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Medical Genetics
Instructor: Prof. Dr. Fadel A. Sharif
Contact

Medical Laboratory Sciences

University Clinic-Genetics Diagnosis lab

[email protected]
Course Syllabus
- Text: Thompson & Thompson Genetics in Medicine, 7th Ed.,
Nussbaum, McInnes, Willard, 2007. Saunders (Required)
-- References: Emery’s Elements of Medical Genetics, 13 Ed.,
Turnpenny & Ellard. 2007. Churchill Livingstone
-- Jorde, Carey, Bamshad. Medical Genetics, 4th edition. Mosby
Elsevier, 2010.
Grades
Quizzes: 10%
Presentation: 10%
One Midterm exam worth 30%
Final exam: 50%
Topics
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Patterns of Single-Gene Inheritance
Genetics of Common Disorders with Complex
Inheritance
Principles of (Clinical) Cytogenetics
Clinical Cytogenetics: Disorders of the Autosomes
and the Sex Chromosomes
Genetic Variation in Individuals and Populations:
Mutation and Polymorphism
Human Gene Mapping and Disease Gene
Identification
Treatment of Genetic Disease
Cancer Genetics
Lecture 1
Patterns of Single-Gene
Inheritance

Occur on average in fixed proportions among
the offspring of specific types of matings
 The 2015 online version of Mendelian
Inheritance in Man (OMIM) lists 3,341 genes
with phenotype-causing mutation.

Primarily disorders of the pediatric age range;
less than 10% manifest after puberty, and only
1% occur after the end of the reproductive
period
 In a study of more than 1 million live births, the
incidence of serious single-gene disorders was
estimated to be 0.36%; among hospitalized
children, ~6% to 8%

A survey of OMIM for mendelian forms of 17 of the
most common adult diseases, such as heart disease,
stroke, cancer, and diabetes, revealed nearly 200
mendelian disorders whose phenotypes included these
common adult illnesses.
 These mendelian forms are important in individual
patients because of their significance for the health of
other family members and because of the availability
of genetic testing and detailed management options
for many of them.
OVERVIEW AND CONCEPTS
Variation in genes:

For many genes, there is a single prevailing allele,
the wild-type or common allele. The other versions
of the gene are variant or mutant alleles
 A given set of alleles at a locus or cluster of loci on
a chromosome is referred to as a haplotype.
 If there are at least two relatively common alleles at
the locus in the population, the locus is said to
exhibit polymorphism
Genotype and Phenotype

Genotype: set of alleles that make genetic
constitution
 Phenotype: observable expression of a
genotype as morphological, clinical, cellular,
biochemical trait
 Pleiotropy: a single abnormal gene or gene
pair producing multiple diverse phenotypic
effects

Compound heterozygous: two different
mutant alleles of the same gene
 Hemizygous: male with respect to X-linked
genes.
Pedigrees


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

Single-gene disorders are characterized by their
patterns of transmission in families
Pedigree: graphical representation of family tree
using standard symbols
The extended family depicted in such a pedigree is a
kindred
Proband (propositus, index case): affected member
through whom a family with genetic disease is
brought to attention
Consultand: who brings family to attention by
consulting a geneticist. May be an affected
individual or unaffected relative of proband
Figure 7-1 Symbols
commonly used in
pedigree charts. Although
there is no uniform system
of pedigree notation, the
symbols used here are
according to recent
recommendations made by
professionals in the field of
genetic counseling.
The proband, III-5, represents an isolated case of a genetic disorder. She has
four siblings. Her partner/spouse is III-6, and they have three children. The
proband has nine first-degree relatives, nine second-degree relatives, two
third-degree relatives (first cousins), and four fourth-degree relatives (first
cousins once removed). IV-3, IV-5, and IV-6 are second cousins of IV-1 and
IV-2. IV-7 and IV-8, whose parents are consanguineous, are doubly related to
the proband.

Consanguineous: couples who have one or more
ancestors in common
 Isolated case: only one affected member in a
family
 Sporadic case: if due to new mutation
 Fitness: a measure of impact of condition on
reproduction. Defined as: number of offspring
(who survive to reproductive age) affected
individuals can have, as compared to an
appropriate control
 Patterns of single-gene inheritance: autosomal
recessive/dominant, X-inked recessive/dominant
Dominant and Recessive Inheritance

Recessive: a phenotype expressed only in
homozygotes (for X-linked, male
hemizygotes) and not in heterozygotes
 Most recessive disorders are due to
mutations that reduce or eliminate function
of a gene (i.e., loss-of-function mutations)

Dominant: a phenotype expressed in both
homozygotes and heterozygotes for a mutant
allele.
 Pure dominant disease: homozygotes and
heterozygotes for mutant allele are equally
affected. Pure dominant disorders rarely if ever
exist in medical genetics
 Codominant: phenotypic expression of two
different alleles for a locus
 Dominant disorders are usually more severe in
homozygotes. Thus in heterozygotes, disease is
incompletely dominant (or semidominant).
Factors affecting pedigree patterns
Penetrance and expressivity

Some disorders are not expressed at all in an
individual despite having same genotype that
causes disorder in others in his family.
 In others, same disorder may have extremely
variable expression in terms of clinical
severity/range of symptoms/onset age
 Phenotypic expression can be modified by effects
of aging/other genetic loci (modifier loci)/effects
of environment/ allelic heterogeneity

Penetrance: probability that a gene will
have any phenotypic expression at all. It is
the percentage of people with a
predisposing genotype who are actually
affected.
 When some completely fail to produce
phenotype, the gene is said to show reduced
penetrance.

Expressivity: severity of expression of
phenotype among individuals with same
disease causing genotype.
 When severity differs, phenotype is said to
have variable expressivity
Neurofibromatosis-I (NF1)

A common AD disorder of the NS,
eye, and skin (1/3500 births)
 Characterized by:
– Growth of multiple benign fleshy tumors
–
–
–
–
(neurofibromas) in skin
Multiple flat, irregular pigmented skin
lesions (café au lait spots)
Small benign tumors (hamartomas) called
Lisch nodules on iris of the eye
Less frequently: MR, CNS tumors,
diffuse plexiform neurofibromas, and
development of cancer of the NS and
muscle.
Thus, the condition has a pleiotropic
phenotype.
NF1

Adult heterozygotes almost always show
some sign (i.e., penetrance is 100% in
adults)
 Some may have café au lait spots, freckles
on axillary skin, and Lisch nodules, others
may have life-threatening benign tumors in
spinal cord or malignant sarcomas of an
extremity (i.e., variable expressivity)
Neurofibromatosis-1: café au lait spots, hyperpigmented
spots on the skin, are a useful diagnostic sign in family
members who otherwise may appear unaffected. Most
patients have six or more spots at least 15 mm in diameter,
usually on the trunk.
 Diagnosis of NF1 is further complicated in children
because the signs develop gradually during childhood.
– e.g., in the newborn period, less than half of all affected
newborns show even the most subtle sign of the disease, an
increased incidence of café au lait spots.
– Penetrance, therefore, is age dependent.
 Many different mutations have been found in the NF1
gene, all of which appear to cause loss of function of its
gene product, neurofibromin. Approximately half the
cases of NF1 result from a new rather than an inherited
mutation

The chief genetic problem in counseling families
of patients with NF1 is to decide between two
possibilities: Is the disease in the proband
sporadic, that is, due to new mutation, or has the
patient inherited a clinically significant form of
the disorder from a parent in whom the gene is
present but only mildly expressed?
 If the proband has inherited the defect, the risk
that any of his or her sibs will also inherit it is
50%;
 but if the proband has a new mutant gene, there is
very little risk that any sib will be affected.

The disorder can be detected presymptomatically
and even prenatally by molecular genetic analysis.
 Unfortunately, molecular testing can generally
only answer whether the condition will occur and
not how severe it will be.
 Except for the association of complete gene
deletions with dysmorphic features, mental
retardation, and increased number of
neurofibromas at an early age, there is no
correlation between severity of the phenotype and
particular mutant NF1 alleles.
Figure 7-4 Pedigree of family with NF-1, apparently originating as a new
mutation in the proband of generation III (arrow). This individual appears
to have a new mutant allele of NF1 because his parents and their
parents are all unaffected.
Split-hand deformity

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Another example of an autosomal dominant
malformation with reduced penetrance is the splithand deformity, a type of ectrodactyly.
The malformation originates in the sixth or seventh
week of development, when the hands and feet are
forming.
The disorder demonstrates locus heterogeneity, with at
least five loci recognized, although the actual gene
responsible has been identified in only a few.
Failure of penetrance in pedigrees of split-hand
malformation can lead to apparent skipping of
generations, and this complicates genetic counseling
because an at-risk person with normal hands may
nevertheless carry the gene for the condition and thus
be capable of having children who are affected.
Figure 7-5 Split-hand deformity, an AD trait involving the
hands and feet, in a 3-month-old boy. A, Upper part of
body. B, Lower part of body.
In the pedigree, the consultand’s mother is a
nonpenetrant carrier of the split-hand mutation.
 Review of the literature on split-hand deformity
suggests that there is reduced penetrance of about
70%.

Figure 7-6 Pedigree of split-hand deformity demonstrating failure
of penetrance in the mother of the consultand. Reduced
penetrance must be taken into account in genetic counseling.
Age of Onset

Genetic disorders can appear at any time in the
lifetime of an individual, ranging from early in
intrauterine development all the way to the
postreproductive years, and all ages in between.
 Some may be lethal prenatally, whereas others
may interfere with normal fetal development
and can be recognized prenatally (e.g., by
ultrasonography) but are consistent with a fulllive-born infant;

Still others may be recognized only at birth
(congenital). Thus, in a pedigree of a family with a
lethal disorder affecting a fetus early in pregnancy, the
pattern of disease occurrence may be obscure because
all that one observes are multiple miscarriages and
fetal losses or apparently reduced fertility, rather than
recurrence of the prenatal disease itself.
 Conversely, in a family with a late-onset dominant
disorder, an affected individual may have parents and
children reportedly free of disease because the carrier
parent died of unrelated causes before the disease
could develop, and the children at risk have not
reached the age at which the mutant gene reveals itself
in a disease phenotype.
Other Factors Affecting Pedigree Patterns

The inheritance pattern of an individual
pedigree may be obscured by a number of
other factors that may make the mode of
inheritance difficult to interpret.
–
Diagnostic difficulties may be due to reduced
penetrance or variable expressivity of the disease;
– other genes and environmental factors may affect
gene expression;
– persons of some genotypes may fail to survive to
the time of birth;
– accurate information about the presence of the
disorder in relatives or about family relationships
may be lacking;
– the occurrence of new mutations can contribute to
the occurrence of dominant and X-linked disease;
and finally,
– with the small family size typical of most
developed countries today, the patient may by
chance alone be the only affected family member,
making determination of any inheritance pattern
very difficult.
CORRELATING GENOTYPE AND PHENOTYPE

An important component of medical genetics is
identifying and characterizing the genotypes
responsible for particular disease phenotypes.
 When a genetic disorder that appears to be inherited as
a single-gene disorder is thoroughly analyzed, it is
frequently found to be genetically heterogeneous; i.e.,
it includes a number of phenotypes that are similar but
are actually determined by different genotypes at
different loci.
 Genetic heterogeneity may be the result of different
mutations at the same locus (allelic heterogeneity),
mutations at different loci (locus heterogeneity), or
both.

Recognition of genetic heterogeneity is an important
aspect of clinical diagnosis and genetic counseling.
 Moreover, distinct phenotypes inherited in different
families can result from different mutant alleles in
the same gene. This phenomenon, known as clinical
or phenotypic heterogeneity, is well known and
must be taken into account in correlating genotype
and phenotype.
Allelic Heterogeneity



Allelic heterogeneity is an important cause of clinical variation.
Many loci possess more than one mutant allele; in fact, at a
given locus, there may be several or many mutations.
E.g., nearly 1400 different mutations have been found
worldwide in the cystic fibrosis transmembrane conductance
regulator (CFTR) among patients with CF.
Sometimes, these different mutations result in clinically
indistinguishable disorders. In other cases, different mutant
alleles at the same locus produce a similar phenotype but along
a continuum of severity; for example, some CFTR mutations
cause patients to have classic CF with pancreatic insufficiency,
severe progressive lung disease, and congenital absence of the
vas deferens in males, whereas patients carrying other mutant
alleles have lung disease but normal pancreatic function, and
still others have only the abnormality of the male reproductive
tract.

Since any particular mutant allele is generally
uncommon in the population, most people with
rare autosomal recessive disorders are compound
heterozygotes rather than true homozygotes.
 Because different allelic combinations may have
somewhat different clinical consequences,
clinicians must be aware of allelic heterogeneity as
one possible explanation for variability among
patients considered to have the same disease.

There are, however, some well-recognized
exceptions to the observation that compound
heterozygotes are more common than true
homozygotes:
– The first is when the affected individuals inherited the
same mutant allele from consanguineous parents, who
both carry the same mutant allele they inherited from a
common ancestor.
– Second, one mutant allele may be responsible for a
large proportion of the cases of an autosomal recessive
condition in a particular ethnic group, and so many
patients from that group will be homozygous for this
allele.
– The third is when the disorder normally has little if any
allelic heterogeneity because the disease phenotype
caused by a particular mutation is specific to that
mutation (e.g., sickle cell disease).
Locus Heterogeneity

For many phenotypes, pedigree analysis alone has been
sufficient to demonstrate locus heterogeneity. For example,
retinitis pigmentosa, a common cause of visual impairment
due to photoreceptor degeneration, has long been known to
occur in autosomal dominant, autosomal recessive, and Xlinked forms.
 In recent years, the heterogeneity has been shown to be even
more extensive; pedigree analysis combined with gene
mapping has demonstrated that there are at least 43 loci
responsible for 5 X-linked forms, 14 autosomal dominant
forms, and 24 autosomal recessive forms of retinitis
pigmentosa that are not associated with other phenotypic
abnormalities.
 If one includes disorders in which retinitis pigmentosa is
found in conjunction with other defects such as MR or
deafness, there are nearly 70 different genetic diseases
manifesting retinitis pigmentosa.
Phenotypic Heterogeneity



Different mutations in the same gene can sometimes
give rise to strikingly different phenotypes. For
example, certain loss-of-function mutations in the
RET gene, which encodes a receptor tyrosine kinase,
can cause dominantly inherited failure of development
of colonic ganglia, leading to defective colonic
motility and severe chronic constipation
(Hirschsprung disease).
Other mutations in the same gene result in unregulated
hyperfunction of the kinase, leading to dominantly
inherited cancer of the thyroid and adrenal glands
(multiple endocrine neoplasia type 2A and 2B).
A third group of mutations in RET causes both
Hirschsprung disease and multiple endocrine
neoplasia in the same individuals.

A comparable situation occurs with the LMNA
gene, which encodes lamin A/C, a nuclear
membrane protein.
 Different LMNA mutations have been associated
with half a dozen phenotypically distinct
disorders, including Emery-Dreifuss muscular
dystrophy, one form of hereditary dilated
cardiomyopathy, one form of the Charcot-MarieTooth peripheral neuropathy, a disorder of normal
adipose tissue called lipodystrophy, and the
premature aging syndrome known as HutchinsonGilford progeria.
AUTOSOMAL PATTERNS OF MENDELIAN
INHERITANCE
Autosomal Recessive Inheritance



Autosomal recessive disease occurs only in homozygotes
or compound heterozygotes.
Homozygotes (affected) must have inherited a mutant
allele from each parent (barring uniparental disomy or new
mutation, which is rare in autosomal recessive disorders).
Three types of matings can lead to homozygous affected
offspring. The mutant recessive allele is symbolized as r
and its normal dominant allele as R. Although any mating
in which each parent has at least one recessive allele can
produce homozygous affected offspring, the most common
mating by far is between two unaffected heterozygotes.
Parental Mating
Offspring
Risk of Disease
Carrier by carrier R/r
×R/r
1/4 R/R, 1/2 R/r, 1/4 r/r
3/4 unaffected, 1/4
affected
Carrier by affected R/r
×r/r
1/2 R/r, 1/2 r/r
1/2 unaffected,
affected
Affected by affected r/r
×r/r
r/r only
All affected
1/2
• The proband may be the only affected family member,
but if any others are affected, they are usually in the
same sibship and not elsewhere in the kindred.
Figure 7-7 Typical pedigree showing autosomal recessive inheritance
Sex-Influenced Disorders

Autosomal recessive disorders generally show the
same frequency and severity in males and females.
 Some autosomal recessive phenotypes, however,
are sex-influenced, i.e, expressed in both sexes but
with different frequencies or severity.
 Among autosomal disorders, hemochromatosis is
an example of a phenotype more common in
males.
 This autosomal recessive disorder of iron
metabolism occurs most commonly in the
approximately 0.5% of individuals of northern
European extraction that are homozygous for a
missense mutation replacing cysteine at position
282 with a tyrosine (Cys282Tyr) in the HFE gene.

Cys282Tyr homozygotes have enhanced
absorption of dietary iron and often demonstrate
laboratory abnormalities suggestive of excessive
body stores of iron, although the condition only
rarely leads to iron overload and serious damage
to the heart, liver, and pancreas.
 The lower incidence of the clinical disorder in
females (one fifth to one tenth that of males) is
believed to be related, among other factors, to
lower dietary intake of iron, lower alcohol usage,
and increased iron loss through menstruation
among females.
Gene Frequency and Carrier Frequency

The mutant alleles responsible for a recessive disorder
are generally rare, and so most people will not have
even one copy of the mutant allele.
 Among individuals with at least one copy of the mutant
allele, however, the frequency of clinically unaffected
heterozygotes with one normal allele and one mutant
allele is always much greater than the frequency of
affected individuals with two rare mutant alleles.
 Because an autosomal recessive disorder must be
inherited through both parents, the risk that any carrier
will have an affected child depends partly on the
chance that his or her mate is also a carrier of a mutant
allele for the condition.
 Thus, knowledge of the carrier frequency of a disease
is clinically important for genetic counseling.

The most common autosomal recessive disorder in
white children is cystic fibrosis (CF), caused by
mutations in the CFTR gene.
 CF is virtually unknown in Asian populations and is
relatively rare in African American populations, but
in white populations, about 1 child in 2000 has two
mutant CFTR alleles and has the disease.
 The frequency of carriers for one of the hundreds of
possible mutant CFTR alleles can be calculated to be
approximately 1/29.

In a population of 3247 white individuals,
therefore, you can expect 1 CF patient, 112
unaffected carriers of a CFTR mutation, and 3134
normal homozygotes.
 Because a patient has two mutant CFTR alleles
and a carrier has only one, (112 ×1)/(112
×1+1×2)=112/114 (about 98%) of all mutant
CFTR alleles in this population of 3247
individuals are hidden in carriers (who usually are
unaware that they are carriers), and only 2% are in
patients.
Consanguinity

Because the majority of the mutant alleles responsible
for autosomal recessive disorders are in carriers rather
than in homozygotes, mutant alleles can be handed
down in families for numerous generations without ever
appearing in the homozygous state and causing overt
disease.
 The presence of such hidden recessive genes is not
revealed unless the carrier happens to mate with
someone who also carries a mutant allele at the same
locus and the two deleterious alleles are both inherited
by a child.

It is believed that everyone carries few (1 to 5)
mutant alleles, of which perhaps half are lethal in
homozygotes before birth. The remainder cause
well-known, easily recognizable autosomal
recessive disorders in homozygotes. This is,
however, a minimal estimate that does not take
into account mutant alleles that exert their effect
by interacting with mutant alleles at other loci
(multifactorial inheritance).

The chance that both parents are carriers of a
mutant allele at the same locus is increased
substantially if the parents are related and could
each have inherited the mutant allele from a single
common ancestor, a situation called
consanguinity.
 Consanguinity is defined arbitrarily as a union of
individuals related to each other as close as or
closer than second cousins.
 Consanguinity of the parents of a patient with a
genetic disorder is strong evidence (although not
proof) for the autosomal recessive inheritance of
that condition.
Figure 7-8 Pedigree in which parental consanguinity suggests autosomal
recessive inheritance.

The genetic risk to the offspring of marriages
between related people is not as great as is
sometimes imagined.
 For marriages between first cousins, the absolute
risks of abnormal offspring, including not only
known autosomal recessive diseases but also
stillbirth, neonatal death, and congenital
malformations, is 3% to 5%, about double the
overall background risk of 2% to 3% for offspring
born to any unrelated couple.
 Consanguinity at the level of third cousins or more
remote relationships is not considered to be
genetically significant, and the increased risk of
abnormal offspring is negligible in such cases.

Consanguinity is not the most common explanation
for an autosomal recessive trait. The mating of
unrelated persons, each of whom happens by chance
to be a carrier, accounts for most cases of autosomal
recessive disease, particularly if a recessive trait has
a high frequency in the population.
 Thus, most affected persons with a relatively
common disorder, such as CF, are not the result of
consanguinity, because the mutant allele is so
common in the general population.
 However, consanguinity is more frequently found in
the background of patients with very rare conditions.
For example, in xeroderma pigmentosum, a very
rare autosomal recessive condition of DNA repair,
more than 20% of cases occur among the offspring
of marriages between first cousins.
The Measurement of Consanguinity

The measurement of consanguinity is
relevant in medical genetics because the
risk of a child's being homozygous for a
rare recessive allele is proportional to how
related the parents are. Some types of
consanguineous mating carry an increased
risk.
Figure 7-9 Types of consanguineous mating. The probability that the offspring
in each of these matings is homozygous by descent at any one locus is equal
to the coefficient of inbreeding, F.

Consanguinity is measured by the coefficient of
inbreeding (F), the probability that a homozygote has
received both alleles at a locus from the same ancestral
source.
 In Figure 7-10, individual IV-1 is the offspring of a
first-cousin mating. Each of the four alleles at locus A
(A1, A2, A3, and A4) in generation I has a 1/8 × 1/8
=1/64 chance of being homozygous in IV-1; thus, the
probability that IV-1 is homozygous for any one of the
four alleles is 4 ×1/64 =1/16.
Figure 7-10 A cousin marriage, used in the text to demonstrate
how to calculate the coefficient of inbreeding, F, of the child IV-1.

Table 7-1 shows the coefficients of
inbreeding for the offspring of a number of
consanguineous matings. If a person is
inbred through more than one line of
descent, the separate coefficients are
summed to find his or her total coefficient
of inbreeding.
Consanguineous Matings
Coefficient of
Inbreeding
of Child (F)
Type
Degree of
relationship
Proportion of Genes
in Common
Monozygotic twins
NA
1
NA
Parent-child
1st
1/2
1/4
Brother-sister (including dizygotic twins)
1st
1/2
1/4
Brother-half sister
2nd
1/4
1/8
Uncle-niece or aunt-nephew
2nd
1/4
1/8
Half uncle-niece
3rd
1/8
1/16
First cousins
3rd
1/8
1/16
Double first cousins
2nd
1/4
1/8
Half first cousins
4th
1/16
1/32
First cousins once removed
4th
1/16
1/32
Second cousins
5th
1/32
1/64
• Coefficients of inbreeding for the offspring of a number of consanguineous matings.
If a person is inbred through more than one line of descent, the separate coefficients
are summed to find his or her total coefficient of inbreeding.
Inbreeding

Inbreeding is closely related to consanguinity.
Inbreeding describes the situation in which
individuals from a small population tend to choose
their mates from within the same population for
cultural, geographical, or religious reasons.
 In this situation, the parents may consider
themselves unrelated but still may have common
ancestry within the past few generations. Just as
with consanguinity, inbreeding increases the
chance that individuals will be homozygous for an
allele inherited from a common ancestor.

Thus, in taking a family history, it is important to
ask not only about consanguinity but also about
the geographical origins of ancestors, especially if
a couple seeking counseling is of similar ethnic or
geographical origin.
 Although we make a distinction between
consanguinity occurring within a family and
inbreeding, which occurs between unrelated
individuals from the same small ethnic group, an
increased risk for mating between heterozygous
carriers of autosomal recessive disorders exists in
both situations.
Rare Recessive Disorders in
Genetic Isolates

There are many small groups in which the
frequency of certain rare recessive genes is greater
than that in the general population.
 Such groups, genetic isolates, may have become
separated from their neighbors by geographical,
religious, or linguistic barriers.
 Although such populations are not
consanguineous, the chance of mating with
another carrier of a particular recessive condition
may be as high as that observed in cousin
marriages.
Tay-Sachs disease (GM2 gangliosidosis)

is an example of AR disease with increased
frequency in certain genetic isolates. The disease is a
neurological degenerative disorder that develops
when a child is about 6 months old. Affected
children become blind and regress mentally and
physically. The disease is fatal in early childhood.
 Among Ashkenazi Jews in North America, e.g., TaySachs disease is 100 times more frequent (1 in 3600)
than in other groups of European ancestry. This
increased disease frequency is because the Tay-Sachs
carrier frequency among Ashkenazi Jews,
approximately 1 in 30, is 10-fold higher than in
similar non-Ashkenazi European populations.

When the mutant alleles causing a recessive disease
are relatively frequent in a particular population,
unrelated spouses have a reasonable chance of both
being heterozygous, and therefore consanguinity is
generally not a striking feature in the families with
affected children.
 For example, among Ashkenazi Jews, the parents of
children with Tay-Sachs disease are usually not
closely related.
 When the mutant allele is rare, however, the frequency
of carriers is very low and consanguinity is often the
explanation for how both members of a couple came to
be heterozygotes.
 For example, consanguinity is often present in the
parents of Tay-Sachs patients in the population of
French ancestry in Quebec, Canada, where mutant
alleles for Tay-Sachs disease are rare.
Characteristics of Autosomal
Recessive Inheritance
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An autosomal recessive phenotype, if it appears in more
than one member of a kindred, typically is seen only in the
sibship of the proband, not in parents, offspring, or other
relatives.
For most autosomal recessive diseases, males and females
are equally likely to be affected.
Parents of an affected child are asymptomatic carriers of
mutant alleles.
The parents of the affected person may in some cases be
consanguineous. This is especially likely if the gene
responsible for the condition is rare in the population.
The recurrence risk for each sib of the proband is 1 in 4.
New Mutation in AR Disorders
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When a child is affected with an AR condition, the
assumption is generally made that both parents are
heterozygous carriers for the condition. Yet, new
mutations occur all the time during the generation
of gametes.
 Might not an individual have two mutant alleles
for an autosomal recessive condition by virtue of
inheriting one mutant allele from a carrier parent
while the other mutant allele arose de novo in a
gamete that came from a parent who was not a
carrier? Such a situation is, of course, not
impossible but is relatively unlikely compared
with the situation in which both parents are
heterozygous carriers.
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This is because the chance that the gamete from a
non-carrier parent had acquired a mutant allele by
spontaneous mutation ranges from 1 in 105 to 1 in
106, which is thousands of times less likely than
the typical 1 in 20 to 1 in 1000 chance that the
gamete contained the mutant allele because the
parent is a heterozygous carrier.
 The relative unimportance of new mutations in
autosomal recessive disease is in stark contrast to
the situation with dominant and X-linked
disorders, as will be discussed later