Inherited Monogenic Causes of Chronic Kidney Diseases Flashcards
What is the global prevalence of CKD?
13%
Over 800 million adults worldwide
What is polygenic?
Dual genetic diagnosis with pathogenic variants in 2 different kidney-associated genes
What is monogenic?
Commonly driven by type IV collagen genes
Can CKD be polygenic and monogenic?
Yes
What is the mode of inheritance of monogenic CKD?
AD or AR
What percentage of CKD patients do genetics affect?
30% of adult CKD
70% of pediatric CKD
How many genes have been implicated in monogenic causes of CKD?
More than 500
What is used for the diagnosis of CKD?
Genetic testing
What is the main causes or etiology of CKD?
Etiology remains elusive; they are known as kidney diseases of unknown etiology
What number of patients with KDUE account for ESRD?
1 in 10 adults
What % of the causes of KDUE can genetic testing identify?
10 to 40%
What are examples of CKDs? (7)
- Cystic kidney disease (including nephronophthisis)
- Congenital anomalies of the kidneys and urinary tract
- Chronic glomerulonephritis
- Tubulointestinal kidney disease
- Nephrolithiasis/nephrocalcinosis
- Steroid-resistant nephrotic syndrome
- Rare chronic kidney disease
What is monogenic CKD?
Mendelian or monogenic disease (single-gene disorder) resulting from a pathogenic mutation of a single causative gene.
What is nephronophtosis?
An inherited disease which usually affects children; mode of inheritance is AR
What is the mode of inheritance of monogenic CKD?
AR, both parental alleles must be mutated to cause disease
AD, where a mutation in one parental allele is sufficient to cause disease
What is age-related penetrance?
As age increases, the chances of getting affected are greater
How many distinct genetic etiologies were discovered for CKD in adults? Using what?
47 distinct genetic etiologies were identified using genome-wide investigations
What is the type of mutation of CKD during the first 10 years of life?
AR, homozygous truncating
What is the type of mutation that would lead to CKD after the age of 10 but before the age of 50?
AR, homozygous missense
What is the type of mutation that would lead to CKD after the age of 50?
AD, incomplete penetrance or “mild” allele
What is the diagnostic approach to monogenic CKD?
- Take a full history, including family history of CKD
- Detect any extrarenal manifestations of syndromic disease
- Early onset kidney disease or early onset kidney failure
Why is taking a complete history important?
It is often the first clue to both monogenic and polygenic components of CKD, especially through family history
What is the procedure in patients with unexplained kidney diseases?
Do a whole diagnostic routine, especially if there is no genetic predisposition
In which cases do you avoid completing a renal biopsy for diagnosis?
In case of bleeding
What is the gold standard for diagnostic approach to monogenic CKD?
Genetic testing except in 2 conditions in which testing may be performed before completion or as part of the initial workup
When should targeted genetic testing be done?
- In cases highly suggestive of a specific genetic diagnosis
- When kidney biopsy poses a greater risk, such as un the setting of bleeding disorders, pregnancy or soltary kidney
In the case of lower possibility of genetic diagnosis what should be done?
Consider genetic testing based on clinical scenario, patient and physician preference, reimbursement considerations
What are the different methods of detecting monogenic causes of CKD in adults? (5)
- Karyotyping & chromosome microarray
- Whole exome sequencing
- Sanger sequencing
- Targeted gene panel sequencing
- Genome sequencing
What is karyotyping and CMA?
Genome-wide tests for structural variants such as translocation CNV, and chromosome aneuploidy
What are the advantages of karyotyping and CMA?
Cheap and fast
Can detect CNV at the exon level
What is CNV?
Copy-number variants
What are the disadvantages of karyotyping and CMA?
Lack of resolution to detect SNV smaller than 1Mb
Cannot detect balanced translocation
What is Sanger sequencing?
PCR-based single nucleotide sequencing
When is Sager sequencing used?
Used for confirmatory testing
What are the advantages of Sanger sequencing?
Highly sensitive and specific for small variants
High resolution
What are the disadvantages of Sanger sequencing?
Cannot detect most structural variation
What is exome sequencing?
Massively sequencing of nearly all protein-CODING (exons) portions of genes
Why is exome sequencing used?
It provides an unbiased survey that can detect disease-causing SNVs
What are the advantages of exome sequencing?
Highly sensitive to exonic SNV
What are the disadvantages of exome sequencing?
Limited detection of indels and CNVs
Expensive and time consuming
Requires expert analysis
What is genome sequencing?
Massive sequencing of the entirety of the genome and can detect most known disease-causing vriants
What are the advantages of genome sequencing?
Sensitive to exonic SNVs and intronic variants
Capable of detecting genomic disorders and sequencing genes with high homology to other loci
What are the disadvantages of genome sequencing?
Can produce undesired incidental finding
Highly resource intensive and requires long-term data storage
What is type IV collagen?
The major structural component of GBM, forming a meshwork together with laminins
What happens if there is a lack of protein (type IV collagen)?
Loss of structural component and thus filtration issues
What is the protein affected with COL4A3, COL4A4, and COL4A5 mutations?
Type IV collagen
What chromosome is COL4A3 mutation on?
2q36.3
What chromosome is COL4A4 mutation on?
2q36
What chromosome is COL4A5 mutation on?
17q12 deletion
What are the phenotypic features of the COL4A3, COL4A4, and COL4A5 mutations? (4)
- Autosomal recessive Alport syndrome
- Chronic nephritis
- FSGS
- AUtosomal dominant Alport syndrome
Which protein is affected if the UMOD gene is mutated?
Uromucoid
What chromosome is the mutation of the UMOD gene on?
16q12.3
What protein is affected if MUC1 gene is mutated?
Mucin 1 cell surface protein
What chromosome is the mutation of the MUC1 gene on?
1q22
What are the phenotypic features of UMOD and MUC1 gene mutations? (2)
- Tubulointestinal kidney disease
- Autosomal dominant tubulointerstitial kidney disease
What are the functions of the Mucin 1 cell surface protein and the Uromucoid protein?
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
What protein is affected by a mutation in the PKD1 gene?
Polycystic kidney disease type 1 protein
What chromosome is the PKD1 gene mutation on?
16p13.3
What protein is affected by a mutation in the PKD2 gene?
Polycystic kidney disease type 2 protein
What chromosome is the PKD2 gene mutation on?
4q21.23
What are the phenotypic features of PKD1 and PKD2 mutations?
Autosomal dominant polycystic kidney disease
What is the function of the PKD protein?
It functions as a calcium-permeable cation channel and involves calcium transport and signaling in renal epithelial cells.
What does PKD protein interact with? What is the result of that interaction?
PKD protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis
What are the common monogenic CKD subtypes?
CAKUT (Congenital Abnormalities of the Kidneys & Urinary Tract)
Cystic Kidney Disease
Alport Syndrome
What are examples of CAKUT?
Horseshoe kidney
Duplicated ureter
Why does every CAKUT case require specific care?
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
When is CAKUT a common cause of CKD?
Usually presents in the first three decades of life
Which structures might be affected in the CAKUT?
Pathologies involving the kidneys, ureter, bladder, urethra, and/or distal genitourinary tract
How many monogenic causes of syndromic CAKUT have been described?
153 monogenic causes of syndromic CAKUT
What is the definition of syndromic CAKUT?
They present along with other syndromes or clinical manifestations
What is the relation between CNVs and CAKUT?
CNVs contributed to the genetic architecture of CAKUT, according to recent studies
Will patients with cystic kidney disease have a normal phenotype?
Most likely no, they present with various different clinical manifestations
What are some clinical manifestations that cystic kidney disease patients present with?
- Distended abdomen due to voluminous kidney leading to respiratory issues
- Abdominal situs of ARPKD with symmetrically enlarged kindey
- Spongy kidney with poor corticomedullary differentiation, multiple tiny cysts
How many types of cystic kidney diseases are there?
2
What are the two types of cystic kidney disease?
- Autosomal dominant polycystic kidney disease (ADPKD)
- Autosomal recessive polycystic kidney disease (ARPKD)
What is the inheritance of ADPKD?
AD
What is the inheritance of ARPKD?
AR
What genes are involved in ADPKD?
PKD1 and PKD2
Which other organ is commonly affected by ARPKD? Why?
The liver, due to the mutation of PKHD1
What genes are involved in ARPKD?
PKHD1
What is the function of PKHD1?
It produces fibrocystin which gives kidneys their structure
What are the associated protein with ADPKD?
Polycystin 1 and polycystin 2
What are the associated proteins with ARPKD?
Fibrocystin
What is the age of presentation with ADPKD?
Adulthood
What is the age of presentation with ARPKD?
Antenatal, neonatal, infant
What is a common presentation of ARPKD in the antenatal phase?
Oligohydramnios
How is PKD diagnosed?
Through physical exam and ultrasound
What is the management of PKD like?
Immediate as it is considered a health crisis, requires a multidisciplinary approach to slow the progression of renal disease
How is the progression of renal disease slowed in the cases of PKD?
Control hypertension, proteinuria and other symptoms
What is the prognosis of PKD like?
It depends on the presentation age and the degree of hepatic and renal involvement
What is the presentation of Alport syndrome under the electron microscope?
Abnormally split and laminated GBM due to mutation in the collagen genes, which causes GBM to split and deform
What is the mode of inheritance of Alport syndrome?
Can be AD or AR, it is usually X-linked (usually affects male sons, passed down from carrier mothers)
What is Alport syndrome also called?
Hereditary nephritis
What causes Alport syndrome?
A mutation in genes encoding for the alpha chains of type IV collagen
What are the associated symptoms of Alport syndrome?
Hypertension, edema, hematuria, proteinuria, cataract, retinopathy, hearing loss
How is the diagnosis of Alport syndrome established?
Urinalysis
Urine microscopy
Renal function panel
Renal biopsy
What would a renal biopsy show in the diagnosis of Alport syndrome?
Characteristic glomerular basement membrane splitting
What is the medical management of Alport syndrome?
Focuses on limiting the progression of disease by prescribing ARI and ACEi
Ultimate solution: renal transplantation
What are the specific mutations that cause Alport syndrome?
COL4A3 –> mild form
COL4A4 –> mild form
COL4A5 –> X-linked, severe form
In the case of Alport syndrome being AR, what are the mutations like?
A mutation in BOTH COL4A3 and COL4A4
In the case of Alport syndrome being AD, what are the mutations like? And the prognosis?
Heterozygous mutation –> slower progression to ESRD –> inheritance but less likely to have extrenal manifestations
