Impact of Genomic Variation
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P57-58
2025-11-30
24
Although it will be self- evident to students of human genetics that new pathogenic or rare variants in the population can have clinical consequences, it may appear less obvious that common variants can be clinically relevant. For the proportion of variation that occurs within protein- coding genes, such loci can be studied by examining variation in the proteins encoded by the different alleles. Any one individual is likely to carry two distinct alleles determining structurally differing polypeptides at an estimated 20% of protein- coding loci; when individuals from different ancestral groups are studied, an even greater fraction of proteins has been found to exhibit detectable polymorphism. In addition, even when the gene product is unaltered, the levels of expression of that product may be very different among individuals, determined by a combination of genetic and epigenetic variation.
Thus a striking degree of biochemical individuality exists within the human species in its makeup of enzymes and other gene products. Furthermore, the products of many of the encoded biochemical and regulatory pathways interact in functional and physio logic networks. Each individual, therefore— regardless of state of health— has a unique, genetically determined chemical makeup and responds in a unique manner to environmental, dietary, and pharmacologic influences. This concept of chemical individuality first put forward over a century ago by Archibald Garrod, the remarkably prescient British physician introduced in Chapter 1, remains true today. The broad question of what is normal— an essential concept in human biology and in clinical medicine— remains very much an open and controversial one when it comes to the human genome.
The following chapters will explore this concept of individuality in detail, first in the context of structural genome and chromosome variants and then in terms of intragenic variants that deter mine the inheritance of genetic disease and influence its likelihood in families and populations.
Assessing the Clinical Significance of a Gene Variant The American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommend that all variants detected during sequencing of genes for monogenic disease (whether from targeted, exome, or genome sequencing) be classified on a five- level scale, spanning pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign variants. Specialists in molecular diagnostics, human genomics, and bioinformatics have developed criteria for assessing where a variant sits among these five categories. None of these criteria are definitive; they must be considered together to provide an overall assessment of the evidence for pathogenicity. These criteria include the following:
• Population frequency— If a variant has been seen frequently in a sizable fraction of the general population, beyond what is expected based on the prevalence of the disease, it is considered less likely to be disease causing. Being frequent, however, is no guarantee that a variant is benign. Autosomal recessive conditions result from homozygosity for disease- causing variants that may be surprisingly common, largely harbored by asymptomatic heterozygous carriers. Conversely, rare variants are not necessarily pathogenic; most variants found in an exome or genome sequence are individually rare.
• In silico assessment— Computational algorithms can evaluate how likely a missense variant is to be dam aging to the protein, by using information such as whether the amino acid at that position is conserved in orthologous proteins (in other species), the structural location of the variant, and machine- learning algorithms. Such tools are limited in their accuracy for predicting functional impact and therefore can never be used alone to definitively determine pathogenicity. They are, however, improving with time, and their contribution to variant assessment may strengthen. Other bioinformatics tools assess the pathogenicity of other types of variants, such as potential splice site variants and other noncoding sequence variants.
• Functional data— If a particular variant adversely affects in vitro biochemical activity, a function in cultured cells, or the health of a model organism, then it is less likely to be benign. However, it remains possible that a particular variant will appear benign by these criteria and still be disease causing in humans because of a prolonged human life span, environmental triggers, or compensatory genes present in the model organism but not in humans. Conversely, functional effects demonstrated in systems that do not fully rep resent the human biologic state may falsely implicate a variant as pathogenic. Caution must be exercised to ensure adequate validation of these assays with variants determined to be pathogenic or benign through other types of evidence.
• Segregation data— If a particular variant is coinherited with a disease in one or more families or, conversely, does not track with a disease in the family under investigation, then it is more or less likely to be pathogenic. Of course, when only a few individuals are affected, the variant and disease may appear to track by random chance; to be considered strong evidence for pathogenicity, the number of times a variant and disease must be coinherited is generally accepted to be in at least five informative meiosis. Finding affected individuals in the family who do not carry the variant would be strong evidence against the variant being pathogenic, but finding unaffected individuals who do carry the variant is less persuasive if the disorder is known to have reduced penetrance.
• De novo variant— The appearance of a severe disorder in a child along with a new variant in a coding exon that neither parent carries (de novo variant) is additional evidence for that variant to be pathogenic. However, between one and two new changes occur in the coding regions of genes in every child. Only de novo variants in genes that are associated with the individual’s phenotype are considered evidence for pathogenicity, given a lower prior probability of de novo mutation for a small, targeted set of genes.
• Variant characterization— A variant may be synonymous, missense, nonsense, a frameshift with a pre mature termination downstream, or cause a highly conserved splice site change. The impact on the function of the gene can be inferred but, once again, is not definitive. For example, a synonymous change that does not alter an amino acid codon might be thought to be benign but may have deleterious effects on normal splicing and be pathogenic. Conversely, one might assume that pre mature termination or frameshift variants are always deleterious and disease causing; however, such an alteration at the far 3′ end of a gene may produce a truncated protein that is still functional and, therefore, be a benign change.
• Prior occurrence— Having been seen multiple times among collections of patients with a similar disorder is important additional evidence that a variant is pathogenic. Even if a missense variant is novel (i.e., never described before) it is more likely to be pathogenic if it occurs at the same position in the protein as other known pathogenic missense variants.
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