Exploration génomique de la déficience intellectuelle Flashcards
Déficience intellectuelle (DI): définition
fonctionnement intellectuel sous la moyenne
l’existence
concomittante de limitations dans deux des sphères suivantes ou plus: communication,
autonomie, habilités sociales, santé et sécurité, utilisation des ressources sociales,
l’apprentissage scolaire, loisirs et travail
tout doit survenir avant l’âge de 18 ans
What are the different classification des variants
Single nucleotide variant (SNV)
[Versus single nucleotide polymorphism (SNP) qui a une fréquence
d’au moins 1% dans une population donnée]
Indel:
* insertion ou délétion de 50 paires de base ou moins
Variants structuraux:
réarrangements chromosomique
délétions, duplications (copy number variant)
* translocations et inversions équilibrées
True or False
All copy number variants are associated to a pathophysiology
False
EXAM EXAM EXAM
What are the main causes of deficient intellectuelles? How do we know this
De Novo mutations
There are more deNovo mutations in DI patients than general population
Number of nucleotides in a haploid gene
Taux de mutation: ~1.0 x 10-8
Génome haploïde: 3 x 109 nucléotides/génome diploïde: 6 x 109 nucléotides (donc, environ
60 mutations de novo par génome diploïde)
What percent does the coding exome represent
Régions codantes (exome) représentent environ 2% du génome (donc, 1,2 mutations de
novo par exome)
How many mutations would each of us have?
60-70 SNVs across the genome (1 SNV/exome)
- 0.01- 0,02 variations de structure (>100 kb)
- 2.94 in/dels (1-20 bp)
- 0.16 variations de structure (>20 bp)
Review a bit page 25
What is the interest of using exome sequencing vs genome
It is a bit cheaper and most issues are in exomes but as genome gets cheaper it will be the best choice
True or False
The main cause of DI in the population are heritage
FASLE
FALSE
FALSE
Aucun cas expliqué par des mutations héritées
Most of the time are deNovo
Impact fonctionnel des mutations dominantes
Most of time a deNovo mutation is related to a DOMINANT MUTATION
All deNovo mutations are not the same.
there are 3 categories:
Haploinsuffisance (mutation amorphique)
complete loss of the transcription of a protein (50% if one alelle, 100% if both alleles) Here simply not as many proteins.
Dominant-négatif (mutation antimorphique):
Mutated protein is produced with anormal function (50% of time)
and so 75% of the proteins will not work. Here, 75% are not working.
Gain de fonction (mutation néomorphique)
A protein that has a damaging activity.
What type of mutations contribute to development of autism?
deNovo mutations
Impact de l’âge paternel sur le taux de mutations de novo
The fathers age is correlated to number of deNovo mutations.
Clearly the age of father impacts the number of deNovo mutations
the risk increases but like its still low (from 0.25% to 0.5%)
Risque de transmission d’une mutation de novo à un membre de la fratrie
1.3%
What is pénétrance
La pénétrance est la proportion des individus possédant un génotype donné qui
exprime le phénotype correspondant
all or nothing
This is associated with the second-hit theory where certain CNV will penetrate only in people where a second mutation is present
True or False,
Dans 95% des cas, la microdélétion est transmise par un parent avec DI.
False False
Dans 95% des cas, la microdélétion est transmise par un parent sans DI.
Penetrance
Parent has no issues, child gets another mutation that goes with the parent mutation -> DI (deficience)
Finish the sentence
The more penetrating a given CNV is the more
likely it is that a single mutation is sufficient to cause a phenotype
Less penetrating -> need multiple mutations
Idea that 1 hit is sufficient or not
Girls vs guys which one has more autism?
Excès de garçons/hommes avec DI: 25%
And this is not necessarily related to X
Mutations du chromosome X n’expliquent que 10% des cas de DI chez les
garçons/hommes
What explain that more guys are autistic then girls
Because girls need larger base pair mutations in order to develop autism
(larger is rarer, smaller is more common)
I.e., boys do not have this sort of protection mechanism
Why are most CNVs given by the mother?
It seems that women have some sort of protection against mutations
They need longer bp mutations to manifest a phenotype
This protection does not exist in males (we do not know why)
And so the mothers can survive longer and pass on the genes to the boys that will express where as their girls might not express it.
Majority of CNVs are found in which chromosomes
autonomic
