Topic 11 - Clinical Genetics Flashcards
What are the three general categories of genetic factors causing disease?
- Environmental
- Monogenic
- Polygenic
What are the five actual classifications of genetic disorders?
- Multifactorial
- Monogenic
- Chromosomal
- Mitochondrial
- Somatic Mutations (cancer)
What is the continuum of penetrance?
From fully penetrant conditions where environmental factors have no effect, to low-penetrance conditions where genes only play a small part
What is an example of a multifactorial disease?
Multiple sclerosis - genetic factors play a major role in determining susceptibility, but each individual factor has low penetrance
What does a mutation in a single gene usually cause?
Loss of function
What do variants in multiple genes usually cause?
Alternation of function
What do chromosomal imbalances usually cause?
Alternations in gene dosage
What are multifactorial genetic disorders?
- common
- environmental influences + genetic disposition = susceptibility to disease
- variants in genes cause alteration of function
- one organ system affected
What are single gene disorders?
- 1% liveborn
- dominant/recessive pedigree patterns
- mutations in single genes often cause loss of function
- can affect structural proteins, enzymes, receptors and transcription factors
What are chromosomal disorders?
- 0.6% liveborn
- thousands of genes may be involved
- chromosomal imbalance causes alteration in gene dosage - multiple organ systems affected at multiple stages in gestation
- usually de novo (trisomies, deletions, duplications)
- in rare cases, can be inherited (translocations)
What does Down’s Syndrome cause?
- Round face
- Protruding tongue
- Upslanting palpebral fissures
- Epicanthic folds
- Developmental delay
What are palpebral fissures?
The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open lids.
What are the epicanthic folds?
The epicanthic fold is the skin fold of the upper eyelid, covering the inner corner (medial canthus) of the eye.
What is a trisomy?
A trisomy is a chromosomal disorder characterised by an additional chromosome, so the person has 47 instead of 46.
What are the ultrasound features of Trisomy 21?
- short femurs
- nuchal translucency
- echogenic bowel
- choroid plexus cyst
- sandal gap, single palmar crease
What are the three different patterns of chromosomes that cause Down syndrome?
- 95% have 3 seperate copies of chromosome 21 - trisomy 21
- 4% have an extra copy of chromosome 21 due to a Robertsonian translocation
- 1% have mosaicism with normal and trisomy 21 cell lines. Occurs postzygotically
What is trisomy 18?
Edwards Syndrome:
- 1/3000 births
- multiple malformations (heart, kidneys)
- Clenched hands with overlapping fingers
What is trisomy 13?
Patau Syndrome:
- 1/5000 births
- multiple malformations
- affects midline structures particularly (incomplete lobation of the brain, cleft lip, congenital heart disease)
What are two conditions caused by sex chromosome number?
- Klinefelter syndrome
- Turner syndrome
What is Klinefelter syndrome?
- 47, XXY
- 1/1000 males
- Infertility (atrophic testes do not produce sperm)
- Poorly developed 2ndy sexual characteristics in some (lack of testosterone)
- Tall, disproportionately long limbs
- Hypogonadism
- Gynecomastia in late puberty
What is Turner syndrome?
- 45, X
- 1/5000 females
- 99% are lost spontaneously in pregnancy
- Short stature
- Primary amenorrhoea (ovaries involute before birth)
- Congenital heart disease (coarctation of aorta) in 20%
- Low hairline, narrow hip development
What is hypogonadism?
Reduction or absence of hormone secretion or other physiological activity of the gonads (testes or ovaries).
What is Gynecomastia?
Enlarged Breast Tissue in Men. True gynecomastia is an enlargement of the male breast gland because of a hormonal imbalance, but the appearance of enlarged may breasts may be ascribed to pseudogynecomastia, a symptom of excess fat which deposits on the chest. It can be common and temporary in boys going through puberty.
What is azoospermia?
The medical condition of a man whose semen contains no sperm
What is oligospermia?
Deficiency of sperm cells in the semen
What are numerical chromosome abnormalities?
- Gain/loss of complete chromosomes
- Common cause is non-disjunction (usually in ger cells)
- When in somatic cells - causes mosaicism
- Often lethal consequences
- Autosomal monosomies are catastrophic
- Fewer serious side effects from sex chromosome anomalities
What are microdeletions?
Chromosomal region is lost: too small to be observed microscopically. Identified by use of specific molecular cytogenetic techniques
What is the DiGeorge syndrome?
-Caused by 22q11.2 microdeletion
-Small mouth
-Prominent nose
-Congenital heart defects
Hypocalcemia, hypoparathyroidism
What is the Williams syndrome?
- Caused by 7q11.23 microdeletion
- Bright eyes
- Stellate irides
- Wide mouth
- Upturned nose
- Long philtrum
- Flattened nasal bridge heart defects
- Heart defects
- Overly sociable
What is the Prader-Willi syndrome?
- Caused by 15q13 microdeletion
- Hypotonia and abnormal neurological function
- Hypogonadism
- Developmental and cognitive delays
- Hyperphagia and obesity
- Short stature
- Behavioral and psychiatric disturbances
- Large appetite
What is the Cat eye syndrome?
- Caused by 22 inverted duplication
- Iris coloboma
- Anal atresia
- Ear tags/ear pits
- Heart defects
- Kidney malformations
What are dominant conditions?
Heterozygotes with one copy of the altered gene are affected
What are recessive conditions?
Homozygotes with two copies of the altered gene are affected
What are X-linked conditions?
Males with one copy of the altered gene on the X-chromosome are affected
What is familial hypercholesterolemia?
- Defect on chromosome 19
- Makes the body unable to remove low density lipoprotein cholesterol from the blood
- High risk of cardiovascular disease
What are examples of autosomal dominant diseases?
- adult polycystic kidney disease
- Huntington disease
- neurofibromatosis
- polyposis coli
What are examples of autosomal recessive diseases?
- cystic fibrosis
- phenypketonuria
- spinal muscular atrophy
- congenital adrenal hyperplasia
What are examples of X-linked diseases?
- Fragile-X mental retardation syndrome
- Duchenne muscular dystrophy
- haemophilia
What is the result of Autosomal dominant inheritance?
Heterozygotes with one copy of the mutated gene are affected
What is the result of Autosomal recessive inheritance?
Homozygotes with two copies of the mutated gene are affected
What is the result of X-linked inheritance?
Males with one copy of the mutated gene on the X-chromosome are affected
What is Huntington disease?
Progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). Adult-onset Huntington disease, the most common form of this disorder, usually appears in a person’s thirties or forties.
What is Cystic fibrosis?
Genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections.
What is Duchenne muscular dystrophy
A genetic disorder characterized by progressive muscle degeneration and weakness. … DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. Symptom onset is in early childhood, usually between ages 3 and 5.
What is Leber hereditary optic neuropathy?
A mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males.
What is genomic imprinting?
An epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner.
What is the genetic basis of sporadic cancer?
Both alleles of a gene become inactivated in a particular somatic cell leading to loss of control of growth and unchecked cell proliferation
What is the genetic basis of dominantly inherited familial cancer syndromes?
An altered allele is inherited and so is in all body cells containing genetic material. When the second (previously normal) allele of the gene pair becomes inactivated in a particular somatic cell this leads to loss of control of growth and unchecked cell proliferation
What is multifactorial inheritance?
- inheritance controlled by many genes with small additive effects (polygenic) plus the effects of the environment
- one organ system affected
What is genetic counselling?
process of communication and education which addresses concerns relating to the development and/or transmission of a hereditary disorder
What is the process of making a diagnosis in clinical genetics?
- History (Family & Medical)
- Examination
- Investigations (Chromosomes, DNA, Biochemical)
