Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)

INTRODUCTION — This topic review discusses the inheritance patterns of monogenic traits, including classic Mendelian inheritance patterns as well as non-Mendelian inheritance patterns such as mitochondrial inheritance and sex-linked expression, along with other factors that can modify trait expression.

Complex (multigenic) disorders and an overview of the causes of genetic variation are discussed separately. (See "Principles of complex trait genetics" and "Basic genetics concepts: DNA regulation and gene expression", section on 'Genetic variation'.)

A glossary of genetic terms is also presented separately. (See "Genetics: Glossary of terms".)

GENETIC BASIS OF MONOGENIC INHERITANCE

Mitosis and meiosis — Mitosis is the process of cell division in somatic cells in which deoxyribonucleic acid (DNA) is replicated and equally partitioned to two daughter cells with identical genetic compositions. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Mitosis'.)

In contrast, meiosis is the process of generating germline cells (also called gametes, or egg and sperm). Meiosis generates four haploid cells. Due to chromosome recombination during meiosis, paternal and maternal chromosome pairs cross over and exchange homologous DNA segments, generating new haploid genomes with unique combinations of genetic variants. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Meiosis'.)

Monogenic traits — Monogenic disorders (monogenic traits) are conditions that result from functional variation in a single gene with high phenotypic impact (large genetic effect size).

These traits are typically recognized by their striking inheritance patterns corresponding to the co-segregation of the disease gene and unique phenotypes within kindreds.

Examples include:

●Sickle cell anemia

●Cystic fibrosis

●Huntington disease

●Duchenne muscular dystrophy

Although some disorders can be caused by variation in one of several genes (eg, four genes in familial hypercholesterolemia, >40 genes in primary ciliary dyskinesia), the term monogenic applies when variation in only one gene is sufficient to manifest the phenotype.

By contrast, complex disorders (complex traits) are those in which variants involving multiple genes, each with small phenotypic impact (small genetic effect size) combine to manifest a phenotype, often together with environmental factors. These include many complex disorders such as cardiovascular disease, asthma, diabetes, and cancer susceptibility. (See "Principles of complex trait genetics".)

Most rare genetic disorders are monogenic. However, even among monogenic disorders, not all inherited traits follow typical Mendelian inheritance patterns. Modifying effects by other genes, epigenetic changes, or environmental factors can complicate recognition of Mendelian inheritance and make it appear to follow a "non-Mendelian" pattern. Causes of non-Mendelian inheritance patterns are discussed below. (See 'Causes of non-Mendelian inheritance' below.)

Mendel's laws — Gregor Mendel was an Augustinian monk and botanist who made observations from a large series of crossbreeding experiments of plants with varying flowering characteristics [1]. Mendel noted that many physical characteristics of seeds and flowers were transmitted from parental strains to offspring in a predictable and reproducible manner.

From these observations, Mendel proposed that traits manifest through the joint effects of two paired elements; these elements were later recognized as genes. Each parent contributes one element, or allele, to each offspring at conception. He further discerned that two elements (genes) encoding characteristics that were co-inherited must be transmitted jointly, and, while many traits manifest in offspring as a blending (or averaging) of two distinct parental variations, there were also many examples in which only one of the two parental variants was manifest in offspring (where one trait was dominant to another).

Based on his observations, he proposed the following laws of inheritance, published in 1866 [2]:

●Law of segregation – The law of segregation states that paired parental copies of genes are separated from each other during gamete formation, with each parental copy (ie, allele) segregating into separate gametes. This process of gamete formation is now known as meiosis. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Meiosis'.)

●Law of independent assortment – The law of independent assortment states that genes segregate into gametes independently from other genes such that the allelic status at one locus does not determine segregation of alleles at other loci. This is only true for genes that are not linked to each other (ie, it is only true for genes that do not reside in close proximity to each other on a chromosome).

●Law of dominance – The law of dominance distinguishes dominant, recessive, and co-dominant traits.

•Dominant – A trait is considered dominant when one allele is sufficient to confer the trait. Thus, dominant traits typically manifest in heterozygous carriers or heterozygotes.

•Recessive – A trait is considered recessive when it is observed only among individuals who carry trait-causing variants on both copies of a gene. This typically involves disease-causing variants that are inherited from both the mother and the father. Recessive traits manifest in individuals who carry the same disease-causing variant on both maternal and paternal copies of the gene), or in individuals who carry two different disease-causing variants, one on the maternally-inherited copy of the gene and one on the paternally-inherited copy (compound heterozygotes). Individuals who are heterozygous for a recessive trait (carriers) are typically phenotypically indistinguishable from unaffected individuals. In some recessive diseases, carrier status can confer increased risk for some disease features. In X-linked disorders, carrier females can sometimes be affected.

•Co-dominant – A co-dominant or semidominant trait is one in which both alleles contribute equally to phenotypic expression. Heterozygous individuals manifest an intermediate phenotype between those of the two homozygous classes. This is particularly relevant for quantitative traits such as protein levels. For example, for the alpha-1-antitrypsin locus (SERPINA1 gene), Pi, MZ heterozygotes (carriers of one normal M allele and one pathogenic Z variant) have serum levels of alpha-1-antitrypsin that are approximately midway between ZZ and MM homozygous individuals.

These laws were translated to the clinical setting by Sir Archibald Garrod and published in 1902, launching the study of medical genetics [3].

The true genius of Mendel was that his postulates were put forward without any knowledge of their molecular basis. Demonstration of DNA as the heritable genetic material came decades later (DNA was identified in 1943, and the structure of the double helix elucidated in 1953).

Although there is a molecular correlate to inheritance patterns, it is the trait (the phenotype or clinical presentation) rather than the genotype that segregates as dominant or recessive. Humans are diploid, and genes (genotypes) are inherited with an equal contribution from each parent. Recognition of Mendelian inheritance requires obtaining a detailed family history and thorough review of pedigree information. Often a three-generation pedigree is required. (See "Genetic counseling: Family history interpretation and risk assessment".)

MENDELIAN INHERITANCE PATTERNS

Overview and definitions — Mendelian inheritance refers to the collection of patterns of expression of physical traits over two or more generations in a kindred that follow the rules of parental-to-offspring transmission (autosomal or sex-linked, dominant or recessive) that Mendel first described (table 1). (See 'Mendel's laws' above.)

These patterns are attributable to the actions of single genes. They are most clinically recognizable for rare, highly penetrant monogenic diseases. (See 'Penetrance and expressivity' below.)

A Mendelian (monogenic) trait is a clinical feature or attribute (disease, phenotype) that follows a Mendelian pattern of inheritance. More than 10,000 Mendelian traits and disorders have been described. Many of these are cataloged in Online Mendelian Inheritance in Man (OMIM) (http://omim.org/), a manually curated and regularly updated comprehensive database of Mendelian and non-Mendelian traits and associated genes.

Typical patterns of Mendelian inheritance include autosomal dominant (AD) (figure 1 and figure 2), autosomal recessive (AR) (figure 3 and figure 4), X-linked (figure 5 and figure 6), and Y-linked (figure 7); their characteristics are summarized in the table (table 1). These patterns depend on two features: whether the trait is dominant or recessive, and whether the trait is sex-linked.

The term X-linked recessive inheritance has classically been used to describe conditions in which the phenotypic trait is manifested in males and transmitted through asymptomatic, or carrier, females. However, due to skewed (uneven) X-inactivation, females can also manifest the clinical features of X-linked conditions. (See "Genetics: Glossary of terms", section on 'X-inactivation'.)

The distinction between X-linked dominant and X-linked recessive inheritance is considered by some to be arbitrary, and it has been suggested that the term X-linked inheritance is an effective term that encompasses both types of inheritance. An example of this is X-linked tubular myopathy, in which carriers typically show no signs of the disease, but carriers can also be affected with a range of disease severity, including generalized weakness that presents in infancy or childhood (resembling affected males), to mild, asymmetric weakness that starts in adulthood. In this and similar diseases that do not follow classic X-linked recessive inheritance, the distinction between X-linked recessive and X-linked dominant inheritance can be blurred.

Terminology is evolving for referring to changes in DNA sequence. The term "mutation" was previously used to refer to disease-causing changes in DNA. However, with greater use of DNA sequencing, base pair changes are increasingly detected for which the health implications are unknown, and use of the term "mutation" may imply a degree of pathogenicity that has not actually been established. As a result, several groups, including the American College of Medical Genetics and Genomics (ACMG), have recommended that the term "variant" be adopted to describe a change in DNA sequence. They have established a five-tier system for assessing pathogenicity, as discussed in more detail separately. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)

The term "mutation" continues to be used on rare occasions by some experts to refer to pathogenic variants, especially those with familiar names and/or when brevity is desirable (eg, "factor V Leiden mutation"). However, the term variant is preferred by many genetics professionals; the term "mutation" can be reserved for observed mutational events that lead to de novo variation.

Pedigrees — The pedigree is a valuable tool in clinical genetics. It provides a graphic representation of familial relationships and enables visualization of trait segregation within families, as well as co-segregation with specific genotype markers or sequence variants. Pedigrees are routinely constructed during genetic counseling. (See "Genetic counseling: Family history interpretation and risk assessment", section on 'Pedigree'.)

Standard pedigree symbols are used to illustrate the sex of each individual, the relationships between individuals, and the presence of one or more traits [4]:

●Males and females are denoted by squares and circles, respectively. Diamonds or triangles are used to denote ambiguous or unknown sex.

●Vertical lines denote parent/offspring relationships.

●Horizontal lines denote a relationship/reproduction between two connected individuals or parents. A double horizontal line denotes parental consanguinity (genetically-related parents who share in common other biologic relatives besides their children), as shown in the figure (figure 3).

●A diagonal line through the symbol for an individual denotes that the individual has died.

●Filling of symbols is used to denote that the individual expresses a trait of interest.

●Unaffected carrier status is designated differently for X-linked disorders (indicated by a dot in the center of the symbol) versus AR disorders (indicated by a half-filled symbol).

Additional filling patterns with an accompanying legend can be used to convey expression patterns of multiple phenotypes. Additional examples are provided in an update from the National Society of Genetic Counselors (NSGC) and various websites [5,6].

Punnett squares — Punnett squares (named for the British geneticist Reginald Punnett) are used to illustrate and calculate the probability of all potential offspring genotypes, or alleles, resulting in offspring from a specific pair of parents.

Columns denote the two alleles contributed by the father and rows denote the two alleles contributed by the mother (paternal and maternal alleles, respectively). Each cell (square) thus represents the offspring genotype resulting from the specific combination of paternal and maternal alleles.

As an example, in the figure (figure 2) the upper right cell provides the product of a paternally inherited pathogenic variant (D) with a maternally inherited wild-type variant (d). Overlay of modes of inheritance and penetrance functions are used to denote trait expression. In this example, the shaded squares in the rightmost column denote trait-expressing genotypes, reflecting an AD mode of inheritance. The squares can be adapted to accommodate multigenic models.

Autosomal patterns

Autosomal dominant — Autosomal dominant (AD) inheritance is observed by dominant traits mapping to one of the autosomal, or non-sex, chromosomes. Autosomal traits manifest in both males and females equally and are transmitted by either parent to approximately 50 percent of their offspring (figure 2).

Because causative gene variants for AD conditions are typically rare, most affected individuals are heterozygous for the pathogenic gene variant, with the other copy of the gene having typical, or wild-type, sequence. Many AD disease-causing variants are not inherited but occur "de novo," arising from a new germline mutational event that is present in the offspring's somatic cells but is not present in either parent. Offspring may also inherit the variant from a heterozygous (and therefore affected) parent.

According to the law of independent assortment, an affected heterozygous parent has a 50 percent chance of transmitting the variant to a child in each pregnancy. The affected children in turn will transmit the variant to 50 percent of their offspring. Offspring who do not inherit the variant are unaffected and have no variant to pass to their offspring.

AD traits often result from "gain-of-function" variants, whereby the variant confers a novel, deleterious function that cannot be overcome by the other normal functioning allele. Examples include Huntington disease (MIM#143100), familial Mediterranean fever (MIM#249100), and Charcot-Marie-Tooth (CMT) disease type 1 (MIM#118200).

Some AD traits result from loss-of-function variants, for which a 50 percent reduction in gene activity (haploinsufficiency) is sufficient to cause disease. AD traits can also be caused by gene variants that prevent typical function of the corresponding protein and also interfere with the function of the protein arising from the typical, or wild-type, allele of the gene (so-called "dominant negative variants"). Pathogenic variants in aquoporin-2 (AQP2) that cause AD arginine vasopressin resistance (previously called nephrogenic diabetes insipidus; MIM#125800) are an example of dominant negative alleles.

Autosomal recessive — Autosomal recessive (AR) inheritance is observed for recessive traits mapping to one of the autosomal chromosomes. As an autosomal trait, AR inheritance manifests equally in both males and females, and deleterious alleles are classically transmitted by both parents to an affected offspring (figure 4).

An AR disorder does not typically manifest in heterozygotes (ie, heterozygotes are typically unaffected carriers), and parents are almost always unaffected. Examples of AR traits include sickle cell anemia (MIM#603903), cystic fibrosis (MIM#219700), and alpha-1-antitrypsin deficiency (MIM#107400). As noted below, heterozygotes may have mild disease manifestations. (See 'Mild disease manifestations in individuals who are heterozygous for autosomal recessive disorders' below.)

Because two deleterious gene variants are required to manifest an AR disease, parents of affected individuals each must be obligate carriers of one disease-causing variant in the same gene, with rare exceptions such as uniparental disomy. Each heterozygous parent has a 50 percent likelihood of transmitting the variant, so there is a 25 percent probability that an offspring will inherit both disease-causing variants and manifest the AR trait. On average, 25 percent of an affected individual's siblings will be affected, 25 percent will carry no variants, and 50 percent will be unaffected carriers.

Though AR disorders result when both copies of a gene are dysfunctional, the causative variants observed in a given patient need not be the same. Often, the affected individual is compound heterozygous, having inherited two different variants in the same gene on opposite alleles (also referred to as "trans" or "biallelic inheritance"). This contrasts with digenic inheritance, which describes disorders that result from the combination of pathogenic variants in two different genes. (See "Genetics: Glossary of terms".)

As an example, the most common pathogenic variant that causes cystic fibrosis (the DF508 variant of the cystic fibrosis transmembrane conductance regulator [CFTR]) is observed on 70 percent of cystic fibrosis chromosomes worldwide, but only 49 percent of patients with cystic fibrosis are homozygous for this variant. Of the remainder, 42 percent are compound heterozygous for DF508 and a second pathogenic variant in CFTR, and 9 percent are either homozygous or compound heterozygous for non-DF508 variants in CFTR. (See "Cystic fibrosis: Genetics and pathogenesis".)

Comparison of family history in AD versus AR inheritance — The family histories in individuals with AR and AD conditions vary substantively from each other.

●In AD disorders, affected individuals are frequently observed in successive generations (as at least one parent is an obligate carrier and thus likely to be affected). In AD conditions, 50 percent of siblings (on average) will be affected.

●In AR conditions, there is typically no history of disease in prior generations (as parents and more distant ancestors are unaffected carriers). In AR conditions, 25 percent of siblings (on average) will be affected.

The parents of children with AR disorders are more likely to report either a history of consanguinity or shared geographic ancestries, whereby the carrier parents share a common ancestor from whom both have inherited the same disease-causing variant. This is because allele sharing among relatives is much higher than between unrelated individuals, particularly for pathogenic variants for rare disorders that have low population frequencies.

Specifically, the probability of two blood relatives both inheriting (and sharing) the same pathogenic variant from a common ancestor is a function of the degree of their relatedness (ie, 0.5 for siblings, 0.125 for first cousins, 0.03125 for second cousins). These probabilities are typically orders of magnitude higher than the probability of two unrelated individuals carrying a rare pathogenic variant. Similarly, for rare variants with frequencies that are higher in specific ancestral groups, the incidence of AR disease will be higher in kindreds in which both parents are from the same ancestral group.

Tay-Sachs disease, a fatal AR condition caused by loss-of-function variants in the HEXA gene, illustrates these probabilities:

●The carrier frequency of HEXA loss-of-function variants is approximately 1 in 250 (0.4 percent) in the general population. The probability of two unrelated individuals having an offspring with Tay-Sachs disease is therefore the joint probability that they both carry a loss-of-function variant (0.004 times 0.004) times the probability of an offspring inheriting the loss-of-function variant from both parents (0.25), which translates to 1 in 250,000 live births.

●In Ashkenazi Jewish individuals, loss-of-function variants in HEXA are approximately 10 times more prevalent due to a common founder mutation (c.1278insTATC), which is observed at a frequency of approximately 1 in 30 (3.3 percent). In the absence of prenatal genetic screening programs, the incidence of Tay-Sachs disease in Ashkenazi Jewish kindreds is 1 in 4444 births; this is 56-fold higher than seen in the general population.

●In consanguineous parings between individuals in kindreds carrying a loss-of-function variant in HEXA (regardless of whether the kindred is of Ashkenazi or non-Ashkenazi ancestry), the incidence of Tay-Sachs disease is 1 in 4096 in offspring of second cousins and 1 in 256 in offspring of first cousins (approximately 1000-fold higher than the general population rate).

AR traits usually result from loss-of-function variants affecting proteins for which a 50 percent reduction in abundance or activity is sufficient to maintain normal physiologic homeostasis. Examples include:

●Hereditary thrombotic thrombocytopenic purpura (hTTP; MIM #274150) is an AR condition caused by biallelic variants in the ADAMTS13 gene, a serine protease responsible for cleaving von Willebrand factor (VWF). Carriers of a single pathogenic variant in ADAMTS13 have a 50 percent reduction in protease activity and yet do not manifest TTP, as the residual protease function is sufficient to cleave VWF and prevent disease. Individuals who have biallelic pathogenic variants in ADAMTS13 can manifest TTP. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)

●Alpha-1 antitrypsin deficiency (AAT deficiency [A1ATD]; MIM #613490) is an AR condition caused by biallelic variants in the SERPINA1 gene, with each normal allele contributing 50 percent of circulating AAT levels. Carriers of a loss-of-function SERPINA1 allele will have reduced AAT levels (40 to 60 percent of normal), but the residual activity confers sufficient anti-neutrophil elastase function to protect against development of emphysema. Individuals who have biallelic loss-of-function variants in SERPINA1 will have markedly reduced AAT levels (<20 percent of normal), which is insufficient to provide anti-neutrophil elastase function, increasing the risk for emphysema.

In both of these examples, enzyme activity levels exhibit co-dominant inheritance, whereas the clinical phenotype demonstrates AR inheritance. (See 'Monogenic traits' above.)

Sex-linked patterns — Sex-linked inheritance describes traits that are inherited on either the X or Y chromosome.

X-linked traits cannot be passed from fathers to sons because fathers provide a Y-chromosome rather than an X-chromosome to their sons, although father to grandson transmission can occur via a daughter carrier. X-linked inheritance can be described as dominant or recessive; however, this distinction is becoming less frequently used.

Examples of X-linked recessive disorders are red-green color blindness or hemophilia (A or B), where males are affected far more often than females, and the conditions are transmitted to them from their (typically unaffected) mothers. As noted above, some believe a use of the terms X-linked recessive and X-linked dominant inheritance creates an artificial distinction [7]. Some female carriers of hemophilia disease variants are in fact affected, although typically to a lesser degree than male relatives. (See 'Overview and definitions' above and "Clinical manifestations and diagnosis of hemophilia", section on 'Bleeding in females/carriers'.)

X-linked disorders are typically recognized by the predominance of clinical manifestations in males, since males carry only one X chromosome and are reliant on normal functioning of the genes carried on that chromosome. Females can manifest the phenotype if they are homozygous (or compound heterozygous) for a particular gene variant, which would only occur in the rare event that both the father and mother are carriers, or one is a carrier and there is a new germline variant. However, due to X-chromosome inactivation in committed cell lineages, heterozygous females occasionally manifest disease due to skewed X-inactivation. If X-inactivation is skewed such that the X chromosome lacking a pathogenic variant is disproportionately inactivated, the chromosome with the pathogenic variant will be preferentially active and expressed at a higher level than the wild-type gene. Skewed X-inactivation can result in phenotypic manifestations that may be present and/or more severe than anticipated. X-linked sideroblastic anemia is another example of this phenomenon. (See "Sideroblastic anemias: Diagnosis and management", section on 'X-linked sideroblastic anemias'.)

All daughters of affected males with an X-linked recessive condition will be obligate carriers (due to obligatory X chromosome transmission from fathers to daughters). Maternal carriers will pass the pathogenic variant to 50 percent of male and female offspring. Therefore, 50 percent of sons will be affected and 50 percent of daughters will be carriers (figure 6).

Whereas X-linked recessive traits exhibit marked male predominance, some X-linked traits, such as vitamin D-resistant rickets and incontinentia pigmenti, demonstrate a female predominance or are rarely seen in males (figure 5). These are referred to by some genetics experts as X-linked dominant traits.

There are two explanations for the female predominance of certain X-linked traits.

●For some conditions, such as incontinentia pigmenti, complete lack of gene function is incompatible with life, and most males do not survive in the absence of mosaicism or other modifying factors.

●For other conditions in which complete lack of gene function is not lethal, the condition may demonstrate a female predominance because the males in the kindred must have passed their Y chromosomes to their sons; thus, the trait can only be present in males who are the children of an affected mother (who will pass the pathogenic X chromosome to 50 percent of her offspring). Likewise, all daughters of an affected father must inherit the variant.

Y-linked inheritance is easily recognized because it manifests exclusively as transmission from fathers to sons, and all affected individuals are male (figure 7). Although several traits affecting males, such as azoospermia, have been linked to variants on the Y chromosome, there are no confirmed examples of other types of Y-linked diseases. This is intuitive since females are healthy despite lacking Y-chromosome genes. Y-linked disease is theoretically possible if a gain-of-function variant occurred (eg, duplication of a Y-chromosome gene that caused "overdosage" of a gene product).

CAUSES OF NON-MENDELIAN INHERITANCE — There are many instances where familial clustering of rare traits is observed, but the pattern of inheritance within a family appears to violate Mendel's laws.

Inheritance of certain monogenic traits can appear to be non-Mendelian due to one or the other of the following:

●Multiple genes impact the phenotype's expression.

●Additional factors impact the genotype-phenotype relationship (table 1).

These factors can make recognizing genetic inheritance more difficult and often confound (or preclude) prediction of recurrence risks.

Mild disease manifestations in individuals who are heterozygous for autosomal recessive disorders — Autosomal recessive (AR) disorders are classically described as requiring two disease-causing variants for the disorder to manifest. However, there are many examples in which individuals who are heterozygous for a pathogenic variant have subtle findings that are likely attributable to the variant. While most manifest as milder forms of traits observed in individuals with biallelic variants, for some genes, the traits observed in heterozygous individuals are distinct.

Examples include the following:

●Sickle cell trait – Sickle cell trait (heterozygosity for the sickle hemoglobin variant) is an asymptomatic carrier state, but individuals are at risk for certain rare complications related to the presence of hemoglobin S. (See "Sickle cell trait", section on 'Clinical findings'.)

●Gaucher disease – Gaucher disease is an AR disorder, but individuals who are heterozygous for pathogenic variants in the glucocerebrosidase 1 (GBA1) gene appear to have an increased risk for Parkinson disease. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Neurologic disease'.)

●Nijmegen breakage syndrome – Nijmegen breakage syndrome (NBS) is an AR chromosomal instability syndrome associated with developmental anomalies and increased cancer risk. Individuals who are heterozygous for a pathogenic variant in the nibrin (NBN) gene also appear to have an increased risk of certain cancers. (See "Nijmegen breakage syndrome", section on 'Clinical manifestations'.)

When patients appear to exhibit classic findings of an AR disease and only one pathogenic variant (from one parent) is identified in the likely causative gene, the following considerations may apply:

●A second variant (inherited from the other parent) may not have been identified due to its location in a non-coding region (an intron, upstream, or downstream regulatory region) not assessed by the genotyping or sequencing method. In these instances, additional evidence is needed to establish a diagnosis. For example, in patients with clinical findings consistent with cystic fibrosis, in the absence of two pathogenic variants in the CFTR gene, a diagnosis can alternatively be established by demonstrating dysfunction of the corresponding protein, either by a positive sweat chloride test or abnormal nasal potential difference. In the era of modulator therapies, establishing a diagnosis is a priority, as patients with only one modulator-responsive pathogenic variant are eligible for therapy. (See "Gene test interpretation: CFTR" and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

●A variant in a different gene may affect the function of the relevant gene. This can be assessed by testing protein function or by using an expanded gene panel.

●The individual may have uniparental disomy, a rare condition in which both chromosomes from one parent are transmitted to the gamete during meiosis. (See "Genomic disorders: An overview".)

Penetrance and expressivity — Penetrance and expressivity are terms that describe how the genotype correlates with the clinical manifestations of a condition or phenotype. Alterations in penetrance or expressivity can influence the expression of Mendelian disorders, making monogenic traits appear as if they are transmitted in a non-Mendelian inheritance pattern.

Incomplete or variable penetrance — Penetrance refers to the proportion of individuals who carry a disease-causing genotype that manifest disease. Penetrance is a probability estimate that ranges from 0 to 1. Some diseases have very high (or full) penetrance, whereas others demonstrate more variable penetrance rates. Penetrance can also be used to describe alleles in the context of complex diseases, but other expressions of risk, such as odds ratio (OR), relative risk (RR), or population attributable risk (PAR), are more commonly used.

●Full penetrance – Genes with penetrance values of 1 are considered fully penetrant. In these cases, the genotype status perfectly predicts the development of disease and can be reliably used for genetic counseling (although genotype may not precisely predict other disease features such as the age of onset or disease severity). Classic examples include autosomal dominant (AD) Huntington disease, in which all individuals with a pathogenic variant (the presence of more than 40 CAG repeats in the huntingtin [HTT] gene) will eventually manifest the disease. Another example is biallelic inheritance of the 1278insTATC frameshift variant in the hexosaminidase A (HEXA) gene in AR infantile Tay-Sachs disease [8,9]. (See "Huntington disease: Genetics and pathogenesis" and "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Tay-Sachs disease'.)

●Incomplete penetrance – Incomplete penetrance refers to penetrance values of <1, in which the expression of disease is not observed among all individuals who carry a disease-associated genotype. When penetrance is incomplete but high (values of 0.8 to 0.9), the disease will appear to be Mendelian but may occasionally skip a generation, such that an obligatory carrier of a causative genotype does not manifest the features of the disease (figure 8); this is most typically observed for conditions with AD inheritance. When penetrance is low, Mendelian inheritance patterns are often very difficult to appreciate in the absence of large extended pedigrees.

●Variable penetrance – Adding further complexity to the recognition of Mendelian traits, variable penetrance across populations or pedigrees refers to penetrance levels that change across families or in patients or populations of different ancestries. For example, the lifetime prevalence of developing breast cancer among female carriers of pathogenic variants in BRCA1 is typically estimated at 60 to 80 percent [10,11]; however, lower rates (<40 percent) have been reported in selected families [12,13]. Striking differences, not thought to be due to differences in variant frequency, have been reported in the annual incidence of breast cancer in individuals with pathogenic variants in BRCA1 between North America (72 percent) and Poland (49 percent) [14].

Variable expressivity — In contrast with penetrance, which describes the probability that a disease will manifest with a disease-causing genotype, variable expressivity refers to phenotypic differences in the degree or spectrum of disease manifestation in individuals with the disease.

Variability is the norm among genetic diseases and is particularly common for disorders that affect multiple organ systems. As an example, in cystic fibrosis there is significant variability in the degree of pancreatic dysfunction and lung function decline among individuals who are homozygous for the F508del CFTR variant, even among siblings and twin pairs [15]. Variable expressivity differs from pleiotropy, which refers to clinical manifestations in multiple tissues or organs in association with disease-causing variants in a single gene. (See 'Pleiotropy' below.)

Causes of incomplete penetrance and variable expressivity — There are several determinants of variable or incomplete penetrance and variable expressivity; some are better understood than others.

●Age – Age is the most widely recognized modifier of penetrance, with increasing age frequently associated with a higher likelihood of disease penetrance. Age-related penetrance can be caused by cumulative rates of cellular damage that occur because additional gene changes accumulate over time until a disease-causing threshold is attained. Selected examples include the BRCA1 gene and breast cancer, C9ORF72 and SOD1 genes and familial amyotrophic lateral sclerosis, and the myocilin (MYOC) gene and primary open-angle glaucoma.

●Allelic heterogeneity – Allelic heterogeneity (the presence of multiple, different disease-causing sequence variants in a gene) is a common cause of variable penetrance and variable expressivity. Not all gene variants have the same phenotypic impact. Variants that induce more deleterious changes in protein structure (ie, nonsense or frameshift mutations that cause loss of function) or those affecting critical positions or structural motifs (eg, in highly conserved functional motifs) in the protein can induce more significant functional consequences than more milder forms of variation, such as gene variants that lead to the substitution of amino acids with similar size, charge, and polarity. This phenomenon has been documented for many conditions, including pathogenic variants in SOD1 in familial amyotrophic lateral sclerosis, pathogenic variants in CFTR in cystic fibrosis, and several beta globin gene (HBB) variants in beta thalassemia [16-18]. Allelic heterogeneity plays an important role in most genetic diseases.

●Genetic heterogeneity – For diseases or traits in which variants in more than one gene can cause the same condition, the penetrance and expressivity typically vary. As an example, the various subtypes of Charcot-Marie-Tooth (CMT) disease type I (A through E) are caused by pathogenic variants affecting four different genes (PMP22 for types 1A and 1E, MPZ for type 1B, LITAF for type 1C, and EGR2 for type 1D). Although the spectrum of manifestations is clinically indistinguishable for some forms of CMT (types 1A and 1C), marked differences in age of onset, rate of progression, patterns of nerve involvement, and severity of conduction abnormalities are typically observed between other CMT types. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)

●Genetic modifiers – Genetic modifiers are sequence variants, most commonly in a different gene, that alter the penetrance or expressivity of a pathogenic variant, but do not cause disease in the absence of the variant. For example, the penetrance of pathogenic variants in DFNB26 that cause AR nonsyndromic deafness is markedly reduced among carriers of a putative modifier gene, DFNM1 [19]. As another example, lung function in cystic fibrosis is highly variable, even among individuals with identical genotypes. Candidate gene and genome-wide association studies have identified several candidate modifier loci, including common variants in the TGFB1 and IFRD1 genes [20,21].

●Environmental exposures – The effect of environmental exposures on the phenotype of genetic disease (both for monogenic and complex diseases) has been recognized since the early days of medical genetics. Phenylketonuria is caused by loss-of-function variants in the phenylalanine hydroxylase (PAH) gene and results in cognitive deficits due to accumulation of phenylalanine in the brain. Restricting the dietary intake of phenylalanine prevents its accumulation in the central nervous system, enabling normal cognitive development in individuals who are homozygous or compound heterozygous for pathogenic variants in PAH [22,23]. This is an example of a predictable environmental modification through substrate manipulation in a metabolic pathway. (See "Overview of phenylketonuria", section on 'Phenylalanine hydroxylase deficiency'.)

Penetrance and expressivity can also be altered through less predictable, indirect means. As an example, exposure to cigarette smoke greatly increases the likelihood and severity of chronic obstructive pulmonary disease and emphysema among individuals who are homozygous for pathogenic variants in the SERPINA1 gene. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'AAT genetics'.)

Environmental exposures can also phenocopy genetic diseases. As an example, an outbreak of porphyria cutanea tarda, which may be associated with pathogenic variants in the UROD gene, occurred after hexachlorobenzene contamination of wheat in Turkey. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Halogenated hydrocarbons'.)

Pleiotropy — Pleiotropy refers to the capacity of variants in a single gene to produce multiple phenotypic effects, often in different tissues or organs. Pleiotropy is distinct from variable expressivity, which describes the occurrence of distinct clinical effects, or different degrees of disease expression, that can manifest in two individuals with the same pathogenic variant (or combination of variants) and thus the same genotype.

As an example of pleiotropy, Marfan syndrome (MIM #154700) is caused by pathogenic fibrillin-1 (FBN1) variants and can exhibit cardiac manifestations (aortic dilatation and rupture), ocular manifestations (ectopia lentis and severe myopia), and connective tissue findings (joint hyperextensibility and arachnodactyly). (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Genetics'.)

Other examples of pleiotropy include the diversity of affected organ systems in ataxia telangiectasia (OMIM #208900) and nail-patella syndrome (OMIM #161200).

Anticipation — Anticipation describes the phenomenon in which successive generations display earlier-onset or more severe disease manifestations or disease progression.

Diseases typified by anticipation are often first recognized in the most severely affected offspring, with subsequent diagnoses of milder disease in parents or grandparents. Anticipation can manifest through several mechanisms, including trinucleotide repeat expansions, environmental modification, or accumulation of variants in disease-modifying genes.

An example of a disease caused by trinucleotide repeat expansions is myotonic dystrophy (OMIM #160900), in which the number of CTG repeats can increase with each generation, resulting in longer repeats that confer a more severe phenotype. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Genetics'.)

Another example of genetic anticipation occurs in the short telomere syndromes, in which telomeres can become shorter with successive generations, leading to a younger age of presentation in children compared with parents. (See "Dyskeratosis congenita and other telomere biology disorders", section on 'Pathophysiology'.)

Mosaicism — Mosaicism refers to the state of having two populations of genetically distinct cells in an individual who arose from a single fertilized egg.

Mosaicism can arise by one of several mechanisms that typically occur in one cell of a developing blastocyst or embryo. Events that occur later during development affect a smaller proportion of cells and a more limited number of cell lineages. Thus, in general, the later a pathogenic variant arises during embryogenesis, the smaller its potential phenotypic impact.

Individuals with mosaicism for a pathogenic variant can only transmit the variant to the next generation if the variant is present in their gametes. If an individual with mosaicism for a disease trait harbors the associated variant in their germline, the trait may present as an apparently new finding in children who inherit the variant.

In contrast with mosaicism, chimerism refers to the uncommon state of having two or more populations of genetically distinct cells due to fusion of two or more fertilized eggs.

Parent-of-origin effects (imprinting) — The expression of some traits is highly dependent on whether the associated gene variant(s) are inherited from one parent or the other (ie, on whether they are imprinted). Parental imprinting is thought to arise through epigenetic modification of DNA that takes place in the ova and sperm during gametogenesis, before fertilization. Genes that are inactivated (silenced) in the female line are said to be maternally imprinted and only the paternally derived allele is expressed and active. Genes that are inactivated (silenced) in the male line are said to be paternally imprinted and only the maternally derived allele is expressed and active (figure 9).

A well-characterized imprinted locus is the 15q11 gene cluster. Several diseases map to this region and exhibit parent-of-origin effects that are dependent on the imprinting pattern. Prader-Willi syndrome (OMIM #176270) results from deletions, absence, or abnormal imprinting of paternally inherited genes in this cluster (eg, SNRPN and NDN). These genes are silenced when inherited from the mother, and disease phenotypes manifest when deletions occur on paternally inherited chromosomes. By contrast, Angelman syndrome (OMIM #105830) can result from deletions of a set of adjacent maternally inherited genes that include UBE3A; these genes are silenced when paternally inherited, and similar deletions on paternally inherited chromosomes do not produce the disease phenotype. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)' and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)'.)

Relatively few confirmed examples of parental imprinting with direct clinical application besides the 15q11 region have been described. However, it is possible that such epigenetic processes will prove to be important disease modifiers. Databases of imprinted genes are available from Geneimprint (https://www.geneimprint.com/). These include entries related to neuropsychiatric illnesses including alcoholism, bipolar disorder, schizophrenia, and autism; diabetes; and asthma. Unlike the 15q11 locus, most of the findings have not been replicated in multiple patient populations, and the extent to which imprinting influences other traits remains unclear.

Mitochondrial inheritance — Mitochondrial inheritance refers to traits that are due to genetic variation in the mitochondrial DNA, also referred to as the mitochondrial genome, rather than the nuclear genome. Mitochondria are organelles present in most somatic cells; numerous mitochondria are present in the cytoplasm. Mitochondria possess a circular strand of DNA that is separate from the cell's nuclear genome or nuclear DNA. Mitochondrial DNA contains 37 genes that encode proteins involved in oxidative phosphorylation, transfer ribonucleic acids (tRNAs), and ribosomal RNAs (rRNAs), all contained in a 16.6 kb circular DNA fragment that replicates autonomously (figure 10).

Human mitochondrial DNA is inherited exclusively through the maternal line (from the egg), as mitochondria from sperm are not contributed during fertilization [24]. Thus, genetic disorders caused by pathogenic variants in mitochondrial genes exhibit exclusive maternal inheritance, although some individuals may be phenotypically unaffected (figure 11). Offspring of affected fathers do not inherit these diseases.

Many of the proteins vital for mitochondrial function are encoded by nuclear DNA (on chromosomes) rather than by the mitochondrial genome. Pathogenic variants that disrupt the function for these genes follow Mendelian inheritance patterns despite interfering with mitochondrial function(s).

Individuals with pathogenic variants in mitochondrial genes commonly exhibit heteroplasmy, in which there is more than one type of mitochondria in every cell, with some affected and some unaffected by the pathogenic variant in the mitochondrial DNA. Females with a mitochondrial variant who exhibit heteroplasmy will pass on varying numbers of affected or unaffected mitochondria in their eggs, meaning that there can be substantial variation in the contribution of the mitochondrial variant (and thus the likelihood of disease development and/or disease severity) in each offspring.

A human mitochondrial DNA database is available (www.mitomap.org); this lists mitochondrial gene variants confirmed as pathogenic by two or more laboratories. Examples of diseases caused by pathogenic variants in mitochondrial DNA include [25]:

●MERRF (myoclonic epilepsy with ragged red fibers, OMIM #545000)

●MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke, OMIM #540000)

●Leber optic atrophy (OMIM #535000)

All of these disorders manifest with prominent neurologic manifestations (a consequence of the high metabolic requirements of neuronal tissues), along with other disease-specific phenotypes. (See "Mitochondrial myopathies: Clinical features and diagnosis" and "Causes and pathophysiology of the sideroblastic anemias", section on 'Myopathy, lactic acidosis, and sideroblastic anemia (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2)' and "Neuropathies associated with hereditary disorders", section on 'Leber hereditary optic neuropathy'.)

In addition to these conditions with confirmed mitochondrial inheritance, numerous reports describe associations between more common mitochondrial variants and a wide range of neurologic and psychiatric disorders including Alzheimer disease, Parkinson disease, and bipolar disorder; metabolic disorders (diabetes, exercise intolerance, obesity); common complex diseases such as nonsyndromic cancer; and lifespan. Most of these associations have not been consistently reproduced by independent groups, and clinical utility has not been demonstrated.

Sex-limited expression — The expression of some traits, regardless of their chromosomal location, can be restricted to one sex, likely due to critical physiologic, anatomic, or hormonal differences. Male pattern baldness, which can be inherited as an AD trait, is the most common sex-limited trait. Others include familial male precocious puberty, caused by variants in the GNAS1 gene, and juvenile hypertrophy of the breast, which is limited to females.

Multigenic disorders — Diseases or traits caused by the combined effects of more than one gene are referred to as multigenic or complex diseases.

Digenic — Digenic inheritance refers to an inheritance pattern in which pathogenic variants at two distinct loci are required for a disease to manifest. Many of the diseases with reports of digenic inheritance typically also exhibit classic AR inheritance patterns. When digenic inheritance is observed, one of the two loci is usually the same gene as implicated in the AR form (though with different alleles). As an example, a digenic form of retinitis pigmentosa (RP; OMIM #268000) has been described (type 7), resulting from the combination of specific heterozygous variants in both the PRPH2 (also known as RDS) and ROM1 genes [26]. Consistent with digenic inheritance, the presence of heterozygosity for pathogenic ROM1 variants in the absence of pathogenic PRPH2 variants does not result in RP. It is also noteworthy that the spectrum of PRPH2 variants includes several that cause AD RP alone and others that cause macular dystrophy. Thus, the PRPH2 gene is an example of a gene demonstrating allelic heterogeneity (a cause of variable penetrance and expressivity), digenic inheritance, and pleiotropy. (See 'Causes of incomplete penetrance and variable expressivity' above and 'Pleiotropy' above.)

Another example of digenic inheritance is Usher syndrome, classically characterized by congenital deafness, vestibular dysfunction, and early-onset RP. Though most commonly presenting as an AR disease caused by pathogenic variants in CDH23 and other genes, some patients have been described with only one CDH23 variant in combination with a second severe, pathogenic variant in PCDH15 [27]. (See "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Genetics'.)

Triallelic — Triallelic inheritance is a relatively rare type of inheritance that requires three gene variants for a disease to manifest: two pathogenic variants at one locus and one additional variant at a different locus associated with the same disease. Triallelic inheritance illustrates the effects of gene dosage and represents a bridge between monogenic and multifactorial traits.

An example is Bardet-Biedl syndrome (OMIM #209900), in which most affected individuals are homozygous or compound heterozygous for a pathogenic variant in one gene, consistent with AR inheritance. However, families with Bardet-Biedl syndrome have been described in which three variants in two genes segregate with the disease phenotype, and family members with two of the three variants are unaffected [28,29], although this situation is rare and triallelic inheritance in Bardet-Biedl syndrome has been considered by some researchers to be controversial.

There are also situations where the occurrence of two or more pathogenic variants has been hypothesized to explain more severe disease presentations. An example of this has been reported in a family with short telomere syndrome, in which a severely affected brother was homozygous for a variant in the TERT gene of intermediate functional impact (p.Lys1050Asn) and was also a carrier for a third, deleterious variant in TERC [30]. His sister, who was homozygous for only the first TERT variant, had a significantly milder clinical presentation.

Complex traits — Complex traits are those that result from variation within multiple genes along with behavioral and environmental factors. Many common diseases including cancers, heart disease, metabolic disorder, diabetes, asthma, and inflammatory bowel disease, are considered predominantly to be complex traits. Complex trait genetics are discussed separately. (See "Principles of complex trait genetics".)

CLINICAL RELEVANCE — Identifying monogenic disease has implications not only for the individuals seeking medical attention but also more broadly for the relatives and future offspring of affected individuals, especially when reliable screening tests are available.

Examples include:

●Diagnosis of members with more subtle or variable phenotypes

●Carrier detection

●Preconception planning

●Prenatal diagnosis

These issues are discussed in more detail separately. (See "Personalized medicine" and "Genetic counseling: Family history interpretation and risk assessment" and "Genetic testing".)

SUMMARY

●Definitions – Monogenic traits are disorders or phenotypes conferred by variation in a single gene. Mendelian disorders are highly penetrant monogenic diseases in which the correlation between genotype and phenotype is strong. These are often rare disorders. Mendelian inheritance refers to the expression of the phenotype rather than the genotype. Recognition of Mendelian inheritance requires a detailed family history and thorough review of pedigree information (often from a three-generation pedigree). (See 'Genetic basis of monogenic inheritance' above.)

●Typical Mendelian inheritance patterns – The five typical patterns of Mendelian inheritance are autosomal dominant (AD) (figure 2 and figure 1), autosomal recessive (AR) (figure 4 and figure 3), X-linked dominant (figure 5), X-linked recessive (figure 6), and Y-linked (figure 7). Some experts group X-linked recessive and X-linked dominant together using the term X-linked inheritance. (See 'Mendelian inheritance patterns' above.)

●Causes of non-Mendelian inheritance – Many monogenic disorders do not exhibit pure Mendelian inheritance patterns. Apparent non-Mendelian inheritance of monogenic traits can result from a variety of phenomena. (See 'Causes of non-Mendelian inheritance' above.)

•Incomplete penetrance and variable expressivity – Incomplete penetrance refers to expression of the trait in some, but not all, individuals with the disease genotype. Variable penetrance refers to variation in penetrance levels in different families. Variable expressivity refers to different clinical presentations of the same disease (variation in phenotype, such as which organ systems are affected) in different family members with the same genotype. Modifiers of penetrance and expressivity include age, allelic heterogeneity, genetic (locus) heterogeneity, modifier genes, and environmental exposures. (See 'Penetrance and expressivity' above.)

•Pleiotropy – Pleiotropy refers to production of multiple phenotypic effects, often in different tissues or organs, from variants in a single gene. Anticipation describes the phenomenon in which successive generations display accelerated, earlier-onset, or more severe disease manifestations. (See 'Pleiotropy' above and 'Anticipation' above.)

•Imprinting – Parent-of-origin effects (imprinting) occur when genes are selectively inactivated (silenced) specifically on the maternal or paternal chromosome. Epigenetic changes are often responsible for imprinting. (See 'Parent-of-origin effects (imprinting)' above.)

•Mitochondrial inheritance – Mitochondrial inheritance refers to traits that are due to genetic variation in the mitochondrial genome rather than the nuclear genome. Transmission is exclusively through the maternal line. (See 'Mitochondrial inheritance' above.)

•Multigenic traits – Traits resulting from the combined effects of more than one gene are referred to as multigenic (eg, digenic, triallelic) or complex. (See 'Multigenic disorders' above and "Principles of complex trait genetics".)

●Clinical implications – Inheritance patterns have important clinical implications for patient management, diagnosis of relatives with subtle phenotypes, carrier detection, reproductive counseling, and prenatal diagnosis. (See "Personalized medicine" and "Genetic counseling: Family history interpretation and risk assessment" and "Genetic testing".)