Clinicians at one time concerned themselves only with what they
could discover by bedside evaluation and laboratory investigation.
In the parlance of genetics, the patient's symptoms and
signs constitute his or her phenotype. Now
the means are at hand for defining a person's genotype, the actual information content
inscribed in the 2 m of coiled DNA present in each cell of the bodyor
half that amount in every mature ovum or sperm. Most phenotypic characteristicsand
this includes diseases as well as human traits such as personality,
adult height, and intelligenceare to some extent determined
by the genes. The importance of the genetic contribution varies
widely among human phenotypes, and methods are only now being developed
to identify the genes involved in complex traits and most common diseases.
Moreover, the importance of interactions between environment and
genotype in producing phenotypes cannot be overstated despite the
obscurity of the actual mechanisms.
The billions of nucleotides in the nucleus of a cell are organized
linearly along the DNA double helix in functional units called genes,
and each of the 20,00023,000 human genes is accompanied
by various regulatory elements that control when it is active in producing messenger
RNA (mRNA) by a process called transcription. In
most situations, mRNA is transported from the nucleus to the cytoplasm,
where its genetic information is translated into proteins,
which perform the functions that ultimately determine phenotype.
For example, proteins serve as enzymes that facilitate metabolism
and cell synthesis; as DNA binding elements that regulate transcription of
other genes; as structural elements of cells and the extracellular
matrix; and as receptor molecules for intracellular and intercellular
communication. DNA also encodes many small RNA molecules that serve
functions still being defined, including regulating gene transcription
and interfering with the translational capacity of some mRNAs.
Chromosomes are the vehicles in
which the genes are carried from generation to generation. Each
chromosome is a complex of protein and nucleic acid in which an
unbroken double helix of DNA is coiled and supercoiled into a space
many orders of magnitude less than the extended length of the DNA.
Within the chromosome there occur highly complicated and integrated
processes, including DNA replication, recombination, and transcription.
In the nucleus of each somatic cell, humans normally have 46 chromosomes,
which are arranged in 23 pairs. One of these pairs, the sex chromosomes X and Y, determines
the sex of the individual; females have the pair XX and males the
pair XY. The remaining 22 pairs are called autosomes (Figure
e21). In addition to these nuclear chromosomes, each
mitochondrionfound in varying numbers in the cytoplasm
of all cellscontains multiple copies of a small chromosome.
This mitochondrial chromosome encodes
a few of the proteins for oxidative metabolism and all of the transfer
RNAs used in translation of proteins within this organelle. Mitochondrial
chromosomes are inherited almost entirely from the cytoplasm of
the fertilized ovum and are therefore maternal in origin.
Normal karyotype of a human male. Prepared from cultured
amniotic cells and stained with Giemsa stain. About 400 bands are
detectable per haploid set of chromosomes.
In all somatic cells, the 44 autosomes and one of the X chromosomes
are transcriptionally active. In males, the active X is the only
X; portions of the Y chromosome are also active. In females, the
requirement for dosage compensation (to
be equivalent to the situation in males) is satisfied by inactivation
of most of one X chromosome early in embryogenesis. This process
of X chromosomal inactivation, although incompletely understood,
is known to be random, so that on average, in 50% of a
female's cells, one of the X chromosomes will be active,
and in the other 50% the homologous member
of the pair will be active. The phenotype of the cell is determined
by which genes on the chromosomes are active in producing mRNA at
any given time.
Transcriptional control is highly complex. Among other processes, an allele of some genes is prevented from transcribing mRNA through the process of imprinting. Imprinting occurs in the gamete, typically by adding a methyl group to cytosine nucleotides in the regulatory region of the allele. Methylation results in downregulation of the allele and is gamete-specific. Thus, the allele of some genes inherited from the father is permanently turned off, while the alleles of other genes inherited from the mother are similarly inhibited. Other processes can affect expression of specific alleles, including biochemical modification of certain histones. Most strikingly, these effects can persist across generations and be influenced by the environment. One example of the latter is the reduction in imprinting seen in times of famine, when methyl groups are deficient in the diet. This field of non-Mendelian inheritance is termed epigenetics.
In all genes, information is contained in parcels called exons, which are interspersed with
stretches of DNA called introns that
do not encode any information about the protein sequence. However,
introns may contain genetic regulatory sequences, and some introns
are so large that they encode an entirely distinct gene.
The exact location of a gene on a chromosome is its locus, and the array of loci constitutes
the human gene map. A variation of this map, identifying selected loci
known to be involved in human disease, is shown in Figure
e22. The difference in the higher resolution of the
ordering of genes achievable by molecular techniques (such as linkage analysis)
compared to cytogenetic techniques (such as visualization of small defects)
is substantial, though the gap is narrowing. The chromosomes in
the "standard" karyotype shown in Figure e21 have about 450 visible bands; under the best
of cytologic and microscopic conditions, a total of about 1600 bands
can be seen. But even in this extended configuration, each band
contains dozenssometimes hundredsof individual
genes. Thus, loss (deletion) of a
small band will involve loss of many coding sequences and will have
diverse effects on the phenotype. Routine cytogenetic techniques of visualizing chromosomes are largely being supplanted by array-based approaches.
A partial "morbid map" of the human
genome. Shown next to the ideogram of the human X and Y chromosomes
are representative mendelian disorders caused by mutations at that
locus. Over 460 phenotypes have been mapped to the X chromosome
and 8 to the Y chromosome.
(Courtesy of V. McKusick and J. Strayer.)
The number and arrangement of genes on homologous chromosomes
are identical even though the actual coding sequences of homologous
genes, or the number of copies of those genes, may not be. Homologous copies
of a gene are termed alleles. In comparing alleles,
it must be specified at what level of analysis the comparison is being
made. When alleles are truly identicalin that their coding
sequences and the number of copies are invariantthe individual
is homozygous at that locus. At a coarser level, the
alleles may be functionally identical despite subtle variations
in nucleotide sequencewith the result either that the
proteins produced from the two alleles are identical or that whatever differences
there may be in amino acid sequence will have no bearing on the
function of the protein. If the individual is being analyzed at
the level of the protein phenotype, allelic homozygosity would again
be an apt descriptor. However, if the analysis were at the level
of the DNAas occurs in nucleotide sequencingthen, despite functional identity,
the alleles would be viewed as different and the individual would
be heterozygous for that locus. Heterozygosity based
on differences in the protein products of alleles has been detectable
for decades and was the first hard evidence concerning the high degree
of human biologic variability. In the past decade, analysis of DNA
sequences has shown genetic variability to be much more commondifferences
in nucleotide sequence between individuals occur about once every
1100 nucleotides. Much longer sequences can also be present in varying number of copies, or they can be entirely deficient, often with no obvious effect on the phenotype. The identification of such copy number variants has been one of the most exciting and useful discoveries in human genetics in the past several years. Because of evolutionary selection against deleterious sequence
changes, DNA variation in coding regions of genes occurs once every
2000 nucleotides, and less than half of those variants cause a change
in an amino acid. However, the level of sequence variation among humans,
regardless of their ethnic origins, is much less common (3- to 10-fold)
than in our primate ancestors.
|Feero WG et al. Genomic medicinean updated primer. N Engl J Med. 2010 May 27;362(21):2001–11. [PMID: 20505179]|
|Rimoin DL et al (editors). Emery and Rimoin's Principles and Practice of Medical Genetics, 6th ed. Churchill Livingstone, 2012.|
|Zhang J et al. The impact of next-generation sequencing on genomics. J Genet Genomics. 2011 Mar 20;38(3):95–109. [PMID: 21477781]|
Allelic heterozygosity most often results when different alleles
are inherited from the egg and the sperm, but it also occurs as
a consequence of spontaneous alteration in nucleotide sequence (mutation). Genetic change occurring
during formation of an egg or a sperm is called a germinal mutation. When the change
occurs after conceptionfrom the earliest stages of embryogenesis
to dividing cells in the body of the oldest adultit is
termed a somatic mutation. As is discussed
below, the role of somatic mutation in the etiology of human disease
is now increasingly recognized.
The coarsest type of mutation is alteration in the number or
physical structure of chromosomes. For example, nondisjunction (failure
of chromosome pairs to separate) during meiosisthe
reduction division that leads to production of mature ova and spermscauses
the embryo to have too many or too few chromosomes, a situation
called aneuploidy. Rearrangement of
chromosome arms, such as occurs in translocation or inversion, is a mutation even if breakage
and reunion do not disrupt any coding sequence. Thus, the phenotypic
effect of gross chromosomal mutations can range from profound (as
in aneuploidy) to nil.
A bit less coarse, but still detectable cytologically, are deletions of part of a chromosome.
Such mutations almost always alter phenotype, because a number of
genes are lost; however, a deletion may involve only a single nucleotide,
whereas about 12 million nucleotides (12 megabases)
must be lost before the defect can be visualized by the most sensitive
cytogenetic methods short of in situ hybridization or array analysis. Deletions and duplications of substantial regions of nucleotide sequence are remarkably common among humans. Many are apparently harmless and are passed from parent to child in an autosomal dominant pattern of inheritance. Others involve one or more genes that can have subtle or profound clinical consequences. The latter are often de novo, meaning that neither parent has the copy number variation, which must have arisen during meiosis of one of the gametes.
Mutations of one or a few nucleotides in exons have several potential
consequences. Changes in one nucleotide can alter which amino acid
is encoded; if the amino acid is in a critical region of the protein,
function might in this way be severely disturbed (eg, sickle cell
disease). On the other hand, some amino acid substitutions have
no detectable effect on function, and the phenotype is therefore
unaltered by the mutation. Similarly, because the genetic code is degenerate (two or more different three-nucleotide
sequences called codons encode the
same amino acids), nucleotide substitution does not necessarily
alter the amino acid sequence of the protein. Three specific codons
signal termination of translation; thus, a nucleotide substitution
in an exon that generates one of the stop codons usually causes a
truncated protein, which is nearly always dysfunctional. Other nucleotide
substitutions can disrupt the signals that direct splicing of the
mRNA molecule and grossly alter the protein product. Finally, insertions
and deletions of one or more nucleotides can have dramatic effectsany
change that is not a multiple of three nucleotides disrupts the
reading frame of the remainder of the exonor potentially
minimal effects (if the protein can tolerate the insertion or loss
of an amino acid).
Mutations in introns may disrupt mRNA splicing signals or regulatory elements, or may
be entirely silent with respect to the phenotype. A great deal of
variation in nucleotide sequences among individuals (averaging one
difference every few hundred nucleotides) resides within introns.
Mutations in the DNA between adjacent genes may also be silent or
may have a profound effect on phenotype if regulatory sequences
are disrupted; these regulatory sequences may affect genes that are millions of bases away, presumably because of the intricate folding of the DNA molecule within chromatin.
A novel mechanism for mutation, which also helps
explain clinical variation among relatives, has been discovered
in myotonic dystrophy, Huntington disease, fragile X mental retardation
syndrome, Friedreich ataxia, and other disorders. A region of repeated trinucleotide sequences close to or within a gene can be unstable in some families; expansion of the number of repeated units within this segment beyond a critical threshold is associated with disease, either by downregulation of that allele or the production of a defective protein. The longer the trinucleotide repeat, the more severe the phenotype, a phenomenon termed anticipation, because the condition worsens from one generation to the next.
Mutations may occur spontaneously or may be induced by environmental
factors such as radiation, medication, or viral infections. Both
advanced maternal and paternal age favor mutation, but of different
types. In women, meiosis is completed only when an egg ovulates,
and chromosomal nondisjunction is increasingly common as the egg
becomes older. The risk that an aneuploid egg will result increases
exponentially and becomes a major clinical concern for women older
than their early 30s. In men, mutations of a subtler sortaffecting
nucleotide sequencesincrease with age. Offspring of men
over age 40 years are at an increased risk for having mendelian conditions,
primarily autosomal dominant ones.
|Alkan C et al. Personalized copy number and segmental duplication maps using next-generation sequencing. Nat Genet. 2009 Oct;41(10):1061–7.
|Barsh G. Genetic disease. In: Pathophysiology
of Disease: An Introduction to Clinical Medicine, 6th ed. McPhee
SJ et al (editors). McGraw-Hill, 2010.|
|Buchanan JA et al. Contemplating effects of genomic structural variation.
Genet Med. 2008 Sep;10(9):63947.
|Klopocki E et al. Copy-number variations, noncoding sequences, and human phenotypes. Annu Rev Genomics Hum Genet. 2011 Sep 22;12:53–72. [PMID: 21756107]|
|Miller DT et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010 May 14;86(5):749–64.
Genes in Individuals
For some quantitative traits such as adult height or serum glucose
concentration in normal individuals, it is difficult to
distinguish the contributions of individual genes; this is because
in general, phenotypes are the products of multiple genes acting in
concert, and obviously influenced by the environment and chance. However, if one of the genes in the system is aberrant,
a major departure from the "normal" or expected
phenotype might arise. Whether the aberrant phenotype is serious
(ie, a disease) or even recognized depends on the nature of the
defective gene product and how resilient the system is to disruption.
The latter point emphasizes the importance of homeostasis in both
physiology and developmentmany mutations go unrecognized
because the system can cope, even though tolerances for further
perturbation might be narrowed.
In other words, most human characteristics and common diseases
are polygenic, whereas many of the disordered phenotypes
traditionally thought of as "genetic" are monogenic but
still influenced by other loci in a person's genome.
Phenotypes due to alterations at a single gene are also characterized
as mendelian, after Gregor Mendel,
the monk and part-time biologist who studied the reproducibility
and recurrence of variation in garden peas. He showed that some
traits were dominant to other traits,
which he called recessive. The dominant
traits required only one copy of a "factor" to
be expressed, regardless of what the other copy was, whereas the
recessive traits required two copies before expression occurred.
In modern terms, the mendelian factors are genes, and the alternative
copies of the gene are alleles. Let A be
the common (normal) allele and let a be
a mutant allele at a locus: If the same phenotype is present whether
the genotype is A/a or a/a, the phenotype is dominant, whereas
if the phenotype is present only when the genotype is a/a,
it is recessive.
In medicine, it is important to keep two considerations in mind:
First, dominance and recessiveness are attributes of the phenotype,
not the gene; and second, the concepts of dominance and recessiveness
depend on how the phenotype is defined. To illustrate both points,
consider sickle cell disease. This condition occurs when a person
inherits two alleles for S-globin, in
which the normal glutamate at position 6 of the protein has been
replaced by valine; the genotype for the -globin
locus is HbS/HbS, compared to the normal HbA/HbA.
When the genotype is HbS/HbA, the individual does not have sickle
cell disease, so this condition satisfies the criteria for being
a recessive phenotype. But now consider the phenotype of sickled
erythrocytes. Red cells with the genotype HbS/HbS clearly sicklebut, if
the oxygen tension is reduced, so do cells with the genotype HbS/HbA.
Therefore, sickling is a dominant trait.
A mendelian phenotype is characterized not only in terms of dominance
and recessiveness but also according to whether the determining
gene is on the X chromosome or on one of the 22 pairs of autosomes.
Traits or diseases are therefore called autosomal dominant, autosomal
recessive, X-linked recessive, and X-linked dominant.
Genes in Families
Since the first decade of the twentieth century, the patterns
of recurrence of specific human phenotypes have been explained in
terms of principles first described by Mendel in the garden pea
plant. Mendel's second principleusually referred
to as his first1is called the law
of segregation and states that a pair of factors (alleles)
that determines some trait separates (segregates) during formation
of gametes. In simple terms, a heterozygous (A/a) person will produce two types of
gametes with respect to this locusone containing only A and one containing only a, in equal proportions. Offspring
of this person will have a 5050 chance of inheriting the A allele and a similar chance of inheriting
the a allele.
first law stated thatfrom the perspective of the phenotypeit
mattered not from which parent a particular mutant allele was inherited.
For years this principle was thought to be too obvious to be codified
as anybody's "law" and was therefore
ignored. In fact, however, recent evidence from studies of human
disorders suggests that certain genes are "processed" (imprinted) as they move through the
gonad and that processing in the testis is different from that in
the ovary. Thus, not only is this first mendelian principle important,
it was incorrect as originally formulated from observations in peas.
The concepts of genes in individuals and in families can be combined
to specify how mendelian traits will be inherited.
The characteristics of autosomal dominant inheritance in humans
can be summarized as follows: (1) A horizontal pattern occurs in
the pedigree, with multiple generations affected (Figure e23).
(2) Heterozygotes for the mutant allele show an abnormal phenotype.
(3) Males and females are affected with equal frequency and severity.
(4) Only one parent must be affected for an offspring to be at risk
for developing the phenotype. (5) When an affected person mates
with an unaffected one, each offspring has a 50% chance
of inheriting the affected phenotype. This is true regardless of
the sex of the affected parentspecifically, male-to-male
transmission occurs. (6) The frequency of sporadic cases is positively
associated with the severity of the phenotype. More precisely, the
greater the reproductive fitness of
affected persons, the less likely it is that any given case resulted
from a new mutation. (7) The average age of fathers is advanced
for isolated (sporadic or new mutation) cases.
A pedigree illustrating autosomal dominant inheritance.
Square symbols indicate males and circles females; open symbols
indicate that the person is phenotypically unaffected, and filled
symbols indicate that the phenotype is present to some extent.
Autosomal dominant phenotypes are often age-dependent, less severe
than autosomal recessive ones, and associated with malformations
or other physical features. They are pleiotropic in
that multiple, even seemingly unrelated clinical manifestations
derive from the same mutation, and variable in that
expression of the same mutation among people will differ.
Penetrance is a concept associated
with mendelian conditionsespecially dominant onesand
the term is often misused. It should be defined as an expression
of the frequency of appearance of a phenotype (dominant or recessive)
when one or more mutant alleles are present. For individuals, penetrance is
an all-or-none phenomenonthe phenotype is either present
(penetrant) or not (nonpenetrant). The term variabilitynot "incomplete
penetrance"should be used to denote differences
in expression of an allele.
The most frequent cause of apparent nonpenetrance is insensitivity
of the methods for detecting the phenotype. If an apparently normal
parent of a child with a dominant condition was in fact heterozygous
for the mutation, the parent would have a 50% chance at
each subsequent conception of having another affected child. A common
cause of nonpenetrance in adult-onset mendelian diseases is death
of the affected person before the phenotype becomes evident but
after transmission of the mutant allele to offspring. Thus, accurate
genetic counseling demands careful attention to the family medical
history and high-resolution scrutiny of both parents of a child
with a condition known to be a mendelian dominant trait.
When both alleles are expressed in the heterozygote, as in blood
group AB, in sickle trait (HbS/HbA), in the major histocompatibility
antigens (eg, A2B5/A3B17), or in sickle-C disease (HbS/HbC), the
phenotype is called codominant.
In human dominant phenotypes, the mutant allele in homozygotes
is almost always more severe than in heterozygotes.
The characteristics of autosomal recessive inheritance in humans
can be summarized as follows: (1) A horizontal pattern occurs in
the pedigree, with a single generation affected (Figure e24).
(2) Males and females are affected with equal frequency and severity.
(3) Inheritance is from both parents, each a heterozygote (carrier)
and each usually clinically unaffected.
(4) Each offspring of two carriers has a 25% chance of
being affected, a 50% chance of being a carrier, and a
25% chance of inheriting neither mutant allele. Thus, two-thirds
of all clinically unaffected offspring are carriers. (5) In matings
between individuals, each with the same recessive phenotype, all
offspring will be affected. (6) Affected individuals who mate with
unaffected individuals who are not carriers have only unaffected
offspring. (7) The rarer the recessive phenotype, the more likely
it is that the parents are consanguineous (related).
A pedigree illustrating autosomal recessive inheritance.
(Symbols as in Figure e23.)
Autosomal recessive phenotypes are often associated with deficient
activity of enzymes and are thus termed inborn errors of metabolism.
Such disorders include phenylketonuria, Tay-Sachs disease, and the
various glycogen storage diseases and tend to be more severe, less
variable, and less age-dependent than dominant conditions.
When an autosomal recessive condition is quite rare, the chance
that the parents of affected offspring are consanguineous is increased.
As a result, the prevalence of rare recessive conditions is high among
inbred groups such as the Old Order Amish. On the other hand, when
the autosomal recessive condition is common, the chance of consanguinity between
parents of cases is no higher than in the general population (about
Two different mutant alleles at
the same locus, as in HbS/HbC, form a genetic
compound (compound heterozygote). The
phenotype usually lies between those produced by either allele present
in the homozygous state. Because of the large number of mutations
possible in a given gene, many autosomal recessive phenotypes are
probably due to genetic compounds. Sickle cell disease is an exception. Consanguinity
is strong presumptive evidence for true homozygosity of mutant alleles
and against a genetic compound.
The general characteristics of X-linked inheritance in humans
can be summarized as follows: (1) There is no male-to-male transmission
of the phenotype (Figure e25). (2) Unaffected
males do not transmit the phenotype. (3) All of the daughters of an affected male are heterozygous carriers. (4) Males
are usually more severely affected than females. (5) Whether a heterozygous
female is counted as affectedand whether the phenotype
is called "recessive" or "dominant"depends often
on the sensitivity of the assay or examination. (6) Some mothers
of affected males will not themselves be heterozygotes (ie, they
will be homozygous normal) but will have a germinal mutation. The
proportion of heterozygous (carrier) mothers is negatively associated
with the severity of the condition. (7) Heterozygous women transmit
the mutant gene to 50% of their sons, who are affected,
and to 50% of their daughters, who are heterozygotes. (8)
If an affected male mates with a heterozygous female, 50% of
the male offspring will be affected, giving the false impression
of male-to-male transmission. Of the female offspring of such matings, 50% will
be affected as severely as the average hemizygous male; in small
pedigrees, this pattern may simulate autosomal dominant inheritance.
A pedigree illustrating X-linked inheritance. (Symbols
as in Figure e23.)
The characteristics of X-linked inheritance depend on phenotypic
severity. For some disorders, affected males do not survive to reproduce.
In such cases, about two-thirds of affected males have a carrier
mother; in the remaining third, the disorder arises by new germinal
mutation in an X chromosome of the mother. When the disorder is
nearly always manifest in heterozygous females (X-linked dominant
inheritance), females tend to be affected about twice as often as
males; and on average an affected female transmits the phenotype
to 50% of her sons and 50% of her daughters.
X-linked phenotypes are often clinically variableparticularly
in heterozygous femalesand suspected of being autosomal
dominant with nonpenetrance. For example, Fabry disease
(-galactosidase A deficiency) may be clinically
silent in carrier women or may cause stroke, renal failure, or myocardial
infarction by middle age.
Germinal mosaicism occurs in mothers of boys with X-linked conditions.
The chance of such a mother having a second affected son or a heterozygous
daughter depends on the fraction of her oocytes that carries the
mutation. Currently, this fraction is impossible to determine. However,
the presence of germinal mosaicism can be detected in some conditions
(eg, Duchenne muscular dystrophy) in a family by analysis
of DNA, and this knowledge becomes crucial for genetic counseling.
Mutations in the genes encoded by the mitochondrial chromosome
cause a variety of diseases that affect (in particular) organs highly
dependent on oxidative metabolism, such as the retina, brain, kidneys,
and heart. Because a person's mitochondria derive almost
entirely from the ovum, the inheritance pattern is distinct from
that of mendelian disorders and is termed "maternal" or,
more appropriately, "mitochondrial." An affected
woman can pass the defective mitochondrial chromosome to all of her
offspring, whereas an affected man has little risk of passing his
mutation to a child (Figure e26). Because each
cell and the ovum contain many mitochondria and because each mitochondrion
contains many chromosomes, two situations are possible: If every
chromosome in every mitochondrion carries the same mutation, the
person is said to be homoplasmic for
the mutation. On the other hand, if only some of the mitochondrial
chromosomes carry the mutation, the person is heteroplasmic. In
the latter case, an offspring may inherit relatively few mitochondria
bearing the mutation and have mild disease or no disease.
Mitochondrial ("maternal") inheritance.
A mitochondrial genetic mutation, indicated by darkened symbols,
is passed by the female (circle) to all of her offspring, including
males (squares). Of subsequent offspring, males do not transmit
the mutation, but females continue to transmit the mutation to all
of their offspring because mitochondria are passed through ova,
not sperm. For simplicity, although both parents are shown for the
first generation, subsequent generations do not show the genetic
partners, who are assumed to lack the mutation. Note: All or only
some of the mitochondria may carry the mutation, a variable that
affects the clinical expression of the mutation. (See text regarding
homoplasmic and heteroplasmic individuals.)
Over 16,000 human genes have been identified or implied through
their phenotypes and inheritance patterns in families. This total
represents 6070% of all genes thought to be encoded
by the 22 autosomes, two sex chromosomes, and the mitochondrial
chromosome. Victor McKusick and colleagues began an international
effort to catalogue human mendelian variation. This persists as Online Mendelian Inheritance in Man (OMIM).
|Greaves LC et al. Mitochondrial DNA and disease. J Pathol. 2012 Jan;226(2):274–86. [PMID: 21989606]|
|Online Mendelian Inheritance in Man, OMIM™®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). http://omim.org|
|Wallace DE et al. Mitochondrial genes in degenerative diseases, cancer and aging. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th ed. Rimoin DL et al (editors). Churchill Livingstone, 2012.|
Many disorders cluster in families but are not associated with
evident chromosomal aberrations or mendelian inheritance patterns.
Examples include congenital malformations such as cleft lip, pyloric stenosis,
and spina bifida; coronary artery disease; type 2 diabetes mellitus;
and various forms of neoplasia. They are often characterized by
varying frequencies in different racial or ethnic groups, disparity
in sexual predilection, and greater frequency (but less than full
concordance) in monozygotic than in dizygotic twins. This inheritance
pattern is called "multifactorial" to signify
that multiple genes interact with various environmental agents to
produce the phenotype. The familial clustering is assumed to be
due to sharing of both alleles and environment.
For most multifactorial conditions, there is little understanding
of which particular genes are involved, how they and their products
interact, and in what way different nongenetic factors contribute
to the phenotype. For some disorders, biochemical and genetic studies
have identified mendelian conditions within the coarse phenotype: Defects
of the low-density lipoprotein receptor account for a small fraction
of cases of ischemic heart disease (a larger fraction if only patients
under age 50 years are considered); familial polyposis of the colon
predisposes to adenocarcinoma; and some patients with emphysema
have inherited deficiency of 1-proteinase
(1-antitrypsin) inhibitor. Despite these
notable examples, this reductionistic preoccupation with mendelian
phenotypes is unlikely to explain the great majority of human disease;
but even so, in the last analysis, much of human pathology will
prove to be associated with genetic factors in cause, pathogenesis,
Our ignorance about fundamental genetic mechanisms in development
and physiology has not completely restricted practical approaches
to the genetics of multifactorial disorders. For example, recurrence
risks are based on empiric data derived from observation of many
families. The risk of recurrence of multifactorial disorders is increased
in several instances: (1) in close relatives (siblings, offspring,
and parents) of an affected individual; (2) when two or more members
of a family have the same condition; (3) when the first case in
a family is in the less commonly affected sex (eg, pyloric stenosis
is five times more common in boys; an affected woman has a threefold to
fourfold greater risk of having a child with pyloric stenosis);
and (4) in ethnic groups in which there is a high incidence of a
particular condition (eg, spina bifida is 40 times more common in
whitesand even more frequent among the Irishthan
For many apparently multifactorial disorders, too few families
have been examined to have established empiric risk data. A useful
approximation of recurrence risk in close relatives is the square
root of the incidence. For example, many common congenital malformations
have an incidence of 1:2500 to 1:400 live births; the calculated recurrence
risks are thus in the 25% rangevalues
that correspond closely to experience.
Much effort has been directed at identifying the genetic contributors to multifactorial disease. Genome-wide association studies (GWAS) have included large cohorts of patients with a given disease. These patients have hundreds of thousands or a million single nucleotide polymorphisms that are documented and compared with a similarly large and ethnically age-matched cohort of individuals with no evidence of the disease. In this way, hundreds of common disorders have been associated with even more specific markers in the human genome. Despite these impressive results, the reality is that a given nucleotide change only alters the relative risk for a given disease slightly (eg, relative risk 1.21.4) with very few exceptions. More importantly, very few of the nucleotide polymorphisms occur within genes, or if they do, they do not alter the function of the gene in any discernable way. Thus, much work remains to define the genetic contributors to common diseases, and the family history remains an important clinical tool in predicting risk.
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Any deviation from the structure and number of chromosomes as
displayed in Figure e21 is, technically, a chromosomal
aberration. Not all aberrations cause problems in the affected individual,
but some that do not may lead to problems in offspring. About 1:200
live-born infants has a chromosomal aberration that is detected
because of some effect on phenotype. This frequency increases markedly
the earlier in fetal life the chromosomes are examined. By the end
of the first trimester of gestation, most fetuses with abnormal
numbers of chromosomes have been lost through spontaneous abortion.
For example, Turner syndromedue to the absence
of one sex chromosome and the presence of a single X chromosomeis
a relatively common condition, but it is estimated that only 2% of
fetuses with this form of aneuploidy survive to term. Even more
striking in live-born children is the complete absence of most autosomal
trisomies and monosomies despite their frequent occurrence in young
Types of Chromosomal
Major structural changes occur in either balanced or unbalanced form. In the latter, there
is a gain or loss of genetic material; in the former, there is no change
in the amount of genetic material but only a rearrangement of it.
At the sites of breaks and new attachments of chromosome fragments,
there may be permanent structural or functional damage to one gene
or to only a few genes. Despite no visible loss of material, the
aberration may nonetheless be recognized as unbalanced through an
abnormal phenotype and the chromosomal defect confirmed by molecular
analysis of the DNA.
Aneuploidy results from nondisjunctionthe
failure of a chromatid pair to separate in a dividing cell. Nondisjunction
in either the first or second division of meiosis results in gametes
with abnormal chromosomal constitutions. In aneuploidy, more or
fewer than 46 chromosomes are present (Table e21).
The following are all forms of aneuploidy: (1) monosomy,
in which only one member of a pair of chromosomes is present; (2) trisomy, in which three chromosomes
are present instead of two; and (3) polysomy,
in which one chromosome is represented four or more times.
If nondisjunction occurs in mitosis, mosaic patterns
occur in somatic tissue, with some cells having one karyotype and
other cells of the same organism another karyotype. Patients with
a mosaic genetic constitution often have manifestations of each
of the genetic syndromes associated with the various abnormal karyotypes.
Translocation results from an exchange
of parts of two chromosomes.
Deletion is loss of chromosomal
Duplication is the presence of
two or more copies of the same region of a given chromosome. The redundancy
may occur in the same chromosome or in a nonhomologous chromosome.
In the latter case, a translocation will also have occurred.
An isochromosome is a chromosome
in which the arms on either side of the centromere have the same
genetic material in the same orderie, the chromosome has
at some time divided in such a way that it has a double dose of
one arm and absence of the other.
In an inversion, a chromosomal
region becomes reoriented 180 degrees out of the ordinary phase.
The same genetic material is present, but in a different order.
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