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Renal System > Inherited Monogenic Causes of Chronic Kidney Diseases > Flashcards

Inherited Monogenic Causes of Chronic Kidney Diseases Flashcards

1
Q

What is the global prevalence of CKD?

A

13%
Over 800 million adults worldwide

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2
Q

What is polygenic?

A

Dual genetic diagnosis with pathogenic variants in 2 different kidney-associated genes

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3
Q

What is monogenic?

A

Commonly driven by type IV collagen genes

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4
Q

Can CKD be polygenic and monogenic?

A

Yes

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5
Q

What is the mode of inheritance of monogenic CKD?

A

AD or AR

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6
Q

What percentage of CKD patients do genetics affect?

A

30% of adult CKD
70% of pediatric CKD

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7
Q

How many genes have been implicated in monogenic causes of CKD?

A

More than 500

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8
Q

What is used for the diagnosis of CKD?

A

Genetic testing

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9
Q

What is the main causes or etiology of CKD?

A

Etiology remains elusive; they are known as kidney diseases of unknown etiology

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10
Q

What number of patients with KDUE account for ESRD?

A

1 in 10 adults

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11
Q

What % of the causes of KDUE can genetic testing identify?

A

10 to 40%

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12
Q

What are examples of CKDs? (7)

A
  1. Cystic kidney disease (including nephronophthisis)
  2. Congenital anomalies of the kidneys and urinary tract
  3. Chronic glomerulonephritis
  4. Tubulointestinal kidney disease
  5. Nephrolithiasis/nephrocalcinosis
  6. Steroid-resistant nephrotic syndrome
  7. Rare chronic kidney disease
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13
Q

What is monogenic CKD?

A

Mendelian or monogenic disease (single-gene disorder) resulting from a pathogenic mutation of a single causative gene.

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13
Q

What is nephronophtosis?

A

An inherited disease which usually affects children; mode of inheritance is AR

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14
Q

What is the mode of inheritance of monogenic CKD?

A

AR, both parental alleles must be mutated to cause disease
AD, where a mutation in one parental allele is sufficient to cause disease

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15
Q

What is age-related penetrance?

A

As age increases, the chances of getting affected are greater

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16
Q

How many distinct genetic etiologies were discovered for CKD in adults? Using what?

A

47 distinct genetic etiologies were identified using genome-wide investigations

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17
Q

What is the type of mutation of CKD during the first 10 years of life?

A

AR, homozygous truncating

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18
Q

What is the type of mutation that would lead to CKD after the age of 10 but before the age of 50?

A

AR, homozygous missense

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19
Q

What is the type of mutation that would lead to CKD after the age of 50?

A

AD, incomplete penetrance or “mild” allele

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20
Q

What is the diagnostic approach to monogenic CKD?

A
  1. Take a full history, including family history of CKD
  2. Detect any extrarenal manifestations of syndromic disease
  3. Early onset kidney disease or early onset kidney failure
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21
Q

Why is taking a complete history important?

A

It is often the first clue to both monogenic and polygenic components of CKD, especially through family history

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22
Q

What is the procedure in patients with unexplained kidney diseases?

A

Do a whole diagnostic routine, especially if there is no genetic predisposition

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23
Q

In which cases do you avoid completing a renal biopsy for diagnosis?

A

In case of bleeding

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24
Q

What is the gold standard for diagnostic approach to monogenic CKD?

A

Genetic testing except in 2 conditions in which testing may be performed before completion or as part of the initial workup

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25
Q

When should targeted genetic testing be done?

A
  1. In cases highly suggestive of a specific genetic diagnosis
  2. When kidney biopsy poses a greater risk, such as un the setting of bleeding disorders, pregnancy or soltary kidney
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26
Q

In the case of lower possibility of genetic diagnosis what should be done?

A

Consider genetic testing based on clinical scenario, patient and physician preference, reimbursement considerations

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27
Q

What are the different methods of detecting monogenic causes of CKD in adults? (5)

A
  1. Karyotyping & chromosome microarray
  2. Whole exome sequencing
  3. Sanger sequencing
  4. Targeted gene panel sequencing
  5. Genome sequencing
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28
Q

What is karyotyping and CMA?

A

Genome-wide tests for structural variants such as translocation CNV, and chromosome aneuploidy

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29
Q

What are the advantages of karyotyping and CMA?

A

Cheap and fast
Can detect CNV at the exon level

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30
Q

What is CNV?

A

Copy-number variants

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31
Q

What are the disadvantages of karyotyping and CMA?

A

Lack of resolution to detect SNV smaller than 1Mb
Cannot detect balanced translocation

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32
Q

What is Sanger sequencing?

A

PCR-based single nucleotide sequencing

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33
Q

When is Sager sequencing used?

A

Used for confirmatory testing

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34
Q

What are the advantages of Sanger sequencing?

A

Highly sensitive and specific for small variants
High resolution

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35
Q

What are the disadvantages of Sanger sequencing?

A

Cannot detect most structural variation

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36
Q

What is exome sequencing?

A

Massively sequencing of nearly all protein-CODING (exons) portions of genes

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37
Q

Why is exome sequencing used?

A

It provides an unbiased survey that can detect disease-causing SNVs

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38
Q

What are the advantages of exome sequencing?

A

Highly sensitive to exonic SNV

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39
Q

What are the disadvantages of exome sequencing?

A

Limited detection of indels and CNVs
Expensive and time consuming
Requires expert analysis

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40
Q

What is genome sequencing?

A

Massive sequencing of the entirety of the genome and can detect most known disease-causing vriants

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41
Q

What are the advantages of genome sequencing?

A

Sensitive to exonic SNVs and intronic variants
Capable of detecting genomic disorders and sequencing genes with high homology to other loci

42
Q

What are the disadvantages of genome sequencing?

A

Can produce undesired incidental finding
Highly resource intensive and requires long-term data storage

43
Q

What is type IV collagen?

A

The major structural component of GBM, forming a meshwork together with laminins

44
Q

What happens if there is a lack of protein (type IV collagen)?

A

Loss of structural component and thus filtration issues

45
Q

What is the protein affected with COL4A3, COL4A4, and COL4A5 mutations?

A

Type IV collagen

46
Q

What chromosome is COL4A3 mutation on?

A

2q36.3

47
Q

What chromosome is COL4A4 mutation on?

A

2q36

48
Q

What chromosome is COL4A5 mutation on?

A

17q12 deletion

49
Q

What are the phenotypic features of the COL4A3, COL4A4, and COL4A5 mutations? (4)

A
  1. Autosomal recessive Alport syndrome
  2. Chronic nephritis
  3. FSGS
  4. AUtosomal dominant Alport syndrome
50
Q

Which protein is affected if the UMOD gene is mutated?

A

Uromucoid

51
Q

What chromosome is the mutation of the UMOD gene on?

A

16q12.3

52
Q

What protein is affected if MUC1 gene is mutated?

A

Mucin 1 cell surface protein

53
Q

What chromosome is the mutation of the MUC1 gene on?

A

1q22

54
Q

What are the phenotypic features of UMOD and MUC1 gene mutations? (2)

A
  1. Tubulointestinal kidney disease
  2. Autosomal dominant tubulointerstitial kidney disease
55
Q

What are the functions of the Mucin 1 cell surface protein and the Uromucoid protein?

A

Both proteins are important in tubular and interstitial function
Function in biogenesis and organization of the apical membrane of epithelial cells of the thick ascending limb of Henle’s loop

56
Q

What protein is affected by a mutation in the PKD1 gene?

A

Polycystic kidney disease type 1 protein

57
Q

What chromosome is the PKD1 gene mutation on?

A

16p13.3

58
Q

What protein is affected by a mutation in the PKD2 gene?

A

Polycystic kidney disease type 2 protein

59
Q

What chromosome is the PKD2 gene mutation on?

A

4q21.23

60
Q

What are the phenotypic features of PKD1 and PKD2 mutations?

A

Autosomal dominant polycystic kidney disease

61
Q

What is the function of the PKD protein?

A

It functions as a calcium-permeable cation channel and involves calcium transport and signaling in renal epithelial cells.

62
Q

What does PKD protein interact with? What is the result of that interaction?

A

PKD protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis

63
Q

What are the common monogenic CKD subtypes?

A

CAKUT (Congenital Abnormalities of the Kidneys & Urinary Tract)
Cystic Kidney Disease
Alport Syndrome

64
Q

What are examples of CAKUT?

A

Horseshoe kidney
Duplicated ureter

65
Q

Why does every CAKUT case require specific care?

A

Every case is unique, people might even go years without knowing of their conditions, so once diagnosed specific treatment/management is applied to each case

66
Q

When is CAKUT a common cause of CKD?

A

Usually presents in the first three decades of life

67
Q

Which structures might be affected in the CAKUT?

A

Pathologies involving the kidneys, ureter, bladder, urethra, and/or distal genitourinary tract

68
Q
A
69
Q

How many monogenic causes of syndromic CAKUT have been described?

A

153 monogenic causes of syndromic CAKUT

70
Q

What is the definition of syndromic CAKUT?

A

They present along with other syndromes or clinical manifestations

71
Q

What is the relation between CNVs and CAKUT?

A

CNVs contributed to the genetic architecture of CAKUT, according to recent studies

72
Q

Will patients with cystic kidney disease have a normal phenotype?

A

Most likely no, they present with various different clinical manifestations

73
Q

What are some clinical manifestations that cystic kidney disease patients present with?

A
  1. Distended abdomen due to voluminous kidney leading to respiratory issues
  2. Abdominal situs of ARPKD with symmetrically enlarged kindey
  3. Spongy kidney with poor corticomedullary differentiation, multiple tiny cysts
74
Q

How many types of cystic kidney diseases are there?

A

2

75
Q

What are the two types of cystic kidney disease?

A
  1. Autosomal dominant polycystic kidney disease (ADPKD)
  2. Autosomal recessive polycystic kidney disease (ARPKD)
76
Q

What is the inheritance of ADPKD?

A

AD

77
Q

What is the inheritance of ARPKD?

A

AR

78
Q

What genes are involved in ADPKD?

A

PKD1 and PKD2

79
Q

Which other organ is commonly affected by ARPKD? Why?

A

The liver, due to the mutation of PKHD1

80
Q

What genes are involved in ARPKD?

A

PKHD1

81
Q

What is the function of PKHD1?

A

It produces fibrocystin which gives kidneys their structure

82
Q

What are the associated protein with ADPKD?

A

Polycystin 1 and polycystin 2

83
Q

What are the associated proteins with ARPKD?

A

Fibrocystin

84
Q

What is the age of presentation with ADPKD?

A

Adulthood

85
Q

What is the age of presentation with ARPKD?

A

Antenatal, neonatal, infant

86
Q

What is a common presentation of ARPKD in the antenatal phase?

A

Oligohydramnios

87
Q

How is PKD diagnosed?

A

Through physical exam and ultrasound

88
Q

What is the management of PKD like?

A

Immediate as it is considered a health crisis, requires a multidisciplinary approach to slow the progression of renal disease

89
Q

How is the progression of renal disease slowed in the cases of PKD?

A

Control hypertension, proteinuria and other symptoms

90
Q

What is the prognosis of PKD like?

A

It depends on the presentation age and the degree of hepatic and renal involvement

91
Q

What is the presentation of Alport syndrome under the electron microscope?

A

Abnormally split and laminated GBM due to mutation in the collagen genes, which causes GBM to split and deform

92
Q

What is the mode of inheritance of Alport syndrome?

A

Can be AD or AR, it is usually X-linked (usually affects male sons, passed down from carrier mothers)

93
Q

What is Alport syndrome also called?

A

Hereditary nephritis

94
Q

What causes Alport syndrome?

A

A mutation in genes encoding for the alpha chains of type IV collagen

95
Q

What are the associated symptoms of Alport syndrome?

A

Hypertension, edema, hematuria, proteinuria, cataract, retinopathy, hearing loss

96
Q

How is the diagnosis of Alport syndrome established?

A

Urinalysis
Urine microscopy
Renal function panel
Renal biopsy

97
Q

What would a renal biopsy show in the diagnosis of Alport syndrome?

A

Characteristic glomerular basement membrane splitting

98
Q

What is the medical management of Alport syndrome?

A

Focuses on limiting the progression of disease by prescribing ARI and ACEi
Ultimate solution: renal transplantation

99
Q

What are the specific mutations that cause Alport syndrome?

A

COL4A3 –> mild form
COL4A4 –> mild form
COL4A5 –> X-linked, severe form

100
Q

In the case of Alport syndrome being AR, what are the mutations like?

A

A mutation in BOTH COL4A3 and COL4A4

101
Q

In the case of Alport syndrome being AD, what are the mutations like? And the prognosis?

A

Heterozygous mutation –> slower progression to ESRD –> inheritance but less likely to have extrenal manifestations

102
Q
A

Renal System (24 decks)

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