Revision notes: 1. Genetics Flashcards by Alexander Knighton

DNA replication. Which enzyme unwinds double-stranded DNA

DNA helicase

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Which enzyme is involved in copying DNA during replication

DNA polymerase

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Which enzyme is involved with reattaching DNA strands

DNA ligase

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4 stages of the cell cycle

G1 –> S (synthesis) –> G2 –> M (mitosis

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Stages of mitosis

Prophase - Chromatins condense

Metaphase - Nuclei disappear, nuclear membrane disintegration, mitotic spindles form and chromosomes align at metaphase plate

Anaphase - ‘kinetochore’ microtubules shorten, splitting the chromatids

Telophase - chromosomes decondense, nuclear membranes reform

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Trisomy 21 - genetic causes

Down’s syndrome

95% - primary trisomy 21 - non-dysjunction at meiosis
3% - robertsonian translocation of chromosomes 14 and 21
1% - mosaicism

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Features of Down’s

Raised nuchal translucency
Dysmorphic features: small ears, upslanting palpebral fissures, flat facial profile, brachycephaly
Hypotonia
Cardiac abnormalities - ASD, VSD, persistent ductus arteriosus, tetralogy of fallot
GIT abnormalities: Duodenal atresia, imperforate anus, hirschsprung’s disease
Conductive hearing loss

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Long-term diseases associated with Down’s

Alzheimer’s
AML/ALL
Hypothyroidism

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Maternal risk of Down’s

25 years old: 1:1500

30: 1:900
35: 1:350
40: 1:100
45: 1:30
50: 1:11

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Trisomy 18

Edward’s syndrome

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Edwards syndrome: Prevalence and M:F ratio

1:3000 live births, M:F 1:2

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Edwards: MSK defects

Rockerbottom feet, overlapping fingers, limb defects

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Edwards: facial defects

Micrognathia, cleft lip, cleft palate

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Edwards: cardiac defects

VSD
ASD
Patent ductus arteriosus

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Edwards: Abdominal defects

Exomphalos
Inguinal hernia
Diaphragmatic hernia
Renal malformations

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Edwards: intrauterine

Causes intrauterine growth restriction

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Edwards: mortality rates

1 month: 30%
2 months: 50%
1 year: 90%

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Trisomy 13

Patau’s syndrome

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Prevalence of Patau

1:5000

Increases with maternal age

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Features of Patau

MIDLINE:
Hypotolerism (eyes close together)
Holoprosencephaly (failure of prosencephalon to develop into two hemispheres
Cleft lip
Cleft palate
Scalp defects

Post-axial polydactyly
Congenital heart defects
Renal abnormalities
Omphalocele
Intrauterine growth restriction

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Mortality rate Patau

Almost 100% by 1 month of age

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Sex chromosome aneuploidies examples

Klinefelter (XXY)

Turner (X0)

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Turner’s syndrome: prevalence

1:2500 female live births

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Features of Turner’s syndrome

Raised nuchal translucency
Cystic hygroma
Lymphoedema
Neck webbing
Short stature
Shield shaped chest, widely spaced nipples
Coarctation of aorta
Gonadaldysgenesis
Renal abnormalities inc horseshoe kidney
Intellectually NORMAL
Risk of gonadoblastoma

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Klinefelter's syndrome, incidence

1:1000 live births

Features of Klinefelter's

Tall Small testes, hypogonadotrophic hypogonadism Infertility

Structural chromosomal abnormalities caused by deletion: 22q11 (+ features)

DiGeorge syndrome ``` Immune deficiency Hypocalcaemia due to parathyroid dysfunction Autism Congenital heart disease Cleft lip +/palate ```

Structural chromosomal abnormalities caused by deletion: 15q11-13 - maternal

Angelman ``` Happy! Macroglossia Ataxia Seizures Learning difficulties ```

Structural chromosomal abnormalities caused by deletion: 15q11-13 - paternal

Prader-Willi Obese Hypogonadism Hypotonia

Give some examples of autosomal dominant inherited conditions

``` Myotonic dystrophy Huntington's Tuberous Sclerosis Polycystic Kidney Disease Neurofibromatosis 1 + 2 Achondroplasia Marfan's syndrome Osteogenesis imperfecta Porphyria ```

Examples of autosomal recessive conditions

``` Cystic Fibrosis Sickle cell disease Thalassaemia Phenylketonuria Glycogen storage disorders Congenital adrenal hyperplasia Wilson's disease ```

Examples of X-linked recessive conditions

G6PD deficiency Duchenne muscular dystrophy Fragile X syndrome Christmas disease (factor XI deficiency) Haemophilia A + B (factors VIII + IX deficiency) Neurogenic diabetes insipidus Lesch-Nyhan syndrome (excess uric acid - gout, kidney stones, a bit dumb) Wiskott-Aldrich syndrome (immune deficiency, thrombocytopenia, eczema)

X-linked recessive inheritance

1:2 sons of carrier females

X-linked dominant: inheritance

1:2 offspring of affected females

X-linked dominant conditions

Severe in males: neonatal death Incontinentia pigmenti Rett syndrome Vitamin D resistance rickets (otherwise known as hypophosphatemic rickets)

Mitochondrial inheritance - features

Can affect both sexes but only passed on by affected mothers

Examples of mitochondrial conditions

Leber's hereditary optic neuropathy | Leigh's syndrome - psychomotor regression

What is tuberous sclerosis

Rare multisystem genetic disease causing tumour growth

Tuberous sclerosis genetics

Mutation in either: TSC1 (codes for hamartin) on chromosome 9 TSC2 (codes for tuberin) on chromosome 16 These proteins suppress tumour growth. Therefore mutations lead to tumours

Features of tuberous sclerosis

Angiofibromas Hypomelanotic macules Shagreen patches (leathery patches of skin) Ungal fibromas Brain: Subependymal nodules, cortical tubers, epilepsy Learning difficulties Cardiac rhabdomyomas Renal angiomyolipomas Learning difficulties

Cystic fibrosis genetics

Mutation in CFTR (CF transmembrane conductance regulator) Chromosome 7 DeltaF508 is most common mutation

Sickle cell disease: genetic cause

Point mutation in beta globin chain of haemoglobin

Complications of sickle cell

``` Vaso-occlusive crisis Acute chest syndrome Aplastic crisis Splenic sequestration crisis Haemolytic crisis (common in patients with co-existing G6PD deficiency) ```

Types of alpha-thalassaemia

1 gene affected: silent carrier 2 genes: trait - mild hypochromic anaemia 3: Haemoglobin H disease - moderate anaemia and splenomegaly 4: Bart's hydrops - intrauterine death

Features of Beta-thalassaemia

Fatigue Anaemia Jaundice Shortness of breath Hepatosplenomegaly due to extramedullary haematopoiesis Haemochromatosis - excess gut iron absorption

QUADRUPLE TEST components

B-HCG Inhibin AFP Unconjugated oestriol

Down's - quadruple test results

DECREASED AFP, UNCONJUGATED OESTRIOL | INCREASED B-HCG, INCREASED INHIBIN

Earliest appropriate gestational age to perform CVS

11 weeks

BRCA1 Breast cancer risk

60-90%

BRCA2 Breast cancer risk

45-80%

BRCA1 Ovarian cancer risk

40-60%

BRCA2 Ovarian cancer risk

10-30%

Which chromosomal abnormality has a known association with severely impaired semen quality?

Microdeletions on Y chromosome

Spermatogenesis. Which cells can undergo mitotic division

Spermatogonia

Combined test. When offered?

10-14 weeks | Often carried out at same time as 12 week scan

Quadruple blood test, when offered

14-20 weeks | Not as accurate as combined test

Combined test - findings in down's

Raised nuchal translucency Increase B-HCG Low PAPP-A

Syndrome caused by microdeletion of chromosome 5

Cri-du-chat

Quadruple blood test findings in Edwards

ALL reduced

Incidence of phenylketonuria

1 in 14,000

Treatment of phenylketonuria

Dietary restriction of phenylalanine

When to commence folic acid in beta thalassaemia patients

3 months prior to conception

When should the Guthrie inhibition assay be taken

>12hours after delivery

Most common enzyme deficiency in CAH

21-hydroxylase

Inheritance pattern of Lynch syndrome

Autosomal dominant

CAH gene mutation

CYP21A

What is the correct description of a chromosome when the p and the q arms are the same length around the centromere?

Metacentric

How many genes are there in the human genome?

Approximately 20000

In meiosis, when does recombination of genetic material occur when considering gamete production?

Prophase 1

Which of the following statements describes meiosis? a. Two daughter cells are generated which are genetically identical b. Four daughter cells are generated which are genetically identical c. Two daughter cells are generated from one dividing germ cell d. Four daughter cells are generated from one dividing germ cell e. One polar body is generated from one dividing germ cell

d. Four daughter cells are generated from one dividing germ cell

Rocker bottom feet are associated with

Edward's

Karyotype results from CVS or fetal blood

Takes 48-72hrs

Amniocentesis result back in

2-3 weeks

Clinical features of myotonic dystrophy

``` Frontal balding Distal muscle weakness Sterno-mastoid weakness Gonadal atrophy Cardiac conduction defects Difficulty relaxing a clenched fist Cardiac conduction defects Retinopathy ```

Pre-natal diagnosis of congenital adrenal hyperplasia

17-HP concencration in amniotic fluid OR DNA analysis from CVS or amnio

Aneuploidy associated with Hashimoto's

Turner's

Chromosomes involved in robertsonian translocation

Acrocentric: 13, 14, 15, 21, 22

Telocentric chromosomes

Not seen in humans | centromere at one end

Osteogenesis imperfecta inheritance pattern

Autosomal dominant

AIS 46XY phenotype?

Female phenotype, normal breast development, absent uterus with blind-ending vagina; paucity of pubic and axillary hair

Complications of AIS

Inguinal hernias | Abdominal/inguinal canal testes ---> inc risk gonadoblastoma

Haemoglobin electrophoresis - normal ranges

* HbA 1: 95%-98% * HbA 2: 1.5%-3.5% * HbF: < 2% (age-dependent) * HbC: Absent * HbS: Absent

Cystic fibrosis caucasian carrier rate

1:25