Genetics in Nephrology. Saeid Morovvati Associate Professor of BMSU Director of Biogene Laboratory

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2 Genetics in Nephrology Saeid Morovvati Associate Professor of BMSU Director of Biogene Laboratory

3 Genetics in: A. Congenital Anomalies of the Kidney and Urinary Tract B. Cystic Diseases of the Kidney C. Nephrotic Disorders

4 A. Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) 1. CAKUT occurs in approximately 1 in 500 fetal ultrasound examinations and represents 35 45% of all congenital abnormalities. 2. Over 250 syndromes and monogenic disorders have been reported to have an increased risk for CAKUT. 3. Many isolated structural anomalies of the urinary tract have multifactorial inheritance.

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7 We discuss genetics in CAKUT in 3 sections: 1. Errors of organogenesis 2. Errors of migration and position 3. Errors resulting in obstruction

8 Errors of Organogenesis 1. Renal Agenesis 2. Renal Hypoplasia/Dysplasia 3. Renal Cystic Disorders 4. Cystic Dysplastic Kidney 5. Ureteral Abnormalities 6. Bladder 7. Urethral Agenesis and Duplication 8. Posterior Urethral Valves

9 1. Renal Agenesis 1. Unilateral or bilateral renal agenesis refers to the complete absence of one or both kidneys. 2. Prevalence of unilateral renal agenesis is 1 in 5000 newborns, renal aplasia is 1 in 1300 and bilateral renal agenesis is about 1 in 30,000 newborns. 3. Mutations in EYA1, SIX1, SIX5, RET, UPK3A genes and all regulators of GDNF, result in defects in renal development. 4. Familial recurrence with autosomal dominant, recessive and X- linked patterns of inheritance has been reported with renal agenesis.

10 2. Renal Hypoplasia/Dysplasia 1. RHD is the second leading cause of chronic renal insufficiency in the pediatric population. 2. Unilateral dysplastic kidneys occur in 1 in 1000, and bilateral dysplasia in 1 in 5000 of the general population. 3. Mutations in PAX2 and HNF1B, and less commonly other renal developmental genes, such as EYA1, SIX1, SALL1 are involved in RHD. 4. PAX2 is one of the earliest genes expressed during fetal kidney development. Also, HNF1B is a critical regulator of a genetic cascade essential to controlling the proliferation and differentiation of renal tubular epithelial cells.

11 3. Renal Cystic Disorders 1. Over 250 congenital disorders are associated with renal cystic disease 2. Some population-based study report a birth incidence of renal cysts of 1 in 2000 total births.

12 4. Cystic Dysplastic Kidney 1. CDK is the most common cause of an abdominal mass in the newborn and the most common abnormality of the kidneys in children with CAKUT. The incidence is estimated to be 1 in 3500 births. 2. Many genes are involved in CDK. For example, mutations in WT1 lead to an abnormal structure in the kidney by failure of the mesenchymal tissue to differentiate into nephrons. Affected individuals or obligate heterozygotes have an empiric recurrence risk of 15 20%. 3. Chromosomal abnormalities in renal dysplasia occur in 10 30% of fetuses. Conversely, 35% of individuals with chromosomal disorders have renal anomalies, most commonly renal dysplasia. 4. Exclusion of associated structural anomalies and also karyotyping test is recommended when renal malformations are identified.

13 5. Ureteral Abnormalities 1. Agenesis of the ureters is not usually found in the absence of other urinary tract malformations. Renal agenesis is frequently associated with partial or complete agenesis of the ureters. 2. Disorders such as sirenomelia frequently have ureteral agenesis or abnormalities. 3. Duplication of the ureters is common, with a prevalence of 1:50 to 1:300, and is found as a feature in a number of syndromes. 4. Ureteral anomalies clearly have a hereditary basis, especially in the presence of associated anomalies. Male-to-male transmission is observed, suggesting autosomal dominant inheritance with variable expression.

14 6. Bladder 1. Major anomalies of the bladder are frequently associated with other malformations including exstrophy of the bladder. A hypoplastic bladder is expected in association with bilateral renal agenesis or other renal anomalies that prevent urine production and delivery to the bladder. 2. Agenesis of the bladder is an almost constant feature in sirenomelia. 3. Bladder diverticulae occur as a clinical feature of heritable disorders, particularly involving abnormal copper metabolism (i.e. cutis laxa syndrome). 4. Bladder dilatation can result from neurologic impairments, including neural tube defects and mitochondrial myopathies.

15 7. Urethral Agenesis and Duplication 1. Absence of the urethra is rare and reported predominantly in males. 2. When a specific disorder is not identified, recurrence risk for urethral atresia appears to be low. 3. Duplication of the urethra may be complete, or partial. The etiology of these conditions is unknown. Urethral duplication has occurred in males with Posterior Urethral Valves.

16 8. Posterior Urethral Valves 1. PUVs are found in males, masculinized females, and, rarely, in normal females. The incidence is estimated to be 1 in male infants. 2. PUVs are recognized to be the most common cause of obstructive uropathy that may lead to renal failure in childhood. The valves functionally obstruct urine outflow. 3. The majority of individuals with PUVs are normal. Isolated PUVs appear to have a recurrence risk of 2 6%.

17 Errors of migration and position 1. Horseshoe kidneys are the most common type of fused kidneys, accounting for 90%. Horseshoe kidneys have been found by radiographs in 1 in 200 individuals. 2. One-third of individuals with horseshoe kidneys remain asymptomatic. The most common clinical symptoms are pain, hematuria, and urinary tract symptoms from obstruction of the ureters. Infants and children may present with a lower abdominal mass. Hydronephrosis is the most commonly associated anomaly, being present in 45% of horseshoe kidneys. 3. Horseshoe kidneys are usually sporadic or related to the underlying genetic, chromosomal, or syndromic disorder. Familial recurrence has been reported. The risk for renal tumors specially Wilms tumor is increased.

18 Errors resulting in obstruction 1. It occur in about 1% of children, and in the majority of cases, it clears over time. A small proportion of these patients progress to end-stage renal disease. 2. The risk for fetal chromosomal abnormalities is three times higher when there is an isolated hydronephrosis, and 30 times higher when there are associated malformations of other organ systems in this abnormality.

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20 3. Autosomal dominant and recessive inheritance has been reported. An overall risk of 17% between first degree relatives and 100% concordance among very young monozygotic twins and 50% concordance among dizygotic twins has been reported. 4. Mutations in ROBO2, growth factor-beta1, and RET genes are associated with these disorders.

21 B. Cystic Diseases of the Kidney Cystic diseases of the kidney are some of the most significant monogenic causes of renal morbidity and mortality in both pediatric and adult populations. Although cystic renal disease can be acquired, we are to focus on those forms that are inherited: 1. Autosomal Dominant Polycystic Kidney Disease 2. Autosomal Recessive Polycystic Kidney Disease 3. Familial Nephronophthisis 4. Medullary Cystic Kidney Disease 5. Genetic Syndromes with Cystic Renal Disease as a Major Component

22 3. Familial Nephronophthisis 1. Nephronophthisis is the most common genetic cause of renal failure in the first three decades of life. 2. Nephronophthisis is an autosomal recessive disorder with variable presentation and considerable locus heterogeneity. 3. Three different variants have been identified and are classified according to age of onset. a. Juvenile nephronophthisis usually presents by age 6 years, with development of ESRD by a median age of 13 years. This variant is the most common of the three variants. b. Infantile nephronophthisis begins in infancy. c. The adolescent variant presents with ESRD at a median age of 19 years.

23 4. In all types, progressive chronic renal insufficiency (CRI) is invariable, and CRI progresses to ESRD, and if untreated, death resulting from uremia. 5. In most cases, mutations in the NPHP2 gene cause infantile nephronophthisis. Recently, mutations in NPHP3 and NPHP9 have been reported in patients with very-early-onset nephronophthisis. NPHP3 was the first gene identified to cause adolescent nephronophthisis. 6. An additional characteristic of nephronophthisis is its association with extrarenal malformations. In children with mutations in NPHP1 4, RP occurs in about 10% of families. However, all patients with NPHP5 mutations have RP.

24 Syndromes associated with Nephronophthisis 1. Joubert syndrome: It is an autosomal recessive condition. Mutations in AHI1, NPHP6, MKS3, and CC2D2A each account for approximately 10% of cases. About 1 2% of patients have a homozygous NPHP1 deletion. 2. Senior-Loken Syndrome, in the majority of cases, is caused by mutations in NPHP5, but mutations in NPHP1, NPHP2, NPHP3, and NPHP4 have been reported. 3. Cogan-Type Oculomotor Apraxia: Mutations in NPHP1 and NPHP4 have been found in this patients with nephronophthisis.

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26 4. Medullary Cystic Kidney Disease 1. Patients can present with polyuria, polydipsia, or isosthenuria, which are the same symptoms of juvenile nephronophthisis. Unlike nephronophthisis however, MCKD is dominantly inherited and has adult onset of disease. 2. A bimodal pattern is observed in the age of onset of disease and ESRD, with one peak in the third to fourth decade of life and another in the fifth to sixth decade of life. This pattern reflects the difference in phenotype of the two loci identified for MCKD. 3. MCKD1 generally presents later while MCKD2 (Uromodulin gene or UMOD) presents earlier.

27 4. Disease progresses rapidly: the average interval from diagnosis to ESRD is 5 years. 5. Since no specific gene has been identified for MCKD1, testing of at-risk individuals requires a family with several affected members and sufficient size in order for linkage analysis to have sufficient power. 6. Prenatal testing or testing of presymptomatic children is not recommended for a disease that is both treatable and does not present until adulthood.

28 5. Genetic Syndromes with Cystic Renal Disease as a Major Component 1. Tuberous Sclerosis Complex is inherited in an autosomal dominant manner with variable expression. Two genes are known to cause the disorder: TSC1 and TSC2. Individuals with a TSC1 mutation appear to have milder disease than TSC2, but TSC2 mutations are more frequent. 2. Bardet Biedl Syndrome is a genetically heterogeneous disorder with 14 gene loci identified to date. It is usually inherited in an autosomal recessive manner. 3. Asphyxiating Thoracic Dysplasia (ATD). Currently, two causative genes, IFT80 and DYNC2H1, are associated with ATD.

29 4. Glutaric Acidemia Type II is an autosomal recessive disorder caused by mutations in ETFA, ETFB, or ETFDH genes. 5. CPT2 Enzyme Deficiency is an autosomal recessive disorder caused by mutations in CPT2 gene. 6. Zellweger Syndrome is a disorder of peroxisome biogenesis and genetically heterogeneous. Mutations have been found in 12 different genes, all encoding proteins necessary for normal peroxisome assembly. PEX1 is the most commonly implicated, and the mode of inheritance for all types is autosomal recessive.

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31 C. Nephrotic Disorders 1. Nephrotic syndrome (NS) is a clinical diagnosis characterized by heavy proteinuria, hypoproteinemia, and edema. It occurs in various forms of acquired renal diseases, or may be part of systemic diseases, and may also be caused by infections and toxic agents. 2. The most common variety of primary NS in children is steroidsensitive nephrotic syndrome (SSNS). Approximately 80% of all children with NS respond to prednisone therapy. 3. During the past decade gene defects both in autosomal recessive and dominant forms of SRNS have been identified.

32 4. To date, approximately 10 20% of sporadic and 30 40% of familial cases of SRNS are associated with a gene defect. 5. These genes include NPHS1, NPHS2, WT1, PLCE1, LAMB2, TRPC6, CD2AP, ACTN4, and INF2. 6. It is to be expected that more pathogenetic gene defects will be identified in the future. The known gene disorders cover about two-thirds of NS in early childhood and less than 20% of the cases with late-onset of NS.

33 Diagnosis OF Nephrotic Disorders 1. NS is easily detected in newborns, infants, and children. Edema, hypoproteinemia, hyperlipidemia, and heavy proteinuria are the cardinal signs of NS. 2. In newborns with proteinuria during the first days of life, possible NPHS1 mutations should be screened, followed by NPHS2 analysis. 3. If kidney biopsy has been performed and shows FSGS histology and/or signs of renal failure, search for NPHS2 mutations is the first option in newborns as well as in older children. In these cases, if no mutation is detected, analysis of NPHS1, WT1 and PLCE1 can be performed. 4. In juvenile and adult patients with sporadic or autosomal recessive SRNS, screening for NPHS2 mutations is the first step.

34 5. A p.r229q variant together with a disease-causing mutation is often found in adult-onset FSGS. 6. In adults with autosomal dominant SRNS, screening for INF2, TPRC6, and ACTN4 is indicated. 7. Mutations in the NPHS1 gene lead especially to congenital NS, whereas NPHS2 mutations can cause NS at any age. The third important gene is WT1, which may cause syndromic and isolated NS. 8. For the clinician, the situation is complicated: several genes can cause NS with overlapping phenotypes. Sequencing several genes one after the other takes time and is costly. However, if causative mutations are found the situation regarding treatment, prognosis as well as risk of recurrence and possibilities for prenatal diagnostics become much more clear.

35 Thank you for your attention