Exploration génomique de la déficience intellectuelle

Question 1

Déficience intellectuelle (DI): définition

Answer 1

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

Question 2

What are the different classification des variants

Answer 2

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

Question 3

True or False

All copy number variants are associated to a pathophysiology

Answer 3

False

EXAM EXAM EXAM

Question 4

What are the main causes of deficient intellectuelles? How do we know this

Answer 4

De Novo mutations

There are more deNovo mutations in DI patients than general population

Question 5

Number of nucleotides in a haploid gene

Answer 5

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)

Question 6

What percent does the coding exome represent

Answer 6

Régions codantes (exome) représentent environ 2% du génome (donc, 1,2 mutations de
novo par exome)

Question 7

How many mutations would each of us have?

Answer 7

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)

Question 8

Review a bit page 25

Question 9

What is the interest of using exome sequencing vs genome

Answer 9

It is a bit cheaper and most issues are in exomes but as genome gets cheaper it will be the best choice

Question 10

True or False

The main cause of DI in the population are heritage

Answer 10

FASLE
FALSE
FALSE

Aucun cas expliqué par des mutations héritées
Most of the time are deNovo

Question 11

Impact fonctionnel des mutations dominantes

Answer 11

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.

Question 12

What type of mutations contribute to development of autism?

Answer 12

deNovo mutations

Question 13

Impact de l’âge paternel sur le taux de mutations de novo

Answer 13

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%)

Question 14

Risque de transmission d’une mutation de novo à un membre de la fratrie

Answer 14

1.3%

Question 15

What is pénétrance

Answer 15

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

Question 16

True or False,

Dans 95% des cas, la microdélétion est transmise par un parent avec DI.

Answer 16

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)

Question 17

Finish the sentence

The more penetrating a given CNV is the more

Answer 17

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

Question 18

Girls vs guys which one has more autism?

Answer 18

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

Question 19

What explain that more guys are autistic then girls

Answer 19

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

Question 20

Why are most CNVs given by the mother?

Answer 20

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.

Question 21

Majority of CNVs are found in which chromosomes

Answer 21

autonomic