Article ; Online: Magnitude of Mendelian versus complex inheritance of rare disorders.
American journal of medical genetics. Part A
2021 Volume 185, Issue 11, Page(s) 3287–3293
Abstract: In medical genetics, the vast majority of patients with a currently known genetic basis harbor a rare deleterious allele explaining its Mendelian inheritance. Increasingly, for these phenotypes, we recognize exceptions to Mendelian expectations from non- ... ...
| Abstract | In medical genetics, the vast majority of patients with a currently known genetic basis harbor a rare deleterious allele explaining its Mendelian inheritance. Increasingly, for these phenotypes, we recognize exceptions to Mendelian expectations from non-penetrance of clinical disease to significant inter-individual variation in clinical manifestations, likely reflecting the actions of additional modifier genes. Despite recent progress, we still remain ignorant about the molecular basis for many rare disorders presumed to be Mendelian. The molecular evidence increasingly suggests a role for multiple genes in some of these cases, but for how many? In this article, I discuss why equating a phenotype as Mendelian or complex may be short-sighted or even erroneous. As we learn more about the functions of the human genome with its genes in networks, we should view the phenotype of an individual patient as arising from his or her total genomic deleterious burden in a set of functionally inter-related genes affecting that phenotype. This can sometimes arise from deleterious allele(s) at a single gene (Mendelian inheritance) creating a specific biochemical deficiency (or excess) but could just as frequently arise from the cumulative effects of multiple disease alleles (complex inheritance) leading to the same biochemical deficiency (or excess). |
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| MeSH term(s) | Alleles ; Genetic Diseases, Inborn/genetics ; Genetic Predisposition to Disease ; Genetics, Medical ; Genome, Human/genetics ; Humans ; Multifactorial Inheritance/genetics ; Mutation/genetics ; Rare Diseases/genetics |
| Language | English |
| Publishing date | 2021-08-21 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2108614-X |
| ISSN | 1552-4833 ; 0148-7299 ; 1552-4825 |
| ISSN (online) | 1552-4833 |
| ISSN | 0148-7299 ; 1552-4825 |
| DOI | 10.1002/ajmg.a.62463 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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