatment responses.
Congenital thrombocytopenia associated with a heterozygous variant in the MEIS1 gene encoding a transcription factor essential for megakaryopoiesis
Published in Platelets, 2022
Orna Steinberg-Shemer, Naama Orenstein, Tanya Krasnov, Sharon Noy-Lotan, Nathaly Marcoux, Orly Dgany, Joanne Yacobovich, Oded Gilad, Evelyn Shabad, Lina Basel-Salmon, Hannah Tamary
Exome sequencing did not reveal a potentially pathogenic variant in any of the genes known to cause thrombocytopenia (Supplementary Tables 1,2); however, it revealed a de novo heterozygous splice site variant NM_002398.3:exon4:c.432 + 5 G > C in the MEIS1 gene. Exome sequencing was also performed on both parents, excluded the possibility of non-maternity or non-paternity, and neither parent was shown to carry this variant. The variant is located in a highly conserved site and has a deleterious prediction (dbscSNV Ada, RF). If MEIS1 had already been known to be associated with an abnormal phenotype in humans, the variant could be classified as “likely pathogenic” using the PS2, PM2 and PP3 criteria. However, as this gene has not been previously reported to be associated with a human phenotype, it can only be classified as VOUS. The variant was validated by Sanger sequencing (Figure 2a). Sequencing of the wild-type allele and the variant revealed similar variant allele frequencies, suggesting heterozygosity. The variant is absent from databases including gnomAD and a local database of Israeli population, including near 2000 individuals.
Association between HLA-DQB1 polymorphisms and pemphigus vulgaris: A meta-analysis
Published in Immunological Investigations, 2018
Si Li, Qin Zhang, Peng Wang, Jun Li, Jing Ni, Jun Wu, Yan Liang, Rui-Xue Leng, Hai-Feng Pan, Dong-Qing Ye
Two investigators (Si Li and Qin Zhang), respectively, reviewed all abstracts for related studies, read full texts of eligible literatures, extracted data in a standardized way, and assessed the study quality. Disagreements were resolved by discussion and by consulting a third investigator (Peng Wang). The following data were gathered from each study: the first author, year of publication, ethnicity, detection type, diagnostic criteria of PV, and the numbers of cases and controls for each genetic type. The genetic data were categorized as allelic data (allele counts of a locus in the certain diploid species) and phenotype data (number of individuals positive for a given allele, regardless of heterozygosity or homozygosity). We assessed the eligible studies based on Newcastle-Ottawa Scale (NOS) systems. This scale contains nine items (one point for each) in three parts: selection (four items), comparability (two items) and exposure (three items). Quality score ranges from 0 to 9. Scores ranging from 0 to 6 denote low quality; whereas, scores ranging from 7 to 9 demonstrate high quality.
Related Knowledge Centers
- Allele
- Eukaryote
- Homologous Chromosome
- Ploidy
- Genotype
- Zygote
- Chromosome
- Gene
- Locus
- Genetic Disorder