Genetics Flashcards
What are monogenic (mendelian) disorders?
ii. what are its patterns of inheritance?
they are caused by defects in a single gene
mainly studied by looking at a single family
ii. Autosomal dominance, Autosomal recessive, X linked dominant, X linked recessive, Y linked and mitochondrial
What are polygenic disorders?
Disorders caused by defects in multiple genes
Usually a combination of genetic and environmental influences
What does a circle mean in a family tree?
female
what does a square mean in a family tree?
male
what does a black shape mean in a family tree?
the person is affected with the trait
what does a shape with a dot mean in a family tree?
the person is a carrier ( autosomal or X-linked inheritance) but are not affected
what does a double line mean in a family tree?
consanguinity - means they are related in some way and have reproduced with each other
where do men inherit there x chromosome from?
their mother
What type of genetic abnormalities (mutations) lead to monogenic disorders?
ii. which of these abnormalities cause loss of function in proteins?
Single nucleotide variants (SNVs) result in several type of protein coding change:
- Missense amino acids change - substitution of one amino acid for another
- Nonsense amino acid change - generation of a stop codon
- Splice site alteration- defect in splicing can cause aberrant protein or premature truncation
small insertions and deletions (indels):
- In-frame indels - results in gains or losses of amino acids, amino acid substitutions or generation of premature stop codons or defects in splicing
- Out- of frame indels - typically result in frameshift changes that frequently result in premature truncation of the encoded protein
ii. Loss of function (LOF) mutations typically result from nonsense, frameshift or canonical splice site mutations
What Genetic tests can be used for monogenic disorders?
1.single gene testing (Sanger):
Suitable for diagnosis of disorders with low genetic heterogeneity e.g. MEN28 and RET mutations)
suitable for predictive testing in relatives at risk of specific mutation
- Disease targeting gene panels (NGS):
appropriate for disorders with high genetic heterogeneity
- Whole-exome sequencing/ whole genome sequencing (NGS):
suitable for disorders with unknown genetic aetiology e.g. severe undiagnosed phenotypes
4.Genetic tests for disorders due to chromosomal abnormalities or copy number variations (CNVs)
Karyotype: suitable when abnormal complement of chromosomes suspected e.g. turner/ Klinefelter syndrome
aCGH: suitable when copy number variants/ chromosomal abnormality suspected e.g. turner, Klinefelter syndrome, developmental delay
FISH - suitable when predetermined chromosomal abnormality suspected e.g. 22q deletion syndrome
What endocrine tumours are caused by Multiple endocrine type 1 (MEN1)
- Pancreatic NETs e.g. insulinoma, Gastrinoma
- Parathyroid adenomas- causes primary hyperparathyroidism in all patients (95%)
- Pituitary adenomas e.g. prolactinoma and somatotropinoma
- adrenocortical tumours e.g. conn’s adenoma
What non endocrine features are caused by MEN1 syndrome?
Lipomas
collagenomas
angiofibromas
Meningiomas
what type of autosomal disorder is MEN1 syndrome?
ii. which gene is affected?
Autosomal dominant
ii. MEN1 gene located in chromosome 11
what is the leading cause of death for people with MEN1 disorder?
50% of people carrying this inheritance disorder will die due to it
malignant pancreatic neuroendocrine tumour
thymic carcinoids
what are the indications for getting germline MEN1 genetic testing?
ii. who else should be tested
iii. when should testing occur?
- clinical : Two or more MEN1- associated tumours or a diagnosis of familial MEN 1
- Suspicious for MEN 1 i.e. multiple parathyroid adenomas <40 years old, recurrent hyperparathyroidism or gastrinoma
- atypical MEN1 - development of tow or non classical MEN1 associated tumours e.g. parathyroid and adrenal tumour
ii. asymptomatic first- degree relative
iii. As soon as possible
What pathways is the MEN1 gene involved ?
- DNA damage - double strand break repair
- involved in chromatin remodelling
- Regulation of key cell signalling e.g. mTOR pathway
What type of autosomal disorder is Multiple endocrine neoplasia type 2 (MEN2)?
ii. which gene is affected?
Autosomal dominant
ii. RET gene - found on 10th chromosome
What are the two types of MEN2?
MEN2A- accounts for 90% of cases
MEN2B
what are the endocrine tumours caused by MEN2A?
Medullary thyroid cancer (MTC)
Pheochromocytoma - occur in 50% of patients but dependent on genotype. May occur in children and are frequently bilateral
Parathyroid tumours - 30% of patients
What are the the endocrine tumours caused by MEN2B?
Medullary thyroid cancer (MTC)
Pheochromocytoma - 50% of patients
Parathyroid tumours - occurs in 30% of patients
What are the non endocrine features caused by MEN2A?
Cutaneous lichen amyloidosis
Hirschsprung disease
what are the non endocrine features caused by MEN2B?
Mucosal neuromas
Marfanoid habitus
Ganglioneuromatosis
what is the main cause of death in MEN2 patients?
MTC
what does Medullary thyroid cancer derive from?
parafollicular C cells in thyroid
what are the clinical features of MTC?
Nick mass
diarrhoea and flushing
Ectopic ACTH and cushing
How do you diagnose MTC?
Imaging:
Neck Ultrasound
Fine needle aspiration (FNA)
measure basal serum calcitonin - can also be used a tumour marker for treatment
How do you manage MTC?
Dependent on stage of disease
curative surgery for localised disease- thyroidectomy with variable extent lymph node dissection
management of advanced disease can use tyrosine kinase receptors
how do you diagnose pheochromocytoma?
based on elevated urinary or plasma metanephrines
How do you manage MEN2?
screening:
RET genetic testing
MTC
Phaeomchromocytoma
primary hyperparathyroidism
What are the endocrine tumours caused Von hippel Lindau syndrome?
Pheochromocytoma
Pancreatic NET
What are the non endocrine features of Von hippel Lindau syndrome?
Renal cell carcinoma - main common feature
Haemangioblastomas - (retinal and CNS) - main common feature
Renal cysts
Pancreatic cysts
What type of autosomal disorder is Von hippel Lindau syndrome?
ii. What gene is affected?
Autosomal dominant
ii. VHL gene - gene is used to regulates the expression of hypoxia inducible factors in cells. if there is a mutation then there is a loss in reaction to hypoxia in cells
How do you diagnose VHL?
screening:
Retinal angioma - ophthalmic examinations - anually and beginin in infancy
CNS haemangioblastoma - MRI scans of the head - every 12-36 months begin at adolescence
Renal cell carcinoma and pancreatic tumours -every 12 months begin at 16 years of age
Phaeochromocytoma - Blood pressure monitoring and 24 hr urine or fractionated plasma metanephrines- annually
Familes at high risk for phaeochromocytoma- more intesen surveillance e.g. adrenal imaging - annually, begin at 8 years of age
what endocrine tumours are caused by Neurofibromatosis type 1?
Pheochromocytoma- rare
what are the non endocrine features of Neurofibromatosis type 1?
Axillary freckling, neurofibromas, optic
gliomas, skeletal abnormalities (scoliosis), GISTs,cafe au lait patches and learning difficulties
what are the endocrine tumours caused by Carney complex?
PPNAD, thyroid tumours,
pituitary adenoma
what are are the non endocrine features of carney complex?
Lentigines, atrial myxomas, sertoli cell
tumours
what gene is mutated to cause carney complex?
PRKAR1A
what type of mutation to cause McCune albright syndrome?
Post-zygotic somatic GNAS
mutation (i.e. not germline)
Constitutive adenylyl
cyclase signaling
Overproduction of several
hormones
what is moasicism?
GNAS mutation occurs in early embryonic stage rather than inheritance. This means a proportion of cells are effected and a proportion are not effected by this trait
Give examples of Monogenic disorders which can cause endocrine related clinical features?
1. Multiple Endocrine Neoplasia Type 1 (MEN1)
2. Multiple Endocrine Neoplasia Type 2 (MEN2A)
3. Multiple Endocrine Neoplasia Type 3 (MEN2B)
4. Multiple Endocrine Neoplasia Type 4 (MEN4)
- Neurofibromatosis Type 1
- Von Hippel Lindau
- Carney Complex
- Familial Isolated pituitary
Adenoma (FIPA) - Familial phaeochromocytoma/paraganglioma syndromes
10.Hyperparathyroidism-Jaw Tumour
(HPT-JT) syndrome
- Tuberous Sclerosis
