Table of Contents- Lesson 1 ) ( Next)
(Glossary)
The rules set by Mendel have survived the test of
time. Concepts of autosomal dominant, autosomal recessive, and
X-linked genetic patterns of transmission remain valid. However,
numerous inconsistencies have been observed, (e.g., earlier expression
in subsequent generations (anticipation), skipping a generation,
etc.), that have been dismissed as bias of ascertainment, variable
penetrance and expressivity, or genetic heterogeneity. Recent
discoveries provide insight into the genetic basis of some of
these puzzling cases.
MOSAICISM
Mosaicism refers to the
presence of two or more distinct cell lines, one normal and one
abnormal. This was first recognized in chromosomal disorders.
Fifty percent of women with Turner syndrome, for instance,
have 45,X in all of their cells. The other 50% have mosaicism,
with chromosomally normal cells and abnormal cells in varying
proportions. Conditions associated with hemihypertrophy or hemihyperplasia,
where one side of the body is bigger than the other side, have
also been shown to be caused by chromosomal mosaicism.
A newer concept is mosaicism for a gene abnormality.
This was first shown in a family with two children (paternal half-sibs)
with dominant osteogenesis imperfecta. In this family the
parents were normal; however, a gene deletion was found in 20%
of the father's sperm. What at first appeared to be a recessive
trait, was in reality a dominant trait due to gonadal mosaicism
in the father. Another example of gene mosaicism involved a parent
with segmental neurofibromatosis (NF). Only certain areas
of his body were affected. Cells from the affected areas were
shown to have the gene coding for NF; cells from the unaffected
areas had the normal gene. As his gonads were involved, he passed
the NF gene on to his children who were in turn fully affected.
IMPRINTING
Imprinting refers to modification
of the gene as it is transmitted through the father or the mother.
In mice studies, imprinting is well recognized, probably as a
mechanism to guard against parthenogenesis (self-fertilization).
Using pronucleus transplantation, mouse zygotes can be constructed
containing both paternal (sperm) pronuclei or both maternal (egg)
pronuclei. With both paternal pronuclei, a relatively well developed
placenta, but poorly developed embryo, results. With both maternal
pronuclei, an embryo develops with a very small placenta leading
to early loss. The human counterpart is ovarian teratoma or dermoid
tumors when the two sets of chromosomes are maternal in origin,
or a hydatidiform mole when the two sets of chromosomes in the
fertilized egg are paternal in origin.
Prader-Willi (PWS) and
Angelman (AS) syndromes exemplify the concept of imprinting.
Both conditions are due to a deletion of the same chromosomal
segment, 15q11-12. If the deleted chromosome 15 is paternal in
origin, the patient will have PWS. If the deleted chromosome is
maternal in origin, the patient will have AS. For the deletion
to have a different clinical effect, when transmitted from the
father or the mother, suggests that there must be some modification
of the chromosome segment that occurs as it passes through paternal
or maternal meiosis.
UNIPARENTAL DISOMY
Uniparental disomy (UPD)
refers to a pair of chromosomes being inherited from one parent.
Uniparental isodisomy refers to both chromosomes coming from one
parent carrying identical genes (from one grandparent). Uniparental
heterodisomy refers to a pair of chromosomes coming from one parent
but carrying different genes (from both grandparents). About 20-30%
of individuals with PWS show no deletion on chromosome analysis,
FISH or DNA studies. In these instances, both number 15 chromosomes
are of maternal origin, i.e., no paternal contribution. This makes
it analogous to PWS which occurs secondary to a paternal deletion
of 15q11. The maternal uniparental disomy (and, therefore, the
absence of a paternally imprinted chromosome 15) creates clinical
features of Prader-Willi syndrome.
Cystic fibrosis (CF) has
been described secondary to uniparental disomy where both number
7 chromosomes, with the F508 mutation, were shown to have come
from the mother (carrier for CF), with no contribution from the
father (not a carrier for CF). In cases such as this, the risk
of recurrence in future children should be minimal. There must
also be some imprinting associated with chromosome 7, since individuals
with CF secondary to uniparental disomy also have intrauterine
and postnatal growth retardation resulting in short stature.
Uniparental disomy is presumed to occur in a zygote
that, at conception, had three copies of chromosome 15 or chromosome
7. These trisomic conditions are ordinarily not compatible with
life. Survival of the embryo occurs following the random loss
of the third chromosome with resulting UPD.
TRIPLET REPEATS
A number of conditions have been associated with
triplet repeats (3 DNA bases), a feature normally present
in the genome. The three bases (e.g., CAG, CTG or CGG) are repeated
sequentially and are of varying lengths in normal individuals.
However, the number of triplet sequences increases above the expected
range in individuals with certain genetic conditions. These triplet
repeats are found close to the beginning, within, or close to
the end of a gene. The function of these repeated DNA sequences
is not clearly defined. As the triplet repeat is passed on to
subsequent generations, it can undergo expansion in size and result
in earlier onset (anticipation) or more severe disease in the
offspring.
Fragile X syndrome is
associated with CGG repeats. Among normal individuals, the number
of CGG repeats is between 6 and 40. Unaffected carriers, who carry
a premutation, have between 50-200 copies of the CGG repeats.
Affected individuals with the full mutation, have over 200-1,000
CGG repeats.
Genes are considered to be constant, or faithfully
replicated characters. As a rule, they do not change as they pass
from generation to generation. Fragile X syndrome (and triplet
repeat diseases in general) is an exception to this rule. Most
males with the fragile X gene (FMR-1) are mentally retarded. However,
20% of carrier males do not have mental retardation. Their carrier
status is proven by the fact that they pass on the FMR-1 gene
to their daughters who, in turn, have affected sons (50%). These
"transmitting" males have been shown to carry a premutation
FMR-1 gene. The gene is stable and unchanged through male meiosis.
This is passed on to daughters who then carry the premutation
FMR-1 gene. However, in female meiosis, there can be an expansion
of the triplet repeat size to greater than 200 copies, or the
full mutation range, resulting in affected grandsons and
granddaughters.
Huntington disease (HD),
associated with CAG repeats, is an adult onset neurodegenerative
condition affecting mainly the basal ganglia. Persons with HD
develop a movement disorder (choreoathetoid or dance-like movement)
and dementia. Their life span, on average, is 15 years after the
onset of symptoms. The number of triplet repeats in normal individuals
is 11-34. Individuals with HD have 39 repeats or more. Those with
repeats in the 60-70 range have a juvenile onset HD. Most individuals
with juvenile expression of HD inherit the gene from their father,
following an expansion of the triplet repeat, which is more likely
to occur in male meiosis.
Myotonic dystrophy is
associated with an increase in the number of CTG repeats. Myotonia
refers to the inability to relax following muscle contraction,
(i.e., opening a clenched hand or extending a flexed elbow). Often,
there is associated frontal balding, testicular atrophy, and subsequent
weakness. Considered a dominant trait, both males and females
are affected. The normal number of CTG repeats is 5-30. There
is a gray zone of 30-70 repeats where there is potential for expansion
during meiosis. Affected individuals have more than 70 repeats.
The peculiarity of this condition is the occurrence of congenital
myotonic dystrophy (severe hypotonia, often not compatible with
life) among newborns inheriting the condition from the mother,
a phenomenon not observed when the condition is inherited from
the father.
CONTIGUOUS GENE SYNDROMES
Contiguous gene syndromes
are conditions that occur secondary to microdeletions or microduplications
involving several neighboring genes. The occurrence of mental
retardation in individuals with syndromes normally associated
with normal psychomotor development (the gene for neurofibromatosis
was discovered on 17q because a chromosome abnormality was seen
in a mentally retarded person with NF), or the association of
ordinarily distinct entities (DiGeorge syndrome and velo-cardio-facial
syndrome on 22q), should trigger a request for a high resolution
chromosome study and/or FISH or molecular DNA studies to rule
out a microdeletion or microduplication. Examples of contiguous
gene syndromes are: PWS, AS, Langer-Giedion syndrome, tricho-rhino-phalangeal
syndrome, aniridia-Wilms tumor association, cri-du-chat, Wolf-Hirschhorn
syndrome, Drash syndrome, retinoblastoma, Miller-Dieker syndrome,
DiGeorge syndrome, velo-cardio-facial syndrome, Smith-Magenis
syndrome, Beckwith-Wiedemann syndrome, and Alagille syndrome.
MITOCHONDRIAL INHERITANCE
There are a few rare conditions due to abnormalities
of mitochondrial DNA (mtDNA). Mitochondria are organelles in the
cytoplasm that provide energy for cellular metabolism through
a process called oxidative phosphorylation. There are several
hundred mitochondria per cell which replicate independent of the
nucleus. Mitochondrial inheritance is characterized by great variability
depending on the number of abnormal versus normal mitochondria
within the cell. Since the mitochondria are inherited from the
cytoplasm of the egg, it has a vertical mode of inheritance. Mitochondrial
DNA abnormalities can affect both males and females, however,
they are inherited solely from the mother. Examples of mitochondrial
DNA abnormalities include: LHON-Leber hereditary optic neuropathy;
MELAS-mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes; and MERRF-myoclonic epilepsy with ragged red fibers.
SUMMARY
Advances in the fields of developmental biology and genetics have provided new insights into the genetic basis of some well recognized syndromes. The advent of high resolution chromosome studies, FISH and molecular diagnostic studies has lead to an understanding of conditions that do not conform to Mendelian patterns of inheritance. For example:
Given the rapid advances in the field of genetics,
families who do not receive a definitive diagnosis during their
initial clinic visit should be encouraged to remain in contact
with the genetics clinic staff. In this way they can remain abreast
of the new technological advances.
PRACTICE ACTIVITY 5
Define the following terms:
1. imprinting
2. contiguous gene syndromes
3. triplet repeats
PRACTICE ACTIVITY 5: ANSWERS
1. Imprinting is a phenomenon whereby genes
or chromosome segments are modified during meiosis. The imprinting
process differs in males and females. Both maternal and paternal
genes are necessary for normal development.
2. Contiguous gene syndromes refer to concurrent
syndromes that occur due to duplication or deletion of a series
of genes that lie next to one another on a chromosome.