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DNA Variants and Mutations


Quasar S. Padiath

, MBBS, PhD, University of Pittsburgh

Reviewed/Revised Jun 2023

Certain situations represent aberrant inheritance, often because genes or chromosomes are altered. However, some of these alterations, such as mosaicism, are very common; others, such as polymorphisms, are so common that they may be considered normal variants.

Mutations and polymorphisms

Variations in DNA can occur spontaneously or in response to cellular insults (eg, radiation, mutagenic drugs, viruses). Some variations are repaired by the cell’s DNA error correction mechanisms. Other variations are not and can be passed on to subsequently replicated cells; in such cases, the variation is termed a mutation. However, offspring can inherit the mutation only if germ cells are affected. Mutations may be unique to an individual or family. Most mutations are rare.

Polymorphisms begin as mutations. They are variations in DNA that have become common in a population (prevalence of ≥ 1%) through sufficient propagation or other mechanisms. Most polymorphisms are stable and do not noticeably change phenotype. A common example is human blood groups (A, B, AB, and O).

Mutations (including polymorphisms) involve random changes in DNA. Many mutations have little effect on cell function. Some mutations change cell function, often in a detrimental way, and some are lethal to the cell. Examples of detrimental changes in cell function are mutations that cause cancer by creating or activating oncogenes or altering tumor suppressor genes (see Molecular Abnormalities Molecular Abnormalities Many factors are involved in causing and permitting the unregulated proliferation of cells that occurs in cancer. (See also Overview of Cancer.) Generation time is the time required for a cell... read more ). Rarely, a change in cell function confers a survival advantage. These mutations are more likely to be propagated. The mutation causing sickle cell disease confers resistance to malaria. This resistance conferred a survival advantage in areas where malaria was endemic and often fatal. However, by causing symptoms and complications of sickle cell disease, the mutation also has harmful effects usually when present in the homozygous state.

When and in what cell type mutations occur can explain certain abnormalities in inheritance patterns. Typically, an autosomal dominant disorder is expected to be present in one or both parents of an affected person. However, some disorders with autosomal dominant inheritance can appear de novo (in people whose parents have a normal phenotype). For example, about 80% of people with achondroplastic dwarfism Osteochondrodysplasias (Osteochondrodysplastic Dwarfism) Osteochondrodysplasias involve abnormal bone or cartilage growth, leading to skeletal maldevelopment, often short-limbed dwarfism. Diagnosis is by physical examination, x-rays, and, in some... read more have no family history of dwarfism and thus represent new (de novo) mutations. In many of these people, the mechanism is a spontaneous mutation occurring early in their embryonic life. Thus, other offspring have no increased risk of the disorder. However, in some of them, the disorder develops because of a germ cell mutation in their parents (eg, an autosomal dominant gene in a phenotypically normal parent). If so, other offspring have an increased risk of inheriting the mutation.


Mosaicism occurs when

  • A person starting from a single fertilized egg develops 2 cell lines differing in genotype

Mosaicism is a normal consequence of X inactivation Chromosomal inactivation Many factors can affect gene expression (and thus phenotypes). Some cause the expression of traits to deviate from the patterns predicted by Mendelian inheritance. (See also Overview of Genetics... read more in females; in most females, some cells have an inactive maternal X, and other cells have an inactive paternal X. Mosaicism can also result from mutations. Mutations are likely to occur during cell division in any large multicellular organism; each time a cell divides, 4 or 5 changes are estimated to occur in the DNA. Because these changes can be passed on to subsequently produced cells, large multicellular organisms have subclones of cells that have slightly different genotypes.

Mosaicism may be recognized as the cause of disorders in which patchy changes occur. For example, McCune-Albright syndrome is associated with patchy dysplastic changes in the bone, endocrine gland abnormalities, patchy pigmentary changes, and occasionally heart or liver abnormalities. Occurrence of the McCune-Albright mutation in all cells would cause early death; however, people with mosaicism survive because normal tissue supports the abnormal tissue. Occasionally, a parent with a single-gene disorder Single-Gene Defects Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more seems to have a mild form but actually represents a mosaic; the parent’s offspring is more severely affected if they receive a germ cell with the mutant allele and thus have the abnormality in every cell.

Chromosomal abnormalities Overview of Chromosomal Abnormalities Chromosomal abnormalities cause various disorders. Abnormalities that affect autosomes (the 22 paired chromosomes that are alike in males and females) are more common than those that affect... read more are most often fatal to the fetus. However, chromosomal mosaicism occurs in some embryos, resulting in some chromosomally normal cells, which can allow offspring to be born alive. Chromosomal mosaicism can be detected with prenatal genetic testing, particularly chorionic villus sampling.

Extra or missing chromosomes

Abnormal numbers of autosomes (chromosomes that are not sex chromosomes) usually result in severe abnormalities. For example, extra autosomes typically cause abnormalities such as Down syndrome Down Syndrome (Trisomy 21) Down syndrome is an abnormality of chromosome 21 that can cause intellectual disability, microcephaly, short stature, and characteristic facies. Diagnosis is suggested by physical anomalies... read more Down Syndrome (Trisomy 21) and other severe syndromes or can be fatal to the fetus. Absence of an autosome is generally fatal to the fetus. Chromosomal abnormalities Diagnosis Chromosomal abnormalities cause various disorders. Abnormalities that affect autosomes (the 22 paired chromosomes that are alike in males and females) are more common than those that affect... read more can usually be diagnosed before birth.

Because of X chromosome inactivation, having an abnormal number of X chromosomes is usually much less detrimental than having an abnormal number of autosomes. For example, the abnormalities resulting from the absence of one X chromosome are usually relatively minor (eg, in Turner syndrome Turner Syndrome In Turner syndrome, girls are born with one of their two X chromosomes partly or completely missing. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis. Treatment... read more Turner Syndrome ). Also, females with 3 X chromosomes (trisomy X Other X Chromosome Abnormalities Approximately 1/1000 apparently normal females has a 47,XXX (trisomy X) karyotype ( 1). Advanced maternal age increases risk of trisomy X, and the extra X chromosome is usually maternally derived... read more ) are often physically and mentally normal; only one X chromosome of genetic material is fully active even if a female has > 2 X chromosomes (the extra X chromosomes are also partly inactivated).

Uniparental disomy

Uniparental disomy occurs when

  • Both chromosomes have been inherited from only one parent

It is very rare and is thought to involve trisomy rescue; ie, the zygote started off as a trisomy (having 3 instead of 2 of a particular chromosome) and one of the 3 was lost, a process that leads to uniparental disomy when the 2 chromosomes that remain are from the same parent (in about one third of cases).

Uniparental disomy may cause abnormal phenotypes and inheritance patterns. For example, if duplicates of the same chromosome (isodisomy) are present and carry an abnormal allele for an autosomal recessive disorder, affected people can have an autosomal recessive disorder even though only one parent is a carrier. Uniparental disomy can result in an imprinting disorder when the disomic chromosome results in the loss of appropriate expression of a critically imprinted region (eg, Prader-Willi syndrome Secondary hypogonadism may result from maternal isodisomy of chromosome 15).

Chromosomal translocation

Chromosomal translocation is

  • Exchange of chromosomal parts between nonpaired (nonhomologous) chromosomes

If chromosomes exchange equal parts of genetic material, the translocation is described as balanced. Unbalanced translocations result in loss of chromosomal material, usually the short arms of 2 fused chromosomes, leaving only 45 chromosomes remaining.

Triplet repeat disorders (trinucleotide repeat disorders)

A triplet repeat disorder results when

  • A triplet of nucleotides is repeated an abnormal number of times within a gene (sometimes up to several hundred times)


Anticipation occurs when a disorder has an earlier age of onset and is expressed more severely in each successive generation. Anticipation may occur when a parent is a mosaic and the child has the full mutation in all cells. It may also occur in triplet repeat disorders when the number of repeats and thus the severity of gene dysfunction increase with each generation.

Key Points

  • An apparently autosomal dominant mutation can arise spontaneously and thus may not indicate increased risk in siblings.

  • Patchy changes in disorders may reflect mosaicism.

  • Chromosomal translocations may have no phenotypic effects or may result in leukemias, Down syndrome, spontaneous abortions, or chromosomal abnormalities in offspring.

  • Inherited disorders may become more severe and begin earlier in life with successive generations, sometimes because of triplet repeat disorders.

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