Theory related to Mendelian genetics, pedigree analysis and modes of inheritance.

1. Dr. Himanshu S Dave
Pediatrician
New Delhi

2. Family History and Pedigree
Notation
 The family history remains the most important
screening tool.
 Through a detailed family history, the physician can
often ascertain the mode of genetic transmission and
the risks to family members.
 The main goal of the family history is to identify
genetic susceptibility, and the cornerstone of the
family history is a systematic and standardized
pedigree.

3. Pedigree
 Provides a graphic depiction of a family's structure and
medical history.
 It is important when taking a pedigree to be systematic and
use standard symbols andconfigurations so that anyone
can read and understand the information.
 In pediatrics , the proband is typically the child or
adolescent who is being evaluated.
 The proband is designated in the pedigree by an arrow.

4. Definitions

5. Symbols

6. Evaluation
&
Testing

7. Assisted
Reproductive
Technique

8.  A 3 to 4–generation pedigree should be obtained for
every new patient as an initial screen for genetic
disorders segregating within the family.
 The pedigree canprovide clues to the inheritance
pattern of these disorders and can aid the clinician in
determining the risk to the proband and other family
members.

9.  First-degree relatives, such as a parent, full sibling, or
child, share one-half their genetic information on
average; first cousins share one-eighth.

11.  3 classic forms of genetic inheritance:
• Autosomal dominant
• Autosomalrecessive
• X-linked
These are referred to as mendelian inheritance forms.

12.  Laws of segregation of characteristics, dominance, and
independent assortment remain the foundation of
single-gene inheritance.

13. Autosomal Dominant Inheritance
 Determined by the presence of one abnormal gene on
one of the autosomes.
 Change in 1 of the paired genes affects the phenotype
of an individual, even though the other copy of the
gene is functioning correctly.
 A phenotype can refer to a physical manifestation, a
behavioral characteristic, or a difference detectable
onlythrough laboratory tests.

14.  These disorders show a vertical transmission (parent-
to-child) pattern and can appear in multiple
generations.
 An affected individual has 50% (1 in 2) chance of
passing onthe deleterious gene in each pregnancy and,
therefore, of having a child affected by the disorder.
This is referred to as the recurrence risk for the
disorder.

15.  Unaffected individuals (family members who do not
manifest the traitand do not harbor a copy of the
deleterious gene)do not pass the disorder to their
children.
 Males and females are equally affected.

16.  Although not a characteristic per se, the finding of
male-to-male transmission essentially confirms
autosomal dominant inheritance.
 Vertical transmission can also be seen with X-linked
traits. However, because a father passes on his Y
chromosome to a son, male-to-male transmission
cannot be seen with an X linked trait.
 Therefore, male-to-male transmission eliminates X-
linked inheritance as a possible explanation.

17.  Male-to-male transmission can occur with Y-linked
genes as well.

18.  Many patients with an autosomal dominant disorder have
no history of an affected family member, for several possible
reasons:
 First : Patient may have the disorder due to a de novo
(new) mutation that occurred in the DNA of the egg or
sperm that formed that individual.
 Second: Many autosomal dominant conditions
demonstrate incomplete penetrance; meaning that not all
individuals who carry the mutation have phenotypic
manifestations. In a pedigree this can appear as a skipped
generation , in which an unaffected individual links 2
affected persons.

19.  Reasons for incomplete penetrance: The effect of
modifier genes, environmental factors, gender, and
age.
 Third: Individuals with the same autosomal dominant
variant can manifest the disorder to different degrees.
This is termed variable expression and is a
characteristic of many autosomal dominant disorders.

20. • Fourth: Some spontaneous genetic mutations occur
not in the egg or sperm that forms a child, but rather
in a cell in the developing embryo.
• Such events are referred to as somatic mutations ,and
because not all cells are affected, the change is said to
be mosaic.
• The phenotype caused somatic mutation can vary but
is usually milder than if all cells wereaffected by the
mutation.

21.  In germline mosaicism: Mutation occurs in cells that
populate the germline that produces eggs or sperm.
 An individual who is germlinemosaic might not have
any manifestations of the disorder but may produce
multiple eggs or sperm that are affected by the
mutation.

24. Autosomal Recessive Inheritance
 Requires deleterious variants in bothcopies of a gene
to cause disease.
 Examples: Cystic fibrosis and sickle cell disease.
 Characterized by horizontal transmission: Observation
of multiple affected members of a kindred in the
same generation,but no affected family members in
other generations.

25.  Recurrence risk of 25% for carrier parents who have
had a previous affected child.
 Male and female offspring are equally likely to be
affected.
 Although some traits exhibit differential expression
between sexes.
 Consanguinity: Increased risk for rare, autosomal
recessive traits due to the increased chance that both
parents may carry a gene affected by a deleterious
mutation that they inherited from a common ancestor.

26.  The risk ofa genetic disorder for the offspring of afirst-
cousin union (6–8%) is about double the risk in the
general population (3–4%).
 A variety of autosomal recessive conditionsare more
common among Ashkenazi Jews than in the general
population.

27.  Heterozygote advantage:
 Carrier frequencies of sickle cell disease in the African
population and of cystic fibrosis in the northern
European population are much higher than would be
expected from the rate of new mutations.
 In these populations, heterozygous carriers may have
had an advantage in terms of survival and
reproduction over noncarriers.

28.  In sickle cell disease thecarrier state is thought to
confer some resistance to malaria.
 In cystic fibrosis the carrier state has been postulated
to confer resistance to cholera or enteropathogenic
Escherichia coli infections.

29.  If the frequency of an autosomal recessive diseaseis
known, the frequency of the heterozygote or carrier
state can be calculated from the Hardy-Weinberg
formula:
p2+2pq+q2=1
wherep is the frequency of one of a pair of alleles an q is
the frequency of the other.

31. PseudodominantInheritance
 Observation of apparent dominant (parent to child)
transmission of aknown autosomal recessive disorder.
 Occurs when a homozygous affected individual has a
partner who is a heterozygous carrier.
 Most likely to occur for relatively common recessive
traits within a population, such as sickle cell anemia or
nonsyndromic autosomal recessive hearing loss
caused by deleterious mutations in the GJB2 , the gene
that encodes connexin 26.

33. X-Linked Inheritance
 X-linked inheritance describes the inheritance pattern
of most disorders caused by deleterious changes in
genes located on the X chromosome .
 In X liked disorders, males aremore commonly
affected than females.
 Female carriers of thesedisorders are generally
unaffected, or if affected, they are affected more mildly
than males.

34.  In each pregnancy, female carriers have a 25% chance of having
an affected son, a 25% chance of having a carrier daughter, and a
50% chance of having a child that does not inherit the mutated
X-linked gene.
 Affected males pass their X chromosome to all their daughters
and their Y chromosome to all their sons, they have a 50%
chance of having an unaffected son that does not carry the
disease gene and a 50% chance of having a daughter who is a
carrier.
 Male-to-male transmission excludes X-linked inheritance but is
seen with autosomal dominant andY-linked inheritance.

35.  A female occasionally exhibits signs of an X-linked
trait similar to a male.
 This occurs rarely from homozygosity for an X-linked
traitor the presence of a sex chromosome abnormality
(45,X or 46,XY female) or skewed or nonrandom X-
inactivation.

36.  X chromosome inactivation:
 Occurs early in development and involves the random
and irreversible inactivation of most genes on one X
chromosome in female cells.
 In some cases, a preponderance of cells inactivates the
same X chromosome, resulting in phenotypic
expression of an X-linked pathogenic variant if it
resides on the active chromosome.

37.  This can occur becauseof chance, selection against
cellsthat have inactivated the X chromosome carrying
the normal gene, or an X chromosome abnormality
that results in inactivation of the X chromosome
carrying the normal gene .

38.  Some X-linked conditions arelethal in a high
percentage of males, such as incontinentia pigmenti.
 In such cases the pedigree typically shows only
affected females and an overall female/male ratio of
2 : 1, with an increased number of miscarriages.

40. X linked dominant with Male
lethality (EX: Incontinentia
pigmentii)

42. Y-Linked Inheritance
 Few Y-linked traits.
 Only male-to-male transmission, and only males are
affected.
 Most Y-linked genes are related to male sex
determination and reproduction and are
associated with infertility.
 Familial transmission of a Y-linked disorder is rare.
 Assisted reproductive technologies might make it
possible tohave familialtransmission of male
infertility.

45.  Pseudoautosomal regions on the X and Y
chromosomes.
 These regions are madeup of homologous sequences
of nucleotides, genes that are located in these regions
are present in equal numbers amongboth males and
females.
 SHOX is one of the best-characterized disease genes
located in these regions.

46.  Heterozygous SHOX mutations cause Leri-Weil
dyschondrosteosis , a rare skeletal dysplasia involves
bilateral bowing of the forearms with dislocationsof
the ulna atthe wrist and generalized short stature.
 Homozygous SHOX mutations cause the much more
severe Langer mesomelic dwarfism .

48.  Explains the occurrenceof retinitis pigmentosa (RP) in
children of parents whoeach carry a pathogenic
variant in a different RP associated gene.
 Both parents have normal vision, as would be
expected, but their offspring who are double
heterozygotes —having inherited both mutations—
develop RP.
 Digenic pedigrees can exhibit characteristics of both
autosomal dominant (vertical transmission) and
autosomal recessive inheritance (1 in4 recurrence
risk).

51.  Sometimes nongenetic reasons for the occurrence of a
particular disease in multiple family members can produce
a pattern that mimics genetic transmission.
 These nongenetic factors include identifiable factors,
teratogenic exposures, or undetermined or undefined
factors.
 Examples of include multiple siblings in a family having
asthma because of exposure to cigarette smoke from their
parents.

52.  In some cases the disease is sufficiently common in
general population thatsome familial clustering
occurs by chance.
 Breast cancer affects 11% of all women, and it is
possible that several women in a family willdevelop
breast cancer even in the absence of a genetic
predisposition.

54.  Does not follow classical mendelian patterns.
 Nontraditional inheritance is seen in:
 Mitochondrial disorders
 Triplet repeat expansion diseases
 Imprinting defects

55. Mitochondrial Inheritance
 Mitochondrial genome is entirely derived from the
mother because sperm contain relatively few
mitochondria, and these are degradated after
fertilization.
 It follows that mitochondrial inheritance isessentially
maternal inheritance.

56.  Mitochondrial DNA mutations are often deletions or
point mutations.
 Overall one in 400 has a maternally inherited
pathogenic mitochondrial DNA mutation.
 In individual families, mitochondrial inheritance may
be difficult to distinguish from autosomal dominant
or X-linked inheritance, but in manycases, the sex of
the transmitting and nontransmitting parents can
suggest a mitochondrial basis.

57.  EXAMPLES
 1) Leber hereditary optic neuropathy
 2) NARP, Leigh disease
 3) MELAS
 4) MERRF
 5) Deafness
 6) Chronicprogressive external ophthalmoplegia
 7) Pearson syndrome
 8) Kearns Sayre syndrome

58.  Organs most affected by abnormal mitochondria are
those that have the greatest energy requirements,such
as the brain, muscle, heart, and liver.
 Common manifestations include developmental delay,
seizures, cardiac dysfunction, decreased muscle
strength and tone, and hearing and vision problems.

59.  Mitochondrial diseases can be highly variable in
clinical manifestation because a cell can have a
mixture of normal and abnormal mitochondrial
genomes, which is referred to as heteroplasmy.
 Homoplasmy : All copies of the mitochondrial genome
carry the same sequence variant.

60.  Because of this, a mother may be asymptomatic yet
have children who are severelyaffected.
 Thelevel of heteroplasmy at which disease symptoms
typically appear can also vary based on the type of
mitochondrial variant.

62. Triplet Repeat Expansion Disorder
 Dynamic nature of the disease-causing variant.
 Triplet repeat expansion disorders include fragile X
syndrome, myotonic dystrophy, Huntington disease,
and spinocerebellar ataxias.
 Caused by expansion innumber of 3-bp repeats.

63.  The fragileX gene, FMR1, normally has 5-40 CGG
triplets.
 An error in replication can result in expansion of that
number to a levelin the gray zone between 41 and58
repeats, or to a level referred to as premutation ,
which comprises 59-200 repeats.

64.  Some premutation carriers, more often males, develop
fragile X–associated tremor/ataxia syndrome (FXTAS)
as adults.
 Female premutation carriers are at risk for fragile X–
associated primary ovarian insufficiency (FXPOI).

65.  Persons with a premutation atrisk for having the
repeat expand further in subsequent meiosis, thus
crossing into the range of a full mutation (>200
repeats) inoffspring.
 With this number of repeats, the FMR1 gene becomes
hypermethylated, and protein production is lost.

66.  Some triplet expansions associated with other genes
can cause disease through a mechanism other than
decreased protein production.
 In Huntington disease the expansioncauses the gene
product to have anew, toxic effect onthe neurons of
the basal ganglia.

67.  For most triplet repeat disorders: There is clinical
correlation to thesize ofthe expansion, with a greater
expansion causing more severe symptoms and having
earlier onset.
 The observation of increasing severity of disease and
early age at onset in subsequent generations is termed
genetic anticipation and is a defining characteristics of
many triplet repeat expansion disorders.

69. Genetic Imprinting
 The 2 copies of most autosomal genes are functionally
equivalent.
 In some cases, only 1 copy of a gene is transcribed and
the 2nd copy is silenced.
 This gene silencing is typically associated with
methylation of DNA, which is an epigenetic
modification, meaning it does not change the
nucleotidesequence of the DNA.

70.  In imprinting , gene expression depends on the parent
of origin of the chromosome.
 Prader-Willi andAngelman syndromes. Both can be
caused by microdeletions of chromosome 15q11-12.
 The microdeletion in Prader-Willi syndrome is on
paternally derived chromosome 15, whereas in
Angelman syndrome it is on the maternal copy.
 UBE3A is the gene responsible for Angelman
syndrome.

71.  Uniparental disomy (UPD) , the rare occurrence of a child
inheriting both copies of a chromosome from the same
parent, is another genetic mechanism that can cause
Prader-Willi and Angelman syndromes.
 Inheriting both chromosomes 15 from the mother is
functionally the same as deletion of the paternal 15q12 and
results in Prader-Willi syndrome.
 Approximately 30% of cases of Prader-Willi syndrome are
caused by maternal UPD15, whereas paternal UPD15
accounts for only 3% of Angelman syndrome.

73.  Multifactorial inheritance: Refers to traits that are
caused by a combination of inherited, environmental,
and stochastic factors.
 Multifactorial traits: Differ from polygenic inheritance
which refers to traits that result fromthe additive
effects of multiple genes.

74.  There is a similar rate of recurrence among all first
degree relatives.
 The risk of recurrence is related to the incidence of
the disease.
 Some disorders have sex predilection as indicatedby
an unequal male:female incidence. Pyloric stenosis,
more common in males, whereas congenital
dislocation of the hips is morecommon in females.

75.  The risk ofrecurrence is increased when multiple
family members are affected.
 The risk ofrecurrence may be greater when the
disorder is more severe.

76. References
 Nelson Textbook of Pediatrics 21st edition.
 Charts taken from Nelson.