Genetics of Endocrine Disorders Flashcards
Monogenic disorders (4)
Single gene aetiology
6 patterns of inheritance
-AD, AR, XLD, XLR, Y-linked, mitochondrial
Historically identified through study of families (‘linkage’)
Polygenic disorders (3)
Multiple genes
Often environmental influences
Evaluated by looking at large populations (GWAS studies)
Utility of genetic testing (8)
Benefits for the Patient
* Allow appropriate investigation + treatment of disease
* screening for clinical features that may not be apparent
Benefits for first degree relatives and/or progeny
* Identify first degree family members who may be at risk of disease and those who do not harbor the genetic change
* pre-conception genetic counseling/pre-natal diagnosis
Academic / Research benefits
Potential Future Clinical Benefits
Potential harms (6)
Anxiety/fear over positive test results
Concern/anxiety regarding implications for children/relatives
Potential for discrimination (e.g. work/insurance)
False-positive/inaccurate reporting of variants
Uncertain tests results
Incidental/secondary findings
Germline genetic testing: DNA sequencing (4)
-sanger seq= 1-10 gene
-disease targeted gene panel= 5-100 genes
-whole exome seq= 30,000 genes
-whole genome seq= everything
Multiple Endocrine Neoplasia Type 1 (MEN1) (10)
endocrine tumours=
Pancreatic NETs
Parathyroid adenoma
pituitary adenomas,
adrenocortical tumours
non endocrine features=
Lipomas
collagenomas
angiofibromas
meningiomas
Multiple Endocrine Neoplasia Type 2 (MEN2A) (7)
endocrine tumours=
Medullary thyroid cancer (MTC)
phaeochromocytoma
parathyroid tumours
non endocrine features=
Cutaneous lichen amyloidosis
Hirschsprung disease
Multiple Endocrine Neoplasia Type 3 (MEN2B) (6)
endocrine tumours=
Medullary thyroid cancer (MTC)
phaeochromocytoma
non endocrine features=
Mucosal neuromas
marfanoid habitus ganglioneuromatosis
Why is MEN1 important? (7)
Premature morbidity and mortality
-50% of affected individuals will die as a direct result of the disease
-Premature mortality observed in high proportion of affected individuals
Leading causes of excess death:
-malignant pancreatic neuroendocrine tumour
-thymic carcinoids
Considerable psychological burden
Clinical Genetics – MEN1(8)
Autosomal dominant inheritance – highly penetrant disorder
‘Classic’ tumour suppressor in endocrine tissues
Mutations occur throughout MEN1 gene located on chromosome 11q13
Bi-allelic inactivation follows Knudson’s ‘two-hit’ hypothesis
Mutations typically result in loss/reduced protein function
~90% MEN1 mutations inherited from an affected parent
~10% MEN1 mutations occur de novo (i.e. for first time in the patient)
>1200 germline MEN1 mutations reported to date (>600 different mutations)
MEN1 pathogenic variant types (3)
Loss of function (LOF) variants: frameshift indels, nonsense SNVs, splice site variants (70%)
Missense SNVs/in-frame indels (30%)
Large-scale deletion of all or part of the MEN1 gene
(1-2.5%) (detected by MLPA)
Current strategy for management of MEN1 (5)
Goal of Management: Preventing premature morbidity and mortality from MEN1-associated tumours, whilst preserving quality of life
‘Expectant’ approach
Combination of clinical evaluation, biochemical and radiological screening
Management often based on that of sporadic counterparts
Lack of MEN1-specific treatments
Multiple Endocrine Neoplasia Type 2 (MEN2) (3)
Autosomal dominant
RET gene – 10q
Classic proto-oncogene
MEN2 – RET mutations
RET mutations affect specific cysteine residues
Mutations result in activation of receptor tyrosine kinase
Clear phenotype/genotype correlation
High frequency of de novo mutations for MEN2B (i.e. absent family history)
Men 2 clinical features
FDG avid MTC in neck
Metastatic MTC in liver
FDG avid left phenochromocytoma
FDG uptake in forearm consistemnt with skeletal mets
