PHYSIOLOGIC OB Dr.
Ordonio
Genetics
Aug 20,2016
OLFU College of Medicine
CHROMOSOMAL ABNORMALITIES - an average intelligence quotient (IQ) score of 35 to 70. Social
skills in affected children are often higher than predicted by
- They are present in approximately 50 percent of their IQ scores
spontaneous abortions, 5 percent of stillbirths, and 0.5
percent of liveborn infants
Standard Nomenclature
- Those of chromosome number, such as trisomy, and those of
chromosome structure, such as a deletion or translocation.
- Each chromosome has a short arm, termed the p or petit
arm, and a long arm known as the q arm, selected because
it is the next letter of the alphabet.
- The two arms are separated by the centromere.
Trisomy 18Edwards Syndrome.
Abnormalities of Chromosome Number
- constellation of abnormalities and their association with
- Aneuploidy is inheritance of either an extra chromosome another autosomal trisomy was first described by Edwards
- More than half die within the first week, and the 1-year
resulting in trisomy, or loss of a chromosome monosomy.
- These differ from polyploidy, which is an abnormal number survival rate is only approximately 2 percent
- The syndrome is three- to fourfold more common in females
of haploid chromosome sets, such as triploidy.
- micrognathia, small mouth, clenched hands with overlapping
digits, radial aplasia, hypoplastic nails, and rockerbottom or
Autosomal Trisomies
clubbed feet.
- Non-disjunction, which is failure of normal chromosomal - Characteristic sonographic findings include a strawberry-
pairing and separation during meiosis shaped cranium and choroid plexus cyst
o (1) fail to pair up, - Pregnancies with trisomy 18 that reach the third trimester
o (2) pair up properly but separate prematurely, often develop fetal-growth restriction, and the mean
o (3) fail to separate. birthweight is less than 2500 grams
- Oocytes are held suspended in mid-prophase of meiosis I - Normal delivery
from birth until ovulation, in some cases for 50 years
- Although each chromosome pair is equally likely to have a Trisomy 13Patau Syndrome.
segregation error, it is rare for trisomies other than 21, 18, or
- As with trisomy 18, trisomy 13 is highly lethal, and most
13 to result in a term pregnancy.
affected fetuses are lost between 10 weeks and term
- Approximately 80 percent of pregnancies with Patau
Trisomy 21Down Syndrome.
syndrome result from trisomy 13. The remainder are caused
- Trisomy 21 is the etiology of 95 percent of Down syndrome by a Robertsonian translocation involving chromosomes 13
cases, whereas 3 to 4 percent is due to a Robertsonian and 14
translocation. - Holoprosencephaly
- The remaining 1 to 2 percent is secondary to an o This is present in approximately two thirds of cases
isochromosome or mosaicism. and may be accompanied by microcephaly,
- Down syndrome is the most common nonlethal trisomy. hypotelorism, and nasal abnormalities that range
- Adult women with Down syndrome are fertile, and a third of from a single nostril to a proboscis
their offspring will have Down syndrome - Preeclampsia with proteinuria might be a possibility of
- Males with Down syndrome are almost always sterile abnormality of fetus as in patau syndrome
because of markedly decreased spermatogenesis - trisomy 13 is the only aneuploidy linked with an increased
- Second-trimester fetuses with Down syndrome will have a risk for preeclampsia
major malformation that can be identified sonographically
- Infants often have loose skin at the nape of the neck, short
fingers, a single palmar crease, hypoplasia of the middle Monosomy
phalanx of the fifth finger, and a prominent space or sandal-
toe gap between the first and second toes.
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Physiologic
- OB
Missing chromosomal Genetics -
material is more devastating Tall stature is common. The overall major
than having extra chromosomal material, and almost malformation rate is not increased with 47,XXX.
all monosomicconceptuses are lost before - That said, atypical phenotypic features have been
described in some individuals and include epicanthal
implantation.
folds, clinodactyly, hypotonia, genitourinary problems,
- The one exception is monosomy for the X
and seizure disorders
chromosome, Turner syndrome.
47,XXYKlinefelter Syndrome.
Polyploidy
- This is the most common sex chromosome
- Polyploidy accounts for approximately 20 percent of abnormality.
spontaneous abortions but is rarely encountered later - Additional X chromosome is maternally or paternally
in gestation. derived with equal propensity
- Triploid pregnancies have three haploid sets or 69 - There is also a slight association with either advanced
chromosomes. maternal age or advanced paternal age
- Triploid can cause Partial H mole - Infants with XXY appear phenotypically normal and
- Diandrictriploidy, also known as type I triploidy, the usually do not have an increased incidence of
extra chromosomal set is paternal, resulting from anomalies.
- As children, boys are typically tall and have normal
fertilization of one egg by two sperm or by a single
prepubertal development.
diploidand thus abnormalsperm. - However, they have gonadal dysgenesis, do not
- Diandrictriploidy accounts for most triploid undergo normal virilization, and require testosterone
conceptions, but the first-trimester loss rate is supplementation beginning in adolescence.
extremely high. - They may develop gynecomastia.
- In a digynic triploid pregnancy, also known as type II - In general, IQ scores are within the normal range but
triploidy, the extra chromosomal set is maternal, and slightly below those of siblings, and delays in speech,
the egg fails to undergo the first or second meiotic reading, and motor skills are not uncommon
division before fertilization
- the fetus often displays asymmetric growth restriction
- Triploidy is a lethal aneuploidy, and more than 90 47,XYY
percent of fetuses with either the diandric or digynic
- There is no association with paternal age, anomaly
form have multiple structural anomalies. rates are not increased, and there are no unusual
- Tetraploid pregnancies have 4 haploid sets or 92 phenotypic features.
chromosomes. - These boys tend to be tall, they have normal puberty,
- Four sets of chromosomes results in either 92,XXXX or and fertility is unimpaired.
92,XXYY. - They are at increased risk for oral and written
- This suggests a post-zygotic failure to complete an language impairments, but intelligence is generally
early cleavage division. normal
- The conceptus invariably succumbs, and the - XYY karyotype was associated with criminal or violent
recurrence risk is minimal. behavior. However, these early reports have been
refuted.
Sex Chromosome Abnormalities
Abnormalities of Chromosome Structure
45,XTurner Syndrome. - what phenotypic abnormalities or later developmental
abnormalities are associated with this finding?
- This is the only monosomy compatible with life. - Second, is evaluation of parental karyotype indicated
- Missing X chromosome is paternally derived in 80 specifically, are the parents at increased risk to
percent of cases carry this abnormality? If so, what is their risk to have
future affected offspring?
47,XXX.
- The extra X is maternally derived Deletions and Duplications
- Pubertal development and fertility are usually normal,
although premature ovarian failure has been reported
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Physiologic
- OB that a portion of a chromosomeGenetics
Deletion indicates is
missing, and a duplication means that a portion has
been included twice
- deletions and duplications occur during meiosis and
result from malalignment or mismatching during the
pairing of homologous chromosomes
Microdeletion Syndromes
- When a specific micro-deletion syndrome is
suspected, it is usually confirmed using fluorescence
in situ hybridization
- There are two typesreciprocal and Robertsonian
translocations.
Reciprocal Translocations
- double-segment or reciprocal translocation develops
when there are breaks in two different chromosomes
and the broken fragments are exchanged, so that each
affected chromosome contains a fragment of the
other
- Balanced translocation carriers are at risk to produce
unbalanced gametes that result in abnormal offspring.
- If an oocyte or sperm contains a translocated
chromosome, fertilization results in an unbalanced
translocation monosomy for part of one affected
chromosome and trisomy for part of the other.
Robertsonian Translocations
- Involve only acrocentric chromosomes, which are
chromosomes 13, 14, 15, 21, and 22
- The p arm is extremely short. In a robertsonian
translocation, the q arms of two acrocentric
chromosomes fuse at one centromere to form a
derivative chromosome. Pericentric Inversion
Chromosomal Inversions - there are breaks in both the p and q arms of a
chromosome, such that the inverted material includes
- When there are two breaks in the same chromosome, the centromere, the inversion is pericentric
and the intervening genetic material is inverted before
the breaks are repaired, the result is a chromosomal Paracentric Inversion
inversion.
- Although no genetic material is lost or duplicated, the - there are two breaks within one arm of a
rearrangement may alter gene function. chromosome, and the inverted material does not
- There are two typespericentric and paracentric. include the centromere, the inversion is paracentric
Ring Chromosomes
- also disrupts cell division, which may cause abnormal
tissue growth and lead to short stature, borderline to
moderate mental deficiency, and minor
dysmorphisms
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Physiologic OB Genetics Heterogeneity
Chromosomal Mosaicism
- Locus heterogeneity indicates that a specific disease
- two or more cytogenetically distinct cell lines that are phenotype can be caused by mutations in different
derived from a single zygote. genetic loci.
- Phenotypic expression of mosaicism depends on - Retinitis pigmentosa, which may develop following
several factors mutations in at least 35 different genes the same gene
- mosaicism found in cells from amnionic fluid culture may affect presentation of a particular disease.
does not always reflect the fetal chromosome - For example, although only one gene has been
complement associated with cystic fibrosisthe cystic fibrosis
conductance transmembrane regulator gene (CFTR)
Autosomal Dominant Inheritance
- If only one member of a gene pair determines the
phenotype, that gene is considered to be dominant.
- Carriers have a 50-percent chance of passing on the
affected gene with each conception.
Penetrance
- This term describes whether or not a dominant gene is
expressed at all.
- With recognizable phenotypic expression in all
individuals has 100-percent penetrance.
- If some carriers express the gene but some do not,
then penetrance is incomplete.
Confined Placental Mosaicism
- The mechanism underlying confined placental
mosaicism may be either mitotic nondisjunction or
partial correction of a meiotic error, and the Expressivity
mechanism appears to be chromosome-specific
- Individuals with the same autosomal dominant trait
Gonadal Mosaicism even within the same familymay manifest the
condition differently
- Spermatogonia and oogonia divide throughout fetal
life, and spermatogonia continue to divide throughout Codominant Genes
adulthood, gonadal mosaicism may also follow a
meiotic error in previously normal germ cells. - if two different alleles in a gene pair are both
- Gonadal mosaicism may explain de novo autosomal expressed in the phenotype, they are considered to be
dominant mutations in the offspring of normal codominant.
parents. Achondroplasia and osteogenesisimperfecta,
as well as X-linked diseases such as Duchenne Autosomal Recessive Inheritance
muscular dystrophy.
- Gonadal mosaicism may also explain the recurrence of - A recessive trait is expressed only when both copies of
such diseases in more than one child in a previously the gene function in the same way.
unaffected family. - develop only when both gene copies are abnormal
- Many enzyme deficiency diseases display autosomal
Monogenic (Mendelian) Inheritance recessive inheritance, and enzyme activity in the
carrier is approximately half of normal.
- Mutation or alteration in a single locus or gene in one
or both members of a gene pair. Inborn Errors of Metabolism
- Types of mendelian inheritance include autosomal
dominant, autosomal recessive, X-linked, and Y-linked
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Physiologic
- Most of OB
these Genetics -
autosomal recessive diseases result Two individuals are considered consanguineous if they
from absence of a crucial enzyme, leading to have at least one recent ancestor in common.
incomplete metabolism of proteins, lipids, or - First-degree relatives share half of their genes
carbohydrates. - Second-degree relatives share a fourth
- Third-degree relativescousinsshare one eighth.
Multifactorial Inheritance - Because of the potential for shared deleterious genes,
consanguinity confers an increased risk to have
- Traits or diseases are considered to have multifactorial offspring with otherwise rare autosomal recessive
inheritance if they are determined by the combination diseases or multifactorial disorders.
of multiple genes and environmental factors. - First cousins have a twofold increased risk4 to 6
- Examples include malformations such as clefts and percent overall, in the absence of a family history of
neural-tube defects, diseases such as diabetes and genetic disease.
heart disease, and features or traits such as head size - Incest is defined as a sexual relationship between first-
or height. degree relatives such as parent-child or brother-sister
and is universally illegal.
Fragile X Syndrome
- This is the most common inherited form of mental
retardation and affects approximately 1 in 3600 males
and 1 in 4000 to 6000 females
- Is caused by expansion of a repeated trinucleotide
DNA segmentcytosine-guanine-guanine (CGG)at
chromosome Xq27.
Consanguinity.
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Physiologic OB Genetics
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Physiologic OB Genetics
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