Genetic Heterogeneity of Nephrotic Syndrome

Question 1

What are the key major players of nephrotic syndrome? Where do you notice the change in structure?

Answer 1

Podocytes (main), foot processes, and slit diaphragms

Question 2

What is the relationship between genetic mutations and nephrotic syndrome?

Answer 2

Multifaceted, involving both monogenic and polygenic factors that contribute to the pathogenesis

Question 3

In which type of nephrotic syndrome, particularly, do genetic mutations play a crucial role?

Answer 3

Steroid-resistant nephrotic syndrome

Question 4

What are the genes that have been identified to be associated with SRNS?

Answer 4

NPHS1
NPHS2
WT1

Question 5

How do you identify a patient who is suffering from SRNS, especially in children?

Answer 5

When ped patients come in, there is no podocyte damage, but there is a genetic mutation. Patients are started on steroids, but proteinuria is still there so SRNS is diagnosed.

Question 6

How is genetic testing important for nephrotic syndrome?

Answer 6

Provides crucial data on the risk associated with nephrotic syndrome

Question 7

What is the importance of podocyte proteins in nephrotic syndrome?

Answer 7

Play an essential role when it comes to glomerular filtration, and pathogenic gene variants in these proteins account for most of the genetic nephrotic syndrome.

Question 8

What are examples of podocyte proteins?

Answer 8

Nephrin,
Podocin,
WT1,
Phospholipase C epsilon,
Laminin beta 2

Question 9

Why is it important to detect the genetic mutation causing nephrotic syndrome?

Answer 9

They have implications for the treatment and prognosis

Question 10

What is Laminin regulated by?

Answer 10

Lam protein

Question 11

What is the function of Podocin?

Answer 11

Essential for the formation of slit diaphragms

Question 12

What is the gene associated with congenital NS - Finnish type?

Answer 12

NPHS1

Question 13

What is the locus of congenital NS - Finnish type?

Answer 13

19q13.1

Question 14

What is the inheritance of congenital NS-Finnish type like?

Answer 14

AR

Question 15

What is the gene product of congenital NS - Finnish type?

Answer 15

Nephrin

Question 16

What is the age of onset of congenital NS-Finnish type?

Answer 16

Infancy

Question 17

What is the gene associated with SRNS / FSGS?

Answer 17

NPHS2

Question 18

What is the locus of SRNS / FSGS?

Answer 18

1q25-31

Question 19

What is the inheritance of SRNS / FSGS like?

Answer 19

AR

Question 20

What is gene product of SRNS / FSGS?

Answer 20

Podocin

Question 21

What is the age of onset for SRNS / FSGS?

Answer 21

3 months to adulthood

Question 22

What is the gene associated with FSGS/diffuse mesangial sclerosis (DMS)?

Answer 22

PLCE1

Question 23

What is the locus of FSGS/diffuse mesangial sclerosis (DMS)?

Answer 23

10q23

Question 24

What is the mode of inheritance of FSGS/diffuse mesangial sclerosis (DMS)?

Answer 24

AR

Question 25

What is the gene product of FSGS/diffuse mesangial sclerosis (DMS)?

Answer 25

Phospholipase C epsilon 1

Question 26

What is the age of onset of FSGS/diffuse mesangial sclerosis (DMS)?

Answer 26

Childhood

Question 27

What is the gene associated with Denys-Drash syndrome (DDS)?

Answer 27

WT1

Question 28

What is the locus of Denys-Drash syndrome (DDS)?

Answer 28

11p13

Question 29

What is the mode of inheritance of Denys-Drash syndrome (DDS)?

Answer 29

AD

Question 30

What is the gene product of Denys-Drash syndrome (DDS)?

Answer 30

WT1

Question 31

What is the age of onset of Denys-Drash syndrome (DDS)?

Answer 31

Infancy

Question 32

What is the gene associated with Pierson syndrome?

Answer 32

LAMB2

Question 33

What is the locus of the Pierson syndrome?

Answer 33

3p21

Question 34

What is the mode of inheritance of Pierson Syndrome?

Answer 34

AR

Question 35

What is the gene product of Pierson Syndrome?

Answer 35

Laminin- β2 chain

Question 36

What is the age of onset of Pierson Syndrome?

Answer 36

Infancy

Question 37

What is the gene associated with FSGS?

Answer 37

ACTN4

Question 38

What is the locus of FSGS?

Answer 38

19q13

Question 39

What is the mode of inheritance of FSGS?

Answer 39

AD

Question 40

What is the gene product of FSGS?

Answer 40

α-actinin-4

Question 41

What is the age of onset of FSGS?

Answer 41

Late (adulthood)

Question 42

Does the focal or diffuse presentation determine whether it is monogenic or not?

Answer 42

No, it just shows the extent of the mutational change

Question 43

Who should be tested for genetic mutation of nephrotic syndrome? (6)

Answer 43

1. Congenital nephrotic syndrome, onset (0 to 3 months) 2. Infantile nephrotic syndrome (3 to 12 months) 3. Childhood nephrotic syndrome > 12 months 4. A child with a family history of nephrotic syndrome or CKD 5. No response to steroid or steroid-resistant 6. An individual with nephrotic syndrome is associated with other congenital malformations

Question 44

What are other congenital malformations that could be associated with nephrotic syndrome?

Answer 44

Ambiguous genitalia

Question 45

What is monogenic nephrotic syndrome?

Answer 45

A single gene defect, a congenital condition

Question 46

What is the mode of inheritance of monogenic nephrotic syndrome?

Answer 46

AR or AD, based on the type

Question 47

What is the incidence of monogenic NS?

Answer 47

1 to 3/100000 live births

Question 48

What is the main cause of monogenic nephritic syndrome?

Answer 48

Idiopathic (80%)

Question 49

Why can monogenic nephrotic syndrome not be secondary?

Answer 49

The injury happens within the podocytes.

Question 50

What are the presentations of monogenic nephrotic syndrome? (6)

Answer 50

Heavy proteinuria, Edema, Hypoalbuminemia, Hypoglobulinemia, Hypercoagulability, Hyperlipidemia

Question 51

Why is hypercoagulability one of the presentations of NS?

Answer 51

Macromolecules, including anticoagulant proteins, also pass through the filtration slits

Question 52

Why is the management of monogenic NS very challenging?

Answer 52

Patients are prone to complications like infections, thrombosis and failure to thrive

Question 53

What is the management of monogenic NS?

Answer 53

It can progress to end-stage renal disease, which would require dialysis and, eventually, kidney transplantation

Question 54

What are the treatment options availbale for monogenic NS?

Answer 54

Immunosuppressive therapy, corticosteroids, or supportive care

Question 55

What is the importance of early detection?

Answer 55

Early genetci diagnosis improves management strategies

Question 56

What is genetic testing crucial for? (3)

Answer 56

1. Identifying specific gene mutations 2. Understanding familial patterns of inheritance 3. Facilitating appropriate treatment plans tailored to the genetic profile of the patient

Question 57

What is the gene associated with Syndromic NS/Congenital NS?

Answer 57

ITGA3

Question 58

What is the locus of Syndromic NS/Congenital NS?

Answer 58

17q21

Question 59

What is the mode of inheritance of Syndromic NS/Congenital NS?

Answer 59

AR

Question 60

What is the phenotype and mode of inheritance associated with CD2AP gene?

Answer 60

FSGS, AD

Question 61

What is the locus of the CD2AP FSGS?

Answer 61

6p12.3

Question 62

What is the gene associated with the Nail-patella syndrome?

Answer 62

LMX1B

Question 63

What is the mode of inheritance of NAIL-PATELLA syndrome?

Answer 63

AD

Question 64

What is the locus of the Nail-Patella syndrome?

Answer 64

9p34.1

Question 65

What is the phenotype of the INF2 gene?

Answer 65

Syndromic NS FSGS

Question 66

What is the locus of the INF2 gene mutation?

Answer 66

14q32

Question 67

What is NPHS1?

Answer 67

An adhesion molecule called nephrin protein

Question 68

Where is NPHS1 found?

Answer 68

At the slit diaphragm of glomerular podocytes

Question 69

What are the characteristics of the congenital NS - Finnish type?

Answer 69

Severe proteinuria, loss of the slit diaphragm and foot processes, and edema

Question 70

What is the prognosis of congenital NS - Finnish type?

Answer 70

Rapidly progressive, resulting in ESRD

Question 71

How is the congenital NS-Finnish type detected?

Answer 71

Antenatally by elevated alpha-fetoprotein levels

Question 72

What is the most common complication of congenital NS - Finnish type?

Answer 72

Failure to thrive and renal failure

Question 73

Which gene is mutated in the SRNS?

Answer 73

NPHS2 on chromosome 1

Question 74

What is the mode of inheritance of SRNS?

Answer 74

AR

Question 75

What are the different types of SRNS?

Answer 75

Familial FSGS, familial/sporadic SRNS

Question 76

What does the NPHS2 gene code for?

Answer 76

Podocin

Question 77

What are the clinical manifestations of SRNS?

Answer 77

Childhood-onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema

Question 78

What is the presentation of SRNS under a light microscope?

Answer 78

Nonspecific or no histological changes, such as minimal change or FSGS

Question 79

What is diffuse mesangial sclerosis NS?

Answer 79

Early onset NS, type 2 NPHS 3

Question 80

What is the alternative name of the NPHS3 gene that causes diffuse mesangial sclerosis?

Answer 80

PLCE 1

Question 81

What is the mutation and the mode of inheritance of diffuse mesangial sclerosis NS?

Answer 81

Homozygous mutation in the PLCE1 gene on chromosome 10, AR

Question 82

What is the function of the PLCE1 gene?

Answer 82

Related to the G-protein signaling pathway and cMYC transcription network

Question 83

What is the main presentation of the PLCE 1 NS?

Answer 83

Diffuse mesangial sclerosis - truncated protein A few cases of homozygous missense show FSGS

Question 84

What is the mutation and mode of inheritance of DDS?

Answer 84

AD and caused by a mutation in the tumor suppressor gene WT1 on chromosome 11

Question 85

What is the triad associated with DDS?

Answer 85

Ambiguous genitalia Nephrotic syndrome Wilm's tumor

Question 86

What is the management of DDS like?

Answer 86

Management is challenging and optimal strategies have yet not been established

Question 87

What are certain indications for prenatal evaluation? (6)

Answer 87

1. Placental weight is below 25% of newborn weight 2. Enlarged prenatal nucha translucency and fetal edema 3. Maternal AFP elevated during the 2nd trimester of pregnancy 4. Pathogenic variant has been previously identified in the family, consanguinity, and history of infantile death 5. Elevated AFP in proteinuria in utero 6. US shows hyperechogenic kidneys

Question 88

What do hyperechogenic kidneys look like in the US?

Answer 88

Very, very light in color

Question 89

Is it an indication for prenatal evaluation if there is elevated AFP in the first trimester?

Answer 89

No, anything prior to the second trimester is not an indication

Question 90

What is the treatment/management of monogenic NS?

Answer 90

Control edema and prevent complications Albumin infusion Intensity and duration of immunosuppression therapy ACE inhibitors, Lipid-lowering agents Renal transplantation

Question 91

When are albumin infusions given?

Answer 91

Only for heavy and constant proteinuria

Question 92

What are ACE inhibitors and lipid-lowering agents added for?

Answer 92

To slow disease progression

Question 93

What is the optimal treatment/management method?

Answer 93

Renal transplantation as it lowers the relapse rate

Question 94

Are there polygenic NS and steroid-sensitive NS?

Answer 94

Yes

Question 95

What contributes to polygenic NS?

Answer 95

Genetic variants in HLA-class II with additional genetic mutations like PLCG2 and FOXP3

Question 96

Can someone live asymptomatically with polygenic NS?

Answer 96

Yes, if the rest of the triggers (genes) are not activated throughout their life, they can carry on living as asymptomatic

Question 97

What is polygenic NS also known as/

Answer 97

Steroid-sensitive NS

Question 98

When does steroid-sensitive NS present?

Answer 98

During adulthood, it has weak heritability patterns and modifies through environmental factors