Medical Genetics in Perspective

Medical genetics

science of human biological variation as it relates to health and disease

continuous traits

height, skin pigmentation

continuous traits

overlapping phenotypic classes

discontinuous traits

hemophilia, albinism

Pisum sativum

species of garden pea used in Mendel's studies

Mendel

studied 2800 pea plants but work is not realized

confirmed Mendel's findings

De Vries, Correns, and Tschermak

established the concept of cells as the fundamental living units

Schleiden & Schwann

hereditary transmission through sperm and egg

1860

sperm was largely nuclear material, postulated that the nucleus was responsible for heredity

Ernst Haeckel

chromosomes within the nucleus

Walther Flemming

behaviour of chromosomes during the production of gametes paralleled the behaviour of Mendel ' s hereditary elements

Sutton and Boveri

early knowledge on chromosomes

They carry the genes. However, at that time, although the chromosomes were known to consist of protein & nucleic acid, it was not clear w/c component was the hereditary material

added heat - killed smooth bacteria to live rough bacteria and found that some of the rough pneumococci were transformed to the smooth, virulent type.

Friedrich Griffith

showed that nucleic acid was the transforming agent. Thus, nucleic acid was shown to carry hereditary information

Avery, MacLeod & McCarty

discovery of the double - helical structure for deoxyribonucleic acid

Watson, Crick, Franklin & Wilkins

it was known that one human chromosome (the X chromosome) did not always have a partner

1890

pattern of human sex chromosomes

Wilson and Stevens

it was believed that there were 47 chromosomes, including one X chromosome

male somatic cell (early belief)

48 chromosomes, including two X chromosomes

female cell (early belief)

small Y chromosome was identified, and both sexes were thought to have 48 chromosomes

1923

showed the normal human chromosome number to be 46

Tijo and Levan

first chromosomal disease in humans, trisomy 21

Lejeune

trisomy 21

first discovered chromosomal disease in humans

over 20 different human chromosomal disorders were known

1970

chromosomal banding

markedly increased the ability to resolve small chromosomal aberrations; refers to alternating light & dark regions along the length of a chromosome, produced after staining with a dye

band (chromosomal banding)

the part of a chromosome that is clearly distinguishable from its adjacent segments by appearing darker or lighter with the use of one or more banding techniques

more than 600 different chromosome abnormalities had been described, in addition to many normal variants

1990

Fluorescence in situ hybridization (FISH)

laboratory technique for detecting & locating a specific DNA sequence (i.e. gene) on a chromosome

probe

FISH relies on exposing chromosomes to a small DNA sequence called a what that has a fluorescent molecule attached to it

Comparative genomic hybridisation (CGH)

is a technique that permits the detection of chromosomal copy number changes w/o the need for cell culturing. The green to red fluorescence ratio measured along the chromosomal axis represents loss or gain of genetic material in the tumour at that specific locus.

Array CGH

increased resolution of the more recently developed techniques has led to greater difficulties in differentiating between the increasingly numerous normal & abnormal chromosomal variants

DECIPHER

international databases of submicroscopic variants; Database of Chromosomal Imbalance and Phenotype in Humans using Ensemble Resources

Mitochondria

have their own chromosomes & these are passed on from a mother to all of her children but not from the father; contain only 37 genes, a high & variable number of DNA copies per cell, very little non - coding DNA and no introns

Leber optic neuropathy

maternally inherited type of blindness; mutation on mitochondrial chromosome

heteroplasmy

tendency for a mitochondrial mutation to be present in only a proportion of the cell 's mitochondrial genome copies

Archibald Garrod

presented his studies on alkaptonuria, a rare condition in w/c patients have urine that darkens on standing & arthritis

alkaptonuria

rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body; the first disease to be interpreted as a single-gene trait

proposed that alkaptonuria was a Mendelian recessive trait w/ affected persons homozygous for the underactive gene

Garrod and Bateson

homogentisate 1,2 dioxygenase

required to breakdown homogentisic acid

suspected an abnormal haemoglobin to be the cause of sickle - cell anaemia

Linus Pauling

altered haemoglobin polypeptide sequence

findings of Ingram in 1956 that confirmed Pauling’s findings

sickle-cell anemia

the first demonstration in any organism that a mutation in a structural gene could produce an altered amino acid sequence

demonstrated the first enzyme defect in an autosomal recessive condition (NADH - dependent methaemoglobin reductase in methaemoglobinaemia)

Gibson

Methaemoglobin

form of hemoglobin that cannot carry oxygen

methaemoglobinemia

tissues cannot get enough oxygen; Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, & blue-colored skin

specific biochemical abnormalities in over 400 inborn errors of metabolism

specific biochemical abnormalities in over 400 inborn errors of metabolism have now been determined, but the polypeptide product is still unknown in many human single - gene disorders

Study of these rare, and not so rare, single - gene disorders

provided valuable insights into normal physiological mechanisms; for instance, our knowledge of the normal metabolic pathways has been derived largely from the study of inborn errors of metabolism

assignment to individual chromosomes, mapping genes’ precise locations, and identifying their entire nucleotide sequences

Great progress has been made in the assignment of genes to [blank]

first human gene assignment

made by Wilson, who identified the X - linked trait for colour blindness in 1911 & assigned the gene to the X -chromosome.

thymidine kinase to chromosome 17

first autosomal gene to be assigned

a complete linkage map of all human chromosomes had been developed and this was followed by the first physical map

1987; 1993

Human Genome Project

aimed to map and sequence all human genes by the year 2005

development of high - throughput automated fluorescence - based DNA sequencing, in addition to competition between the publicly funded (International Human Gene Sequencing Consortium) and private company (Celera) schemes

led to the early completion of the human genome sequence in 2003

associations with human diseases, gene mapping data, cross - species comparisons, expression patterns and predicted protein features

sequence information, together with an enormous body of associated data

studied continuous human characteristics such as intelligence and physique, which did not seem to conform to Mendel ' s laws of inheritance

Galton

inheritance could be explained by multiple pairs of genes, each with a small but additive effect

Fisher

Discontinuous traits w/ multifactorial inheritance

explained by introducing the concept of a threshold effect for the disorder: manifestation only occurred when the combined genetic & environmental liability passed the threshold

Usually factors in the environment interact with the genetic background.

Many human characteristics are determined in this fashion.

the number & nature of the genes involved & their mechanisms of interaction between each other & environmental factors are largely unknown

Although the genetic contribution to multifactorial disorders is now well accepted,

insulin - dependent diabetes mellitus, rheumatoid arthritis, dementia due to Alzheimer ' s disease, premature vascular disease, schizophrenia, Parkinson disease, atopic dermatitis and asthma

current focus of a great deal of research and progress has been made in identifying the genetic contribution for several of these conditions

accumulation of genetic mutations

What is the cause of all cancers

after conception

in cancer, when do the mutations occur

certain somatic cells; initial key mutation is inherited

in cancer, where are the mutations confined

first advanced the idea that chromosomal changes caused cancer

Theodor Boveri

demonstration of a specific chromosomal translocation (the Philadelphia chromosome) in a type of leukaemia

where did the early support for the idea of Boveri come from? (clue: 1973)

reciprocal translocation between chromosome 9 and 22

causes chronic myelogenous leukemia

key determinants of progression to cancer

Subsequently, a large number of both specific and non-specific chromosomal changes have been found in a wide variety of cancers. In turn, these changes were clues to specific genes

tumor suppressor genes (e.g. P53 gene),

when mutated, causes cancer

Many of these genes have now been cloned

this has resulted in an improved understanding of the molecular basis of cancer and provided the clinician w/ a means of detection of presymptomatic carriers of cancer - predisposing genes.

ageing and in certain mosaic disorders

it is now recognised that changes in the DNA sequence occurring within somatic cells play an important role in [blank] such as McCune - Albright syndrome, which results from post - zygotic somatic activating mutations in the GNAS1 gene; changes in the chromosome can lead to changes in DNA sequence

McCune-Albright syndrome

disorder that affects the bones, skin, and several hormone-producing (endocrine) tissues. People with this syndrome develop areas of abnormal scar-like (fibrous) tissue in their bones, a condition called polyostotic fibrous dysplasia

GNAS1 gene

where are the mutations for Mccune-Albright Syndrome found?

inherited disorders

Changes in the DNA sequence also may be responsible for the exacerbation of symptoms with age in some [blank] such as myotonic dystrophy, in which there is somatic expansion of the inherited mutation and mitochondrial disorders

Myotonic dystrophy (DM)

is a form of muscular dystrophy that affects muscles and many other organs in the body. The word "myotonic" is the adjectival form of the word "myotonia," defined as an inability to relax muscles at will.

Genetically determined disease

[blank] has become an increasingly important part of ill health in the community now that most infections can be controlled and now that modern medical and nursing care can save many affected infants who previously would have succumbed shortly after birth

Genetic counselling, carrier detection

This has led to an increased demand for informed genetic counselling and for screening tests both for carrier detection and to identify pregnancies at risk.

Charles Davenport

began to give genetic advice as early as 1910 in the USA, and the first British genetic counselling clinic was established in 1946 at Great Ormond Street, London

genetic counselling

The scope for [blank] has, in recent years expanded dramatically with the increasingly available data on human genetic disorders (e.g. their mechanism of inheritance in addition to their associated genes and markers) and the increasing availability of mutation analysis

Clinical geneticists

[blank] play an increasingly important role in the clinical assessment and genetic testing of patients with genetic conditions and their at - risk relatives

geneticists; coordinating with several other specialties and initiating patient participation

[blank] are now much more involved in the management of patient follow - up, often [blank] in multicentre clinical studies. These include trials of clinical screening methods and of new therapeutic strategies.

reproductive options

In addition to an accurate assessment of the risks in a family, the clinical geneticist also needs to discuss [blank].

prenatal diagnosis w/ the option of selective termination

Important advances in this respect have been made w/ regard to [blank], & this has been a major factor in increasing the demand for genetic counselling

Prenatal Diagnosis; preimplantation diagnosis

[blank] and now, in certain cases, [blank], offer reassurance for couples at high risk of serious genetic disorders and allow many couples, who were previously deterred by the risk, the possibility of having healthy children

Genetic amniocentesis; Trisomy 21

[blank] was first attempted in 1966 and the first prenatally detected chromosome abnormality was [blank] in 1969.

Chromosome analysis

[blank] following amniocentesis is now a routine component of obstetric care, and over 200 different types of abnormality have been detected.

Amniocentesis or earlier chorionic villus sampling

can also be used to detect biochemical alterations in inborn errors of metabolism; was first used in 1968 for a pregnancy at risk of Lesch - Nyhan syndrome and has since been used for successful prenatal diagnosis in over 150 inborn errors of metabolism

DNA analysis of fetal samples

another way to perform prenatal diagnosis, has become the main method

alpha-thalassaemia; cystic fibrosis, the fragile X syndrome and Duchenne muscular dystrophy

This approach was first used in 1976 for a pregnancy at risk of [blank] and has now been used in over 200 single - gene disorders, and for many of these, including [blank]

Preimplantation diagnosis (PGD); In Vitro Fertilization (IVF)

[blank], first used clinically (for sex determination) in 1990, is a more recently established technique that permits the testing of embryos at a very early stage following [blank], prior to implantation in the uterus.

In vitro fertilization (IVF)

[blank] is a complex series of procedures used to help with fertility or prevent genetic problems & assist w/ the conception of a child. During this, mature eggs are collected (retrieved) from ovaries & fertilized by sperm in a lab.

a single cell or blastomere is removed by suction, apparently harmlessly, from the embryo. This is usually carried out at the five - to ten - cell stage, at approximately 3 days post - fertilization.

In vitro fertilization (IVF)

polymerase chain reaction (PCR) or FISH

Using the [blank], it is then possible to determine the fetal sex in cases of sex - linked disease or to detect a specific mutation or chromosomal abnormality .

preimplantation genetic haplotyping (PGH)

In this technique, as in PGD, a cell is extracted from an embryo following IVF. In [blank], however, the DNA undergoes testing for a set of DNA markers closely linked to the disease gene without requiring the prior identification of the precise causative mutation

multiplex PCRs

This can be performed by carrying out simultaneous or [blank] of several DNA markers, using fluorescence to detect and differentiate the products.

major congenital malformations

The prenatal tests that detect chromosomal, biochemical or DNA alterations cannot, however, detect many of the [blank]

High-resolution ultrasound scanning; anencephaly

The alternative approach of fetal vizualisation has been necessary for these. [blank] was first used to make a diagnosis of fetal abnormality ([blank]) in 1972 & since then over 400 different types of abnormality have been detected.

human supplementation gene therapy; adenosine deaminase deficiency

A great deal of research has been undertaken into the possibility of effective treatment of genetic diseases. In 1990, the first attempts at [blank] for a single - gene disorder ([blank]) was performed.

gene therapy

Since then, different [blank] methods have been devised, depending on the nature of the mutation, and several hundred gene therapy trials are now underway.

safe, effective, non-immunogenic, well -regulated system

The development of a [blank] that permits the efficient delivery of the therapeutic DNA to sufficient numbers of target cells continues to present a significant challenge.