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Diagnosis of Genetic Diseases > Lecture 15 > Flashcards

Lecture 15 Flashcards

1
Q

what is ADNFLE epilepsy?

A

autosomal dominant nocturnal frontal epolepsy

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2
Q

what is ADNFLE epilepsy characterized by?

A

interfamilial variability, so we have a heterogenous onset, severity, and symptoms → seizures occur during sleep, in particular during the non-REM phase (a specific phase of nocturnal sleep)

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3
Q

what type of inheritance is ADNFLE epilepsy characterized by?

A

autosomal dominant inheritance with incomplete penetrance

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4
Q

what do all the causative genes associated with ADNFLE epilepsy encode for?

A

different subunits of the neuronal nicotinic receptor - we have an alteration of the cholinergic system

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5
Q

why do we not have a clear genotype-phenotype heterogeneity when studying ADNFLE epilepsy?

A

we have genetic heterogeneity, meaning that different mutations of that gene are associated to the same form

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6
Q

what other type of gene was found to have implications in ADNFLE epilepsy?

A

a gene encoding for the potassium voltage channel

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7
Q

when they studied a family with ADNFLE epilepsy through GWAS, where did they find an associated among those tested?

A

a specific loci on chromosome 9

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8
Q

when they followed up the finding on chromosome 9 through whole-exome sequencing, what did they find?

A

identified a novel variant (missense) that had a positive segregation in all the affected family members

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9
Q

if a variant is present in all affected family members is this enough to demonstrate that it is a causative gene?

A

no → we must investigate other family cases that are negative for the genetic analysis

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10
Q

what is done when it is not possible to have other positive familial cases, what do we have to use to analyze a specific mutation?

A

use functional analysis (such as in the case of the TRDN KO syndrome and the zebrafish model)

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11
Q

since the familial mutation was found in other cases of undiagnosed ADNFLE epilepsy, what gene was added to the panel of causative genes for ADNFLE epilepsy?

A

KCNT1

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12
Q

what is colon cancer due caused by?

A

abnormal proliferation of epithelial cells and it can occur in different parts of the intestine, but the major of the cases affect the rectum → formation of polyps that are benign but can become malignant or even metastatic

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13
Q

what percentage of colorectal cancers are from the sporadic form?

A

80%

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14
Q

how does the sporadic form of colorectal cancer occur?

A

the neoplasm occurs after the accumulation of different mutations on the intestinal cells → environmental factors, diet, as well as inflammatory conditions play an important role in development

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15
Q

what percentage of colorectal cancers present an inheritance pattern?

A

50% present a genetic form and the majority of those cases are autosomal dominant - positive family history plays a role

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16
Q

what is characterized by the presence of polyps and is responsible for 1% of colorectal cancers?

A

familial adenomatous polyposis

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17
Q

what gene is associated with familial adenomatous polyposis?

A

APC gene localized on chromosome 5 with a high variability in the severity of the disorder and in the number of polyps

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18
Q

what type of colorectal cancer is known as Lynch Syndrome?

A

hereditary non polyposis colon-rectal cancer

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19
Q

describe Lynch syndrome:

A

the form without polyps and is responsible for 5% of all colorectal cancers

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20
Q

describe the inheritance of Lynch syndrome:

A

autosomal dominant and mismatch repair genes are associated with this form

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21
Q

describe Lynch I:

A

tumors are localized mainly on the proximal colon

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22
Q

describe Lynch II:

A

may have tumors also in other organs such as the endometrial or urinary tract cancer → also associated with a higher risk to develop more severe symptoms and have a variable onset

23
Q

what are two major risk factors for Lynch syndrome?

A

old age and inflammation

24
Q

how old are the majority of Lynch syndrome patients?

A

over 50

25
Q

how is inflammation a risk factor of Lynch syndrome?

A

chronic inflammatory disease may stimulate the hyperstimulation of cells

26
Q

describe the steps of humoral progression in colorectal cancer:

A
  1. colon cells carry a genetic predisposition
  2. accumulation of other mutations on the genes and the formation of polyps
  3. if other genetic variations occur we have a progression of the disorder, and we have the literati of the mismatch repair gene and therefore metastatic progression
27
Q

what is the gold standard for the clinical diagnosis of colorectal cancer?

A

biopsy

28
Q

what is tissue biopsy essential for?

A

diagnosis and in some case also to have information about the prognosis to identify which Is the best surgical approach

29
Q

what must we first analyze to see if we have a familial case?

A

the family pedigree

30
Q

when we want to analyze the entire panel of genes, what do we want to focus on?

A

analyzing specific genes that are associated with the specific clinical phenotype

31
Q

who must also be consulted during the process of whole genome sequencing?

A

a medical geneticist in the case of incidental findings

32
Q

it is important to consider what genes are altered not only to better define the clinical form of the disease, but also for what other reason?

A

necessary for the clinicians to explain the risk associated with that gene, and in some cases the genetic date could be important for the prognosis factors and for the classification and management of other family members

33
Q

what is bronchopulmonary dysplasia (BPD)?

A

a chronic lung disease that affects newborns (mostly premature, born 10 or more weeks before gestation) or infants → present sever conditions: they need oxygen therapy with CPAP and mechanical ventilation

34
Q

what is CPAP?

A

continuous positive airway pressure

35
Q

why is it especially hard to treat BPD?

A

it is not easy to treat patients based on their size and weight and their lungs are not fully developed

36
Q

how is the clinical diagnosis of BPD performed once the baby is born, and what does it show?

A

x-rays are performed and it shows that the lungs are like a sponge

37
Q

what can CPAP cause?

A

increase the predisposition of respiratory infections

38
Q

what can be used before birth to accelerate the maturation of the lungs when we are near birth, and after birth in children with low birth weights?

A

corticosteroids

39
Q

what gender is mainly affected by BPD?

A

males

40
Q

what are the three main subgroups for BPD?

A

mild, moderate, and severe

41
Q

what must we consider when categorizing BPD?

A

since we have a multifactorial etiology, we have to consider both genetic predisposition as well as environmental factors → necessary to have specific criteria to have a clear characterization (a homogenous form) to analyze

42
Q

what do we want to look for when studying the potential for BPD?

A

we want to identify genetic markers that are present in affected families in which there are more than 2 affected family members → also look for incomplete penetrance and variable expressivity

43
Q

what did researchers find when the conducted familial genetic studies for BPD?

A

identified SNPs in 5 different genes encoding for surfactant proteins which may be related with the phenotype, as they have collapsed alveoli possible due to the deficiency of this protein

44
Q

what was one of the main limitations of the group of babies studied?

A

we don’t have a homogenous cohort: the majority of the children had mild forms but were analyzed alongside those with severe forms and were analyzed with the same approach

45
Q

how are twins an excellent way to study BPD?

A

we know monozygotic twins share 100% of genetic information, but as we are looking at a disorder about the development of the lungs during gestation, the environment is also the same - useful to identify predisposition

46
Q

what were the main limitations on the papers published with twin studies?

A

clinical criteria was used for classification, and most studies don’t distinguish between monozygotic twins and dizygotic twins → however the twin studies suggested that we have a high hereditability and a high role in genetics

47
Q

what did GWAS studies show about BPD?

A

the is an involvement of the surfactant gene related to inflammation, proteins important for the matrix remodeling of the lungs, or adhesion molecules that can be involved in lung development and therefore in their function after birth

48
Q

what was the disadvantage to GWAS studies?

A

a very high number of patients is needed in order to provide statistical significance and there was not a clear association of a specific gene

49
Q

if you are able to identify a candidate gene, what is the next step?

A

then you are able to confirm that gene in a bigger cohort of patients in order to confirm it as a causative gene

50
Q

what was the first analysis through NGS of BPD based on?

A

based on the analysis of the gene described or associated with bronchopulmonary dysplasia by other previously published studies

51
Q

what was found about the genes associated with bronchopulmonary dysplasia?

A

the variant was described to demonstrate that they wr causative, but it is not sufficient to say that those genes were associated to the pathway underlying the pathogenic predisposition

52
Q

if we do not know the specific altered gene, what can we use?

A

STRING → it can identify the main pathway the can be altered based on other altered genes we have identified

53
Q

which pathways were discovered to have involvement in BPD by SWIFT?

A

toll-like receptors and other genes that code for surfactant proteins - all related to inflammatory pathways or the development of the lungs before birth

Diagnosis of Genetic Diseases (18 decks)

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