Unusual inheritance mechanisms

Unstable mutations
It has generally been assumed that mutant alleles causing
mendelian disorders are transmitted unchanged from parent to
child. In 1991 the discovery of unstable trinucleotide repeat
expansion mutations identified a novel genetic mechanism
underlying a number of important disorders.

Several genes

Several genes are known to contain regions of trinucleotide
repeats. The number of repeats varies from person to person in
the general population, but within the normal range these
repeats are stably transmitted. When the number of repeats is
increased beyond the normal range, this region becomes
unstable with a tendency to increase in size when transmitted to
offspring. In some conditions there is a clear distinction
between normal and pathological alleles. In others, the
expanded alleles may act either as premutations or as full
pathological mutations. Premutations do not cause disease but
are unstable and likely to expand further when transmitted to
offspring. Once the repeat reaches a certain size it becomes a
full mutation and disease will occur. Since the age at onset and
severity of the disease correlate with the size of the expansion,
this phenomenon accounts for the clinical anticipation that is
seen in this group of conditions, where age at onset decreases
in successive generations of a family. There is a sex bias in the
transmission of the most severe forms of some of these
disorders, with maternal transmission of congenital myotonic
dystrophy and fragile X syndrome, but paternal transmission of
juvenile Huntington disease.

onset neurodegenerative disorders

A number of late onset neurodegenerative disorders (for
example Huntington disease and spinocerebellar ataxias) are
associated with expansions of a CAG repeat sequence in the
coding region of the relevant gene, that is translated into
polyglutamine tracts in the protein product. These mutations
confer a specific gain of function and cause the protein to form
intranuclear aggregates that result in cell death. There is
usually a clear distinction between normal- and disease-causing
alleles in the size of their respective number of repeats and no
other types of mutation are found to cause these disorders.

other disorders

In other disorders (for example fragile X syndrome and
Friedreich ataxia) very large expansions occur, which prevent
transcription of the gene, and act recessively as loss of function
mutations. Other types of mutations occur occasionally in these
genes resulting in the same phenotype. In myotonic dystrophy the
pathological mechanism of the expanded repeat is not known. It
is likely that the expansion affects the transcriptional process of
several neighbouring genes. Juvenile myoclonus epilepsy is due to
the expansion of a longer repeat region (CCCCGCCCCGCG)
normally present in two to three copies in the gene promoter
region, expanding to 40 or more repeats in mutant alleles.
Trinucleotide repeat expansions have also been found in other
conditions (for example polysyndactyly from HOXD13 mutation),
where the pathological expansion shows no instability.

Uniparental disomy

Another unusual mechanism causing human disease is that of
uniparental disomy (UPD), where both copies of a particular
chromosome are inherited from one parent and none from the
other. Usually, UPD arises by loss of a chromosome from a
conception that was initially trisomic (trisomy rescue). The
resulting zygote could contain one chromosome from each
parent (normal), two identical chromosomes from one parent
(isodisomy) or two different chromosomes from one parent
(heterodisomy). Occasionally UPD may arise by fertilisation of
a monosomic gamete followed by duplication of the
chromosome from the other gamete (monosomy rescue). This
mechanism results in uniparental isodisomy. Theoretically, UPD
could also arise by fertilisation of a momosomic gamete with a
disomic gamete, resulting in either isodisomy or heterodisomy.

Uniparental disomy

Uniparental disomy may have no clinical consequence by
itself. It is occasionally detected by the unmasking of a recessive
disorder for which only one parent is a carrier when there is
isodisomy for the parental chromosome carrying such a
mutation. In this rare situation the child would be affected by a
recessive disorder for which the other parent is not a carrier.
Recurrence risk for the disorder in siblings is extremely low
since UPD is not likely to occur again in another pregnancy.
The other situation in which UPD will have an effect is
when the chromosome involved contains one or more
imprinted genes, as described in the next section.

Imprinting

It has been observed that some inherited traits do not conform
to the pattern expected of classical mendelian inheritance in
which genes inherited from either parent have an equal effect.
The term imprinting is used to describe the phenomenon by
which certain genes function differently, depending on
whether they are maternally or paternally derived. The
mechanism of DNA modification involved in imprinting
remains to be explained, but it confers a functional change
in particular alleles at the time of gametogenesis determined
by the sex of the parent. The imprint lasts for one generation
and is then removed, so that an appropriate imprint can be
re-established in the germ cells of the next generation.

The effects of imprinting

The effects of imprinting can be observed at several levels:
that of the whole genome, that of particular chromosomes or
chromosomal segments, and that of individual genes. For
example, the effect of triploidy in human conceptions depends
on the origin of the additional haploid chromosome set. When
paternally derived, the placenta is large and cystic with molar
changes and the fetus has a large head and small body. When
the extra chromosome set is maternal, the placenta is small and
underdeveloped without cystic changes and the fetus is
noticeably underdeveloped. An analogous situation is seen in
conceptions with only a maternal or paternal genetic
contribution. Androgenic conceptions, arising by replacement
of the female pronucleus with a second male pronucleus, give
rise to hydatidiform moles which lack embryonic tissues.
Gynogenetic conceptions, arising by replacement of the male
pronucleus with a second female one, results in dermoid cysts
that develop into multitissue ovarian teratomas.

imprinting in human disease

One of the best examples of imprinting in human disease is
shown by deletions in the q11-13 region of chromosome 15,
which may cause either Prader–Willi syndrome or Angelman
syndrome. The features of Prader–Willi syndrome are severe
neonatal hypotonia and failure to thrive with later onset of
obesity, behaviour problems, mental retardation, characteristic
facial appearance, small hands and feet and hypogonadism.
Angelman syndrome is quite distinct and is associated with
severe mental retardation, microcephaly, ataxia, epilipsy and
absent speech.

Prader–Willi and Angelman syndromes

Prader–Willi and Angelman syndromes are caused by
distinct genes within the 15q11-13 region that are subject to
different imprinting. The Prader–Willi gene is only active on
the chromosome inherited from the father and the Angelman
syndrome gene is only active on the chromosome inherited
from the mother. Similar de novo cytogenetic or molecular
deletions can be detected in both conditions. Prader–Willi
syndrome occurs when the deletion affects the paternally
derived chromosome 15, whereas the Angelman syndrome
occurs when it affects the maternally derived chromosome. In
most patients with Prader–Willi syndrome who do not have a
chromosome deletion, both chromosome 15s are maternally
derived (uniparental disomy). When UPD involves imprinted
regions of the genome it has the same effect as a chromosomal
deletion arising from the opposite parental chromosome. In
Prader–Willi syndrome both isodisomy (inheritance of identical
chromosome 15s from one parent) and heterodisomy
(inheritance of different 15s from the same parent) have been
observed. Uniparental disomy is rare in Angelman syndrome,
but when it occurs it involves disomy of the paternal
chromosome 15. Other cases are due to mutations within the
Angelman syndrome gene (UBE3A) that affect its function.

Imprinting

Imprinting has been implicated in other human diseases,
for example familial glomus tumours that occur only in people
who inherit the mutant gene from their father and
Beckwith–Wiedemann syndrome that occurs when maternally
transmitted.

Mosaicism

Mosaicism refers to the presence of two or more cell lines in an
individual that differ in chromosomal constitution or genotype,
but have been derived from a single zygote. Mosaicism may
involve whole chromosomes or single gene mutations and is a
postzygotic event that arises in a single cell. Once generated,
the genetic change is transmitted to all daughter cells at cell
division, creating a second cell line. The process can occur
during early embryonic development, or in later fetal or
postnatal life. The time at which the mosaicism develops will
determine the relative proportions of the two cell lines, and
hence the severity of the phenotype caused by the abnormal
cell line. Chimaeras have a different origin, being derived from
the fusion of two different zygotes to form a single embryo.
Chimaerism explains the rare occurrence of both XX and XY
cell lines in a single individual.

Functional mosaicism

Functional mosaicism occurs in all females as only one
X chromosome remains active in each cell. The process of
X inactivation occurs in early embryogenesis and is random.
Thus, alleles that differ between the two chromosomes will be
expressed in mosaic fashion. Carriers of X linked recessive
mutations normally remain asymptomatic as only a proportion of
cells have the mutant allele on the active chromosome.
Occasional females will, by chance, have the normal
X chromosome inactivated in the majority of cells and will
then manifest systemic symptoms of the disorder caused by
the mutant gene. In X linked dominant disorders such as
incontinentia pigmenti, female gene carriers have patchy skin
pigmentation that follows Blaschko’s lines because of the mixture
of normal and mutant cells in the skin during development.

Chromosomal mosaicism

Chromosomal mosaicism is not infrequent, and arises by
postzygotic errors in mitosis. Mosaicism is observed in
conditions such as Turner syndrome and Down syndrome, and
the phenotype is less severe than in cases with complete
aneuploidy. Mosaicism has been documented for many other
numerical or structural chromosomal abnormalities that would
be lethal in non-mosaic form. The clinical importance of
chromosomal mosaicism detected prenatally may be difficult to
assess.

gene mutations

Single gene mutations occurring in somatic cells also result
in mosaicism. In mendelian disorders this may present as a
patchy phenotype, as in segmental neurofibromatosis type 1.
Somatic mutation is also a mechanism responsible for
neoplastic change.

Germline mosaicism

Germline mosaicism is one explanation for the transmission
of a genetic disorder to more than one offspring by apparently
normal parents. In these cases the mutation may be confined to
the germline cells or may be present in a proportion of somatic
cells as well. In Duchenne muscular dystrophy, it has been
calculated that up to 20% of the mothers of isolated cases,
whose carrier tests performed on leucocyte DNA give normal
results, may have gonadal mosaicism for the muscular
dystrophy mutation. The possibility of germline mosaicism
makes it difficult to exclude a risk of recurrence in other
X linked recessive disorders where the mother’s carrier tests
give normal results, and autosomal dominant disorders where
the parents are clinically unaffected.

Mitochondrial disorders

Not all DNA is contained within the cell nucleus. Mitochondria
have their own DNA consisting of a double-stranded circular
molecule. This mitochondrial DNA consists of 16 569 base pairs
that constitute 37 genes. There is some difference in the
genetic code between the nuclear and mitochondrial genomes,
and mitochondrial DNA is almost exclusively coding, with the
genes containing no intervening sequences (introns). A diploid
cell contains two copies of the nuclear genome, but there may
be thousands of copies of the mitochondrial genome, as each
mitochondrion contains up to 10 copies of its circular DNA and
each cell contains hundreds of mitochondria. The
mitochondrial genome encodes 22 types of transfer and two
ribosomal RNA molecules that are involved in mitochondrial
protein synthesis, as well as 13 of the polypeptides involved in
the respiratory chain complex. The remaining respiratory
chain polypeptides are encoded by nuclear genes. Diseases
affecting mitochondrial function may therefore be controlled
by nuclear gene mutation and follow mendelian inheritance, or
may result from mutations within the mitochondrial DNA.

Mutations

Mutations within mitochondrial DNA appear to be 5 or 10
times more common than mutations in nuclear DNA, and the
accumulation of mitochondrial mutations with time has been
suggested as playing a role in ageing. As the main function of
mitochondria is the synthesis of ATP by oxidative
phosphorylation, disorders of mitochondrial function are most
likely to affect tissues such as the brain, skeletal muscle, cardiac
muscle and eye, which contain abundant mitochondria and rely
on aerobic oxidation and ATP production. Mutations in
mitochondrial DNA have been identified in a number of
diseases, notably Leber hereditary optic neuropathy (LHON),
myoclonic epilepsy with ragged red fibres (MERRF),
mitochondrial myopathy with encephalopathy, lactic acidosis,
and stroke-like episodes (MELAS), and progressive external
ophthalmoplegia including Kaerns–Sayre syndrome.

Disorders due to mitochondrial mutations

Disorders due to mitochondrial mutations often appear to
be sporadic. When they are inherited, however, they
demonstrate maternal transmission. This is because only the
egg contributes cytoplasm and mitochondria to the zygote. All
offspring of a carrier mother may carry the mutation, all
offspring of a carrier father will be normal. The pedigree
pattern in mitochondrial inheritance may be difficult to
recognise, however, because some carrier individuals remain
asymptomatic. In Leber hereditary optic neuropathy, which
causes sudden and irreversible blindness, for example, half the
sons of a carrier mother are affected, but only 1 in 5 of the
daughters become symptomatic. Nevertheless, all daughters
transmit the mutation to their offspring. The descendants of
affected fathers are unaffected.

multiple copies of mitochondrial DNA

Because multiple copies of mitochondrial DNA are present
in the cell, mitochondrial mutations are often heteroplasmic –
that is, a single cell will contain a mixture of mutant and wildtype
mitochondrial DNA. With successive cell divisions some
cells will remain heteroplasmic but others may drift towards
homoplasmy for the mutant or wild-type DNA. Large deletions,
which make the remaining mitochondrial DNA appreciably
shorter, may have a selective advantage in terms of replication
efficiency, so that the mutant genome accumulates
preferentially. The severity of disease caused by mitochondrial
mutations probably depends on the relative proportions of
wild-type and mutant DNA present, but is very difficult to
predict in a given subject.