Title: Explain the term contiguous gene deletion syndrome. Use examples to explain the phenotypic effects of such deletions (excluding imprinted genes). Outline the methods available for identifying contiguous gene deletions.
1Explain the term contiguous gene deletion
syndrome.Use examples to explain the phenotypic
effects of such deletions (excluding imprinted
genes).Outline the methods available for
identifying contiguous gene deletions.
2Essay Plan
- Definition of a Contiguous Gene Deletion
- Features of the Deletions
- Examples of X linked Contiguous Gene Deletions
- Detailed Examples and the phenotypic effects
- Identification of Contiguous Gene Deletions
- The limitations of such techniques
3Definition
- A contiguous gene deletion syndrome is caused by
a microdeletion that spans two or more genes
tandemly positioned along a chromosome. - Contiguous gene deletion syndromes result from
deletions of small amounts of chromosomal
material containing a few genes that are
functionally unrelated but are linked by location
on the chromosome. - As a result the phenotype observed is the result
of a loss of the contiguous genes involved.
4Features of the Syndromes
- The microdeletion involved is often too small to
be visualized using conventional cytogenetic
techniques so detection often requires
fluorescent in situ hybridization (FISH) or
another high resolution technique. - In some cases, specific features of the syndrome
can vary in different patients with the same
syndrome as the phenotype can depend on the
breakpoints of the deletion and which genes are
deleted.
5Features of the Syndromes
- Some of the syndromes are due to a common
deletion size in the majority of cases - e.g. William syndrome has a 1.6Mb deletion in
most patients - Some are due to deletion of variable sizes which
can affect the phenotype - e.g. Wolf Hirshhorn Syndrome
- A lot of the best characterised deletion
syndromes have developmental delay as a major
feature.
6Examples of Contiguous Gene Deletion Syndromes
- Examples of syndromes that can be due to
deletions of contiguous genes include - William Syndrome
- WAGR
- Miller Dieker
- Di George/VCFS
- Langer-Gideon,
- Prader Willi Syndrome/Angelman Syndrome
- Wolf Hirschorn
- 1p deletion syndrome.
7X linked Contiguous gene deletions
- In males, X-chromosome microdeletions produce
well-defined contiguous gene syndromes that show
the features of several different X-linked
mendelian diseases. - e.g. Boy BB' who suffered from Duchenne muscular
dystrophy, chronic granulomatous disease and
retinitis pigmentosa, together with mental
retardation. - He had a chromosomal deletion in Xp21
- helped to map disease genes for DMD and chronic
granulomatous disease. - Deletions of the tip of Xp are seen in another
set of contiguous gene syndromes. - Successively larger deletions remove more genes
and add more diseases to the syndrome - Kallman disease and STS deficiency have been
reported to be frequently deleted together.
822q11.2 deletion syndrome
- 22q11.2 deletion syndrome, also known as
Velocardiofacial Syndrome or DiGeorge Syndrome - Microdeletion of chromosome 22 accounts for more
than 90 of cases and most deletions are de novo,
with 10 or less inherited from an affected
parent. - This region contains about 45 genes, but some of
these genes have not been well characterized. - A small percentage of affected individuals have
shorter deletions in the same region.
9Symptoms and Cause
- Symptoms can include
- Congenital heart disease
- Cleft palate,
- characteristic facial features including
hypertelorism, - learning difficulties,
- hypocalcemia (which can result in seizures),
- a decrease in blood platelets (thrombocytopenia),
feeding problems, renal anomalies, hearing loss,
growth hormone deficiency, autoimmune disorders
and skeletal abnormalities. - The most common deletion (3 Mb), is seen in about
90 of patients and occurs between the two most
distant low copy number repeats (LCRs).
10Genes Involved and Phenotype
- The COMT and TBX1 genes are deleted in the
22q11.2 deletion syndrome. - The TBX1 gene codes for a protein called T-box 1.
The T-box 1 protein appears to be necessary for
craniofacial development development, heart
development, structures in the ear, and glands
such as the thymus and parathyroid. - Using a knockout model TBX1 has been shown to be
the dominant gene contributing to the cardiac
phenotype. - Catechol-O-methyltransferase helps maintain
appropriate levels of neurotransmitters in the
brain. - It is thought that depletion of this enzyme in
the brain may be responsible for the increased
risk of behavioral problems and mental illness
associated with 22q11.2 deletion syndrome.
11William Syndrome
- The clinical manifestations of William Syndrome
include - a distinctive facial appearance (elfin face),
- cardiovascular anomalies (specifically
supravalvular aortic stenosis (SVAS) - hypercalcemia,
- characteristic neurodevelopmental and behavioral
profile. - Williams syndrome is caused by a deletion of
chromosome 7q11.23 - The deleted region includes more than 25 genes,
many of which have been linked to the phenotypes
seen in the syndrome - The Williams critical region is flanked by low
copy repeats that predispose to nonallelic
homologous recombination. WS is due to a 1.6Mb
deletion in most patients (95).
12Genes Involved
- The main gene involved in the syndrome is the
Elastin gene (ELN). - The ELN gene product is the structural protein
elastin, a major component of elastic fibers
found in many tissues. - Deletion of ELN is responsible for the connective
tissue abnormalities, including the
cardiovascular disease in WS. - LIMK1 (lim kinase 1) is likely to be a component
of an intracellular signaling pathway and may be
involved in brain development. - LIMK1 hemizygosity is implicated in the impaired
visuospatial constructive cognition of Williams
syndrome. - CYLN2 is strongly expressed in the brain,
- it is believed postulated to be involved in
cerebellar and neurological abnormalities in WS.
13WAGR
- WAGR syndrome is a rare genetic syndrome in which
affected individuals are predisposed to develop - Wilms tumor (nephroblastoma),
- Aniridia (absence of the iris),
- Genitourinary anomalies
- mental Retardation.
- WAGR syndrome is caused by either submicroscopic
or cytogenetically visible deletions involving
varying amounts of 11p that include band 11p13.
14Genes Involved
- The two genes know to play a role in WAGR are
PAX6 and WT1. - WT1 encodes a zinc finger transcription factor
that is critical to normal development of the
kidneys and gonads. - The loss of WT1 produces genitourinary and renal
abnormalities and predisposes the patient to
Wilms tumor. - The PAX6 gene encodes the PAX6 protein, which is
a transcription factor, believed to act as the
major controller of ocular development during
embryogenesis. - Deletion of one PAX6 gene causes aniridia through
halpoinsufficiency. - PAX6 also plays a role in CNS development and may
be responsible for the mental retardation seen in
WAGR patients.
15Miller Dieker
- Miller-Dieker Syndrome (MDS) is a contiguous gene
deletion syndrome of chromosome 17p13.3,
characterised by classical lissencephaly (aka
lissencephaly type 1) and distinct facial
features. - Lissencephaly (smmoth brain) leads to severe
mental retardation, significant developmental
problems, and seizures. Death tends to occur in
infancy and childhood. - The cause of MDS is due to haploinsufficiency of
several genes on chromosome 17p13.3. - Lissencephaly is caused by mutations in the LIS1
gene or by deletion (of part) of this gene. - Facial dysmorphism and other anomalies in
Miller-Dieker patients appear to be the
consequence of deletion of additional genes
distal, one of which may be the 14-3-3 epsilon
gene.
16Neurofibromatosis type 1 (NF1)
- Neurofibromatosis type 1 (NF1) is a common
autosomal dominant disorder characterised by
neurofibromas, café-au-lait spots, freckles, bone
deformities, learning disabilities, macrocephaly,
short stature and predisposition to developing
tumors such as myeloid malignancies, gliomas and
pheochromocytomas. eople. - The disease is caused by mutations of the tumour
suppressor gene NF1 which may be either single
nucleotide substitutions or large genomic
deletions. - Approximately 5-20 of patients with deletions of
the entire gene and at least 11 contiguous genes,
typically have a more severe presentation than
those with intragenic mutations.
17Methods for Identification
- Conventional G-banded cytogenetic analysis can
often be used for some of the larger deletions - e.g. In the 1p terminal deletion syndrome and
Wolf Hirschorn syndrome - In many cases, the deletions involved are beyond
the resolution of a light microscope so much
higher resolution methods may be required for
detection. - Detection often requires fluorescent in situ
hybridization (FISH).
18FISH Analysis
- There are now many commercially available FISH
probes available for analysis of these disorders.
- e.g. TUPLE1 and N25 probes can be used to detect
22q11.2 deletions. - probes for the 7q11.23 elastin gene should be
performed in patients in whom Williams syndrome
is suspected. - However in cases of the disorder with variable
deletion sizes such as 22q11.2, - FISH analysis may not be sensitive enough to
detect very small deletions - it is difficult to accurately characterize the
extent of the large deletions using this
technique.
19MLPA
- Now many of the disorders mentioned above are
included in the MLPA developmental delay screen - MLPA kits containing probes for many of the genes
in the syndrome critical region have been
developed and can quickly and accurately detect
deletions within the critical region. - In the Mental Retardation MLPA kits, probes are
available from many of the syndromes so many of
the syndromes can be tested for simultaneously. - This is a quicker and cheaper method than FISH,
and for those with a positive result, FISH probes
can be used to confirm the result.
20Array CGH
- Another diagnostic approaches is array CGH which
can be used to detect very small deletions. - Now high-density CGH array analysis is being used
more and more with the clinical cytogenetic
laboratories and research labs. - It is more sensitive than FISH analysis for
deletion detection and provides clinically useful
results on the extent of the deletion.
21Array CGH
- High-resolution genomic arrays are becoming
increasingly important in diagnosing cases of
developmental delay of unknown genetic etiology - They suggest that contiguous genomic alterations
are the underlying pathogenic cause of a
significant number of cases of developmental
delay. - Recording the deletions found on such databases
as DECIPHER means that more rare contiguous gene
deletions are being identified and characterised. - Doing a PubMed search for contiguous gene
deletion brings up hundreds of results.
22References
- www.genereviews.org
- Strachan and Read
- www.mlpa.com
- Elsea SH, Girirajan S. Smith-Magenis syndrome.
Eur J Hum Genet. 2008 16(4)412-21. - Bergemann AD, Cole F, Hirschhorn K. The etiology
of Wolf-Hirschhorn syndrome.Trends Genet. 2005
Mar21(3)188-95. - Baldini A. 279-84.Dissecting contiguous gene
defects TBX1. Curr Opin Genet Dev. 2005
Jun15(3) - Morris CA, Mervis CB. Williams syndrome and
related disorders. Annu Rev Genomics Hum Genet.
20001461-84.