Basic Principles of Genetics

Abstract

Human disease can arise from genetic changes ranging from mutations in single nucleotides to alterations affecting entire chromosomes. Genetic skin diseases include Mendelian (monogenic) disorders caused by defects in one gene as well as polygenic disorders due to defects in more than one gene; complex (multifactorial) disorders result from the interaction of environmental and genetic factors. Tremendous progress has been made in determining the genetic basis of human diseases. Functional and positional cloning as well as positional candidate approaches have been utilized to identify pathogenic mutations for Mendelian disorders, while genome-wide association studies (GWAS) and functional genomics have more recently been employed to investigate complex disorders. The advent of massively parallel sequencing technology has also enabled identification of novel pathogenic variants. A basic understanding of genetics and the methods currently used to study genetic diseases is essential for the incorporation of research advances into patient care.

Keywords

genodermatoses, gene, mutation, monogenic, polygenic, Mendelian disorder, autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, mosaicism, chromosomal disorders, incomplete penetrance, variable expression, de novo mutations, pseudodominant inheritance, genomic imprinting, mitochondrial inheritance, functional cloning, positional cloning, linkage analysis, single nucleotide polymorphism (SNP), comparative genomic hybridization (CGH), copy number variation, loss of heterozygosity, genome-wide association studies (GWAS), massively parallel sequencing, whole-exome sequencing, whole-genome sequencing, functional genomics

Introduction

The completion of the human genome sequence, with an estimated size of 3.2 gigabases (Gb) and containing ~20 000–25 000 genes , represents a powerful tool in medicine that facilitates the identification of disease-associated genes. Detailed information on human sequence variation and advanced technologies for its detection have broadened our knowledge of the genetic basis of human disease. The pathogenesis of many disorders also involves epigenetics, which represent heritable changes in phenotype and/or gene expression that do not result from changes in the DNA sequence.

Rapid advances in the development of molecular biology techniques (see Ch. 3 ), together with information-based tools derived from the sequencing of the human genome, provides the physician with direct access to clinically relevant genetic information. Consequently, it is important for physicians in general, and dermatologists in particular, to understand basic concepts of genetics ( Table 54.1 ). Familiarity with new technology and approaches to identifying disease-causing genes is essential in order to appropriately utilize and interpret the results of genetic studies in the patient care setting. The wealth of new information emphasizes the need to bridge the gap between the bench and the bedside, bringing together efforts from both the clinical and research arms of dermatology.

Table 54.1

Basic concepts in genetics.

BASIC CONCEPTS IN GENETICS
Nuclear DNA	• Deoxyribonucleic acid (DNA) contained within nuclei of eukaryotic organisms • Packed into chromosomes • Selectively folded and unfolded to allow the expression of hundreds of genes at different times and in different cell types • Each somatic cell contains approximately 2 meters of DNA
Chromosome	• Organized structures of DNA and proteins that are found within the nucleus • Each diploid organism (including humans) has two sets of chromosomes, one from its father and one from its mother • Each pair of chromosomes is composed of two homologous chromosomes, one from each parent • Humans normally have 23 pairs of chromosomes: 22 pairs of autosomes and one pair of sex chromosomes (XX in females and XY in males) • Chromosomes X and Y share only two small regions, known as the pseudoautosomal regions
Karyotype	• Describes the chromosomal constitution of an individual (e.g. 46, XY or 46, XX)
Haploid cell	• Contains only one chromosome complement or “n” (for humans, n = 23) • Gametes (paternal and maternal) are haploid cells
Diploid cell	• Contains two chromosome complements or “2n” (for humans, 2n = 46) • Human cells (other than gametes) are diploid
Centromere	• A site of constriction in a chromosome that is essential for correct cell division • Depending on the position of the centromere, chromosomes can be: – Metacentric : centromere near the middle, two “arms” of similar length – Submetacentric : centromere between the center and end, two “arms” of somewhat different lengths – Acrocentric : centromere near the end, two “arms” of very different lengths • Composed of a series of histone proteins and repetitive DNA sequences (several thousand kilobases) • Divides the chromosome into two arms: the short (petite) arm or p, and the long arm or q
Telomere	• A region of repetitive DNA (TTAGGG sequence) and proteins at the ends of each chromosome • Plays a key role in the maintenance of chromosomal integrity and ensuring correct replication
Meiosis	• The process of cell division by which a diploid cell from the germline gives rise to haploid gametes via segregation and random assortment of homologous chromosomes • Results in combinations of chromosomes in the daughter cells that are different than that in the parental cell
Mitosis	• The process of somatic cell division of proliferating cells by which the genetic material of a cell is duplicated and equally distributed between the two resulting daughter cells • To achieve this duplication of genetic material, the chromosome replicates itself and forms two sister chromatids , which will each become the chromosome of a daughter cell
Locus	• The location of a particular sequence of DNA (e.g. a gene or DNA fragment) on a chromosome • Since we have two copies of each chromosome, we also have two copies of each locus, which can be identical or different
Gene	• A segment of DNA that encodes a protein (or occasionally an RNA chain) that serves a function
Allele	• Alternative forms of a particular gene or DNA sequence at a given locus • An individual has two alleles at each autosomal locus (one from each parent), and the locus/individual is referred to as: – Homozygous if the alleles are identical – Heterozygous if the alleles are different • Since males have only one copy of the X and Y chromosomes, they are hemizygous for loci on these two chromosomes
Polymorphic locus	• Exhibits at least two alleles with a frequency in the general population of >1% • Can be located within or outside of a gene
Single nucleotide polymorphism (SNP)	• A single nucleotide in a particular location within the genome that has at least two different forms with a frequency of >1% in the general population • Occurs on average every 1000 nucleotides
Mutation	• A change in the DNA sequence • Refers to variation resulting in a disease phenotype • Although any change in the DNA is technically a mutation, the term is often used to refer to a pathogenic variant that results in a disease phenotype
Genotype	• The alleles present at a specific locus (or in the whole genome) of an individual
Phenotype	• The manifestation of a particular genotype (in the context of the environment in which it is expressed) • Different genotypes are not always recognizable as distinct phenotypes • A change in a phenotype can be caused by variant alleles that are present in the general population (normal variation) or by pathogenetic variation that leads to a disease

Access to patients with genetic disorders and accurate clinical descriptions are essential for investigations aimed at the identification of disease-causing genes. Combined with functional studies and translational approaches, these findings can in turn provide benefits to affected individuals. Such insights have importance in genetic counseling and prenatal diagnosis, and they can also contribute to the identification of at-risk individuals/families, prediction of disease course and possible complications, determination of response to therapeutic interventions, and even the development of targeted treatments.

Since the early 1980s, the molecular bases of numerous cutaneous genetic disorders have been elucidated, including multiple forms of epidermolysis bullosa (EB; see Ch. 32 ), ectodermal dysplasia (ED; see Ch. 63 ), ichthyosis (see Ch. 57 ), and hypotrichosis (see Chs 68 & 69). The gene-identification strategies employed for these relatively uncommon Mendelian (single-gene) disorders have provided a foundation for the study of common complex disorders such as atopic dermatitis, psoriasis, and alopecia areata. Advances in mapping and detecting human sequence variation have led to more sophisticated approaches, including genome-wide association studies (GWAS) and whole-exome sequencing. Functional genomic studies, e.g. comparison of the transcriptome (expressed genes) in samples from patients and unaffected individuals, have also helped to identify candidate genes for further investigation. The clinician plays a key role in enabling such research, which requires a well-characterized collection of patient samples.

Genetic Diseases

Key features

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Accurate information about phenotype and family history is essential in identifying the pattern of inheritance of a genetic disease
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Genetic diseases include Mendelian (monogenic) disorders caused by defects in one gene as well as polygenic disorders due to defects in more than one gene; complex (multifactorial) disorders result from the interaction of environmental and genetic factors
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The major Mendelian patterns of inheritance are autosomal recessive (e.g. oculocutaneous albinism), autosomal dominant (e.g. Darier disease), X-linked recessive (e.g. hypohidrotic ectodermal dysplasia), and X-linked dominant (e.g. incontinentia pigmenti)
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Factors modifying the basic Mendelian pattern of inheritance include incomplete penetrance, age-dependent penetrance, variable expression, de novo mutations, pseudodominant inheritance, genomic imprinting, and mitochondrial inheritance
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Chromosomal anomalies can consist of abnormalities in the number (e.g. polyploidy, aneuploidy) or structure (e.g. translocations, inversions) of the chromosomes
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Heterogeneity at the locus or allelic level can make identification of a gene defect challenging

Genetic diseases can manifest in multiple members of a family. However, not every disease present in more than one family member is genetic. Pedigrees of families in which a genetic disease is transmitted (i.e. segregates or is inherited) can range from a single affected member to many affected members in several generations.

Mendelian (monogenic) diseases are caused by defects in one gene, while polygenic diseases result from defects in more than one gene and complex (multifactorial) diseases result from the interaction of environmental and genetic factors. In addition to mutations within particular genes, abnormalities in the structure, number, or parental contribution of chromosomes can cause disease.

In the following sections, we provide an overview of the different types of genetic diseases.

Mendelian Patterns of Inheritance

A key initial step in the assessment of the risk for a particular inherited disease is determination of its mode of inheritance. For this purpose, it is essential to collect accurate information on the clinical phenotype and to examine as many family members as possible to classify their status – affected or unaffected. The family is usually ascertained through one family member, the proband , around whom the pedigree is built with information on the phenotypes and relationships between different individuals.

Even when a single-gene defect is enough to cause a disease phenotype (monogenic disorders), the clinical expression can be affected by variable expression and even incomplete penetrance (see below). Genes are expressed on a particular genetic background, which is different in every individual, and genes and their products interact with other genes and proteins. One can therefore expect that monogenic disorders will show some degree of variability.

Allelic heterogeneity refers to mildly or even considerably different clinical entities due to different mutations in the same gene ( Table 54.2 ). In contrast, locus (genetic) heterogeneity refers to mutations in different genes that result in the same phenotype ( Table 54.3 ). Of note, there are some diseases, such as EB simplex, that display both allelic and locus heterogeneity. Thus, diagnosis based purely on either clinical signs/symptoms or the results of genetic testing can lead to misclassification, underscoring the importance of integrating clinical and molecular findings.

Table 54.2

Examples of allelic heterogeneity in genodermatoses .

ABCA12 , ATP binding cassette, family 1 member 12 gene; AD, autosomal dominant; AR, autosomal recessive; ATP7A , ATPase, Cu ²⁺-transporting, α-polypeptide gene; EBS, epidermolysis bullosa simplex; GJB3 , gap junction β3 gene (encodes connexin 31).

EXAMPLES OF ALLELIC HETEROGENEITY IN GENODERMATOSES
Mutated gene	Phenotypes
GJB3	Erythrokeratodermia variabilis AR and AD non-syndromic hearing impairment AD peripheral sensory neuropathy and hearing impairment
Desmoplakin ( DSP )	Striate palmoplantar keratoderma Dilated cardiomyopathy with woolly hair and keratoderma (Carvajal syndrome) Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome Skin fragility–woolly hair syndrome Acantholytic EBS Arrhythmogenic right ventricular cardiomyopathy
ABCA12	Harlequin ichthyosis Lamellar ichthyosis
Plectin ( PLEC )	EBS and limb-girdle muscular dystrophy EBS of the Ogna type EBS with pyloric atresia
ATP7A	Menkes disease Occipital horn syndrome

Table 54.3

Examples of genodermatoses with genetic/locus heterogeneity .

AP3B1/D1 , adaptor related protein complex 3, β1/δ1 subunit gene; BLOC1S3/6 , biogenesis of lysosome-related organelles complex-1, subunit 3/6 gene; DSG1, desmoglein 1 gene; DSP , desmoplakin gene; DTNBP1 , dystrobrevin binding protein 1 gene; KRT , keratin gene.

EXAMPLES OF GENODERMATOSES WITH GENETIC/LOCUS HETEROGENEITY
Phenotype	Gene
Striate palmoplantar keratoderma	DSG1 DSP KRT1
Epidermolytic ichthyosis	KRT1 KRT10
Epidermolysis bullosa simplex (localized and generalized variants)	KRT5 KRT14
Hermansky–Pudlak syndrome (HPS)	HPS1, HPS3, HPS4, HPS5, HPS6 AP3B1, AP3D1 DTNBP1, BLOC1S3, BLOC1S6
Tuberous sclerosis complex (TSC)	TSC1 TSC2
Hypohidrotic ectodermal dysplasia *	EDA (ectodysplasin A) EDAR (ectodysplasin A receptor) EDARADD (EDAR-associated death domain)

* Mutations in different genes result in X-linked recessive (EDA), autosomal recessive (EDAR, EDARADD), and autosomal dominant (EDAR, EDARADD) forms of the disorder.

Once a phenotype and its range of clinical findings are defined, the trait can be followed within a pedigree. The transmission of the trait in the pedigree defines the pattern of inheritance of the disease. The genes responsible for monogenic traits can be located either on autosomes, resulting in an autosomal pattern of inheritance, or on the X chromosome in the case of an X-linked pattern of inheritance. Irrespective of the gene location, when a mutation in one of two alleles is sufficient to produce the phenotype, the trait is considered dominant . In contrast, when both alleles of a gene (or one allele in hemizygotes) must be altered in order to produce the phenotype, the condition is considered recessive . Hence, Mendelian inheritance patterns include autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive ( Table 54.4 ). There are also Y-linked genes that primarily affect male fertility , although their relevance in more general diseases is possible.

Table 54.4

Patterns of inheritance.

PATTERNS OF INHERITANCE
Pattern	Parents affected	Gender affected	Transmission	Recurrence risk	Risk factors
Autosomal recessive	No (carriers)	Both equally	Disease seen in siblings of proband, not in parents or offspring Usually only in one generation	1 in 4	Consanguinity, isolated population (e.g. geographically, linguistically)
Autosomal dominant	Yes *	Both equally	Disease seen in successive generations	1 in 2	De novo mutations
X-linked recessive	Mother a “carrier” *	Males have the “complete” disease Female “carriers” may have mild manifestations (e.g. in a mosaic pattern) **	No male-to-male transmission (but all daughters of an affected male are “carriers”)	1 in 2 male children born to a female “carrier” will be affected (and 1 in 2 of her female children will be carriers)	De novo mutations
X-linked dominant	Yes *	Predominantly females if lethal in males during embryonic development; otherwise milder in females (often with a mosaic pattern of skin lesions) and more severe in males	Affected males have: (1) no affected sons; and (2) all daughters affected No male-to-male transmission	1 in 2 children born to affected female; may spontaneously abort male fetuses if “male-lethal” condition	De novo mutations

* Unless the proband has a de novo mutation and is therefore the first generation affected.

** Does not represent a “pure” X-linked recessive disorder if there are manifestations in female “carriers”.

This chapter focuses on genodermatoses, but the explanations of Mendelian and complex traits also apply to extracutaneous diseases.

Autosomal Dominant Inheritance

In a pedigree of an autosomal dominant disease, each affected person other than the first affected family member, who has a de novo mutation, has an affected parent. Both sexes are equally affected and can transmit the trait, and there is vertical transmission from generation to generation ( Fig. 54.1A ) . Since a single mutant allele is enough to produce the phenotype, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and therefore the disorder. Examples of autosomal dominant genodermatoses include EB simplex, Darier and Hailey–Hailey diseases, and nail–patella syndrome.

A patient with an autosomal dominant disease is usually heterozygous for the disease-causing mutation. Homozygosity for autosomal dominant traits occasionally occurs, and this usually results in a more severe phenotype. For example, a mutation in the keratin 14 gene ( KRT14 ) may give rise to localized EB simplex when heterozygous but generalized EB simplex when homozygous . Exceptions to the expected autosomal dominant inheritance pattern may also be due to incomplete penetrance or variable expression (see below).

Dominant mutations can give rise to a phenotype by: (1) haploinsufficiency, in which the protein produced from one wild-type (non-mutant) allele is not sufficient to sustain normal function; or (2) a dominant negative effect , where the mutated proteins physically interfere with wild-type proteins and prevent them from functioning properly. The latter mechanism often occurs when the mutated protein forms dimers or polymers; examples include keratins (e.g. KRT14 in EB simplex) and tyrosine kinase receptors (e.g. KIT in piebaldism).

Autosomal Recessive Inheritance

In a pedigree of an autosomal recessive disease, an affected individual has clinically unaffected parents, both sexes are equally affected, and there is no transmission from generation to generation ( Fig. 54.1B ). Both alleles of a given gene must be mutated for the disease to develop. When both parents are heterozygous carriers of a mutant allele, the chance of inheriting the disorder is 25% for each of their offspring. Oculocutaneous albinism type 1 and atrichia with papular lesions are examples of autosomal recessive genodermatoses.

There is often an increased frequency of consanguinity (sharing a common ancestor) in families with recessive conditions. Consanguineous matings (inbreeding) increase the probability that a mutated allele present in the common ancestor will become homozygous in the offspring (homozygosity by descent); these individuals are typically also homozygous for the region surrounding this mutated gene. When more than one affected family member with an autosomal recessive disease is present in a single pedigree, they are usually part of the same generation. However, the presence of consanguinity can also explain some pedigrees in which an autosomal recessive trait is observed in more than one generation. For example, matings between unaffected carriers and affected patients can give rise to affected family members in two consecutive generations (pseudo-dominant inheritance; see below).

Patients with an autosomal recessive disease have two mutant alleles (biallelic mutations), while both of their parents are typically heterozygous carriers of one mutant allele as well as having one wild-type allele. If both parents carry the same mutation, their affected offspring will be homozygous for the disease-causing mutation; this is the usual mechanism in consanguineous families. However, the parents may carry two different mutations in the same gene, and their affected offspring will be compound heterozygous .

X-Linked Recessive Inheritance

Patients with an X-linked recessive disease are typically male, and they classically have unaffected parents. However, in several X-linked “recessive” disorders, patients’ mothers have some clinical evidence of the condition due to functional mosaicism (see Ch. 62 ). These mosaic manifestations in female “carriers” blur the distinction between recessive and dominant forms of X-linked inheritance, thereby removing such conditions from the “pure” X-linked recessive category. With variable skewing of X-inactivation (see below), the spectrum of disease in female “carriers” can range from absent to severe.

There is no male-to-male transmission, since an affected male will transmit the Y chromosome and not the mutant X chromosome to his son, and the complete (non-mosaic) trait does not appear in successive generations ( Fig. 54.1C ). However, one rare exception is the offspring of an affected male and a female carrier.

The inheritance risk for the offspring depends on the parent transmitting the disease allele. An affected father will transmit the mutated allele (but not the complete disease) to all his daughters, but to none of his sons. Thus, his daughters become obligate carriers and will transmit the mutated allele to 50% of their children. As a result, the sons and daughters of a carrier mother will have a 50% chance of being affected or carriers, respectively.

Examples of recessive X-linked diseases in dermatology are X-linked recessive ichthyosis (steroid sulfatase deficiency; see Ch. 57 ), hypohidrotic ectodermal dysplasia, and congenital generalized hypertrichosis.

X-Linked Dominant Inheritance

In a pedigree of an X-linked dominant disease, affected individuals have an affected parent, with the exception of the first affected family member. Unless male-lethal, these disorders occur in both males and females. However, because females are heterozygous rather than hemizygous, they generally have a milder and/or mosaic phenotype (see below). There is no male-to-male transmission, and the trait appears in successive generations ( Fig. 54.1D ). The risk of the offspring inheriting the disease depends on the transmitting parent. An affected father will transmit the trait to all his daughters, but to none of his sons. An affected mother, on the other hand, will transmit the trait to 50% of her children, regardless of the sex of the offspring.

Some X-linked dominant diseases are lethal in males during early intrauterine development. In this situation, the disorder is seen almost exclusively in females, and when these women become pregnant they may have an increased frequency of spontaneous abortions. Occasional male patients can be explained by mosaicism, either functional in the setting of Klinefelter syndrome (47, XXY karyotype) or genomic due to mosaicism secondary to a de novo half-chromatid or postzygotic mutation (see Ch. 62 ).

Because female embryos undergo lyonization, i.e. the random epigenetic inactivation of one of the two X chromosomes in each cell, female patients with X-linked dominant skin diseases typically have a mosaic pattern of cutaneous lesions (see Ch. 62 ). Non-random patterns of X-inactivation in these patients may reflect preferential survival of cells expressing the normal X chromosome. Examples of X-linked dominant, male-lethal diseases in which girls present with a mosaic pattern of skin findings are focal dermal hypoplasia (Goltz syndrome) and incontinentia pigmenti .

Exceptions to Basic Mendelian Patterns of Heritance

Although the genotype at a single locus is responsible for the development of a Mendelian disease, other factors can affect the phenotypic manifestations and pattern of inheritance. Exceptions to basic Mendelian inheritance patterns are presented in Table 54.5 and Fig. 54.2 .

Table 54.5

Exceptions to basic mendelian inheritance patterns.

AD, autosomal dominant; AR, autosomal recessive, EB, epidermolysis bullosa; NF1, neurofibromatosis type 1; SNP, single nucleotide polymorphism; X-L, X-linked.

EXCEPTIONS TO BASIC MENDELIAN INHERITANCE PATTERNS
Type of exception	Impact on phenotype and inheritance	Examples in dermatology	Impact on genetic counseling
Variable expression	• Different degrees of phenotypic manifestation of a particular genotype, either between or within families • Genetic anticipation refers to the tendency of certain traits (primarily neuromuscular conditions) to increase in severity through successive generations	Broad ranges of severity in Darier disease and neurofibromatosis type 1	• Difficult to predict the severity of the phenotype
Incomplete/reduced penetrance	• Not all individuals with the disease genotype manifest with the condition • An AD trait may appear to skip a generation (see Fig. 54.2A )	Hereditary leiomyomatosis and renal cell cancer syndrome	• With incomplete penetrance, the phenotype may not correlate with the genotype
Age-dependent penetrance	• In late-onset diseases , some individuals are too young to exhibit manifestations	Late onset in Darier and Hailey–Hailey diseases	• Genetic testing may be needed to determine whether younger individuals are affected
X-inactivation (lyonization; see Ch. 62 ) *	• The phenotype of an X-L condition in a female patient depends on the proportion of cells expressing the mutant allele in a particular tissue • Skewed/non-random X-inactivation can result from negative selection against cells with an active mutant allele • X-L skin disorders typically have a mosaic distribution	Skewed X-inactivation favoring the wild-type allele in the skin of girls with incontinentia pigmenti and the hematopoietic cells of female carriers of X-L dyskeratosis congenita	• In general, X-L dominant traits are milder in females than in males, and female “carriers” of X-L “recessive” conditions can exhibit some symptoms
De novo mutations	• A de novo (new) mutation (e.g. during meiosis) can produce an AD disease in a child who has no family history of that condition • De novo mutations account for a higher proportion of affected individuals in AD diseases that are severe or otherwise decrease reproductive fitness	De novo mutations account for ~30–50% of patients with NF1 and >60% of those with tuberous sclerosis complex	• Future offspring of the unaffected parents of a child with an AD disease due to a de novo mutation are not at increased risk of the condition
Genomic mosaicism: somatic and gonadal (see Ch. 62 )	• Genomic mosaicism results from a postzygotic alteration in the DNA sequence that gives rise to a genetically heterogeneous organism • The timing of the mutational event and the cell type(s) affected influence the extent, distribution, and type of clinical findings • Although a postzygotic mutation in somatic cells is not transmitted to the offspring, a mosaic mutation affecting the gonads may transmit generalized disease to the offspring	Transmission via gonadal mosaicism has been documented in NF1, dominant dystrophic EB, and epidermolytic ichthyosis (± an epidermolytic epidermal nevus reflecting somatic mosaicism in the parent)	• The proportion of gonadal cells that carry the dominant mutation determines the risk for generalized disease in the offspring; affected children are born to clinically unaffected or mosaic parents in the first generation, with an AD inheritance pattern in subsequent generations
Type 1 and 2 mosaicism/ segmental manifestations in AD disorders (see Ch. 62 )	• Cutaneous mosaicism can result in skin changes following the lines of Blaschko or in other segmental patterns (e.g. a block-like distribution) • In type 1 mosaicism , segmental affected skin is heterozygous for a dominant mutation, with a wild-type, unaffected background • In type 2 mosaicism , the genetic background is heterozygous for a mutation that causes an AD disorder, and a postzygotic mutation in the other allele (“second hit” resulting in loss of heterozygosity; see below) leads to a segmental region of skin with two mutations and often more severe disease	Type 1: epidermal nevi, linear Darier disease Type 2: linear porokeratosis superimposed on disseminated superficial actinic porokeratosis, segmental Hailey–Hailey disease in the setting of milder classic symmetric disease	• In patients with type 1 segmental skin disease, the potential presence of gonadal (in addition to somatic) mosaicism may result in some risk for generalized disease in offspring • In type 2 segmental diseases, the “background” condition has an AD inheritance pattern, with a 50% chance of the mutant allele being transmitted to each offspring
Loss of heterozygosity in AD tumor predisposition syndromes	• Affected individuals have a constitutional heterozygous loss-of-function mutation in a tumor suppressor gene that is involved in the regulation of cell growth • These individuals are at high risk of tumor formation, which can result from a single somatic mutation (“second hit”) inactivating the second (normal) allele of the same gene; this process often involves loss of heterozygosity (LOH) resulting from deletion of the normal allele or gene conversion leading to two copies of the mutant allele	Skin tumors in hereditary leiomyomatosis and renal cell cancer and basal cell nevus (Gorlin) syndrome	• Affected individuals often develop multiple tumors
Revertant mosaicism ** (see Ch. 62 )	• A postzygotic mutation leads to partial or complete recovery of the wild-type phenotype in segment(s) of skin	Several types of EB, ichthyosis with confetti	• These somatic mutations are not transmitted to offspring
Consanguineous mating (inbreeding)	• In inbred populations, the probability that two carriers of a mutation originating from a common ancestor will mate and have a child with an AR disease is significantly higher than in the general population • Conversely, consanguinity is relatively common in families with AR diseases, especially when the mutant alleles are rare within the general population	A founder effect due to ancestors (Dutch settlers) carrying a recessive mutation explains the high incidence of porphyria variegate in Caucasian South Africans	• When analyzing a pedigree, the possibility of consanguinity/over-representation of recessive mutations should be considered, especially for individuals in geographically, linguistically, and/or socially isolated populations where the probability of mating with related individuals is higher
Quasidominant (pseudodominant) inheritance	• Inheritance of an AR trait can mimic an AD pattern when an individual with an AR disorder mates with a carrier of a recessive mutation in the same gene (see Fig. 54.2C ) • This parent-to-child transmission does not usually occur in successive generations	Consanguineous families with atrichia with papular lesions or pseudoxanthoma elasticum	• Mating between a homozygous affected individual and heterozygous carrier of an AR disorder produces a 50% risk of the disease in each offspring
Mitochondrial inheritance	• Inheritance of a mutation in the mitochondrial genome, with all ( homoplasmy ) or some ( heteroplasmy ) of the mitochondria affected • Only women can transmit the disease, but both male and female offspring may be affected • The phenotype depends on proportion of mutant versus normal mitochondria in a particular tissue	Mutation in the mitochondrial serine tRNA gene underlying palmoplantar keratoderma with or without associated sensorineural deafness	• Mitochondrial diseases have variable expression and incomplete penetrance
Phenocopy	• Clinical findings caused by environmental factors sometimes mimic the phenotype of a genetic disorder	A clinical presentation similar to porphyria cutanea tarda (PCT; an AD disorder) can result from exposure to certain hydrocarbons and pesticides	• Possible environmental as well as genetic etiologies for a condition should be considered
Imprinting and uniparental disomy (UPD)	• Imprinting is an epigenetic phenomenon in which the sex of the transmitting parent determines which allele of a given gene is expressed in the offspring (see Fig. 54.3A ) • UPD represents inheritance of both homologous chromosomes from one parent due to errors in meiosis, either as heterodisomy with two different homologs from the same parent or isodisomy with a duplicated chromosome	Prader–Willi and Angelman syndromes (see Fig. 54.3B ); uniparental isodisomy involving a recessive mutant allele has been reported in junctional EB, recessive dystrophic EB, and Harlequin ichthyosis	• Rare event with low risk for subsequent offspring • Prenatal screening can detect UPD by analysis of copy number variants and SNP/microsatellite markers