genetics of endocrine disorders Flashcards
how many patterns of inheritance are there in monogenic disorders?
6
AD,AR, XLD, XLR, Y-linked and mitochondrial
which type of inheritance is most influenced by the envirnoment?
polygenic
what so single nucleotide variants result in?
several types of protein coding change:
* Missense amino acid change (i.e. substitution of one amino acid with another)
* Nonsense amino acid change (i.e. generation of a stop codon)
* Splice site alteration (e.g. defective splicing from change to donor or acceptor splice site)
what do small insertions and deletions result in?
In-frame indels: result 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
what causes loss of function mutations?
typically result from nonsense, frameshift or canonical splice site mutations
what are the potential harms of genetic testing
Anxiety/fear over positive test results – implications of positive result
* Concern/anxiety regarding implications for children/relatives
* Potential for discrimination (e.g. work/insurance)
* Harms resulting from interventions of unproven value
* False-positive/inaccurate reporting of variants
* Uncertain tests results - potential for diagnostic confusion
* Incidental/secondary findings – implications for future health
where does multiple endocrine neoplasia T1 (MEN1) happen?
Parathyroid
Pituitary
Enteropancreatic
what type of inheritance is MEN1?
Autosomal dominant inheritance
what chromosome is the MEN1 mutation located on?
11q13 chromosome
why is MEN1 important?
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
→ Also need to consider morbidity associated with interventions
Considerable psychological burden
Dealing with uncertainty (both patient and clinician)
why is MEN1 management difficult?
Lack of genotype-phenotype correlation
* Variable age-related penetrance
* Inability to predict disease course
* Asynchronous/synchronous development of multiple tumours
* Lack of high-quality evidence to guide treatment
* Lack of MEN1-specific or personalised therapies
what is the goal of MEN1 management?
Preventing
premature morbidity and mortality
from MEN1-associated tumours,
whilst preserving quality of life
are there lots of MEN1 specific treatments?
no
