- Email: [email protected]
Hereditary Renal Diseases
Hereditary Renal Diseases Lakshmi Mehta, MD,* and Belinda Jim, MD†
Summary: Hereditary kidney disease comprises approximately 10% of adults and nearly all children who require renal replacement therapy. Technologic advances have improved our ability to perform genetic diagnosis and enhanced our understanding of renal and syndromic diseases. In this article, we review the genetics of renal diseases, including common monogenic diseases such as polycystic kidney disease, Alport syndrome, and Fabry disease, as well as complex disorders such as congenital anomalies of the kidney and urinary tract. We provide the nephrologist with a general strategy to approach hereditary disorders, which includes a discussion of commonly used genetic tests, a guide to genetic counseling, and reproductive options such as prenatal diagnosis or pre-implantation genetic diagnosis for at-risk couples. Finally, we review pregnancy outcomes in certain renal diseases. Semin Nephrol 37:354-361 C 2017 Elsevier Inc. All rights reserved. Keywords: Hereditary renal disease, genetic counseling, pre-implantation genetic diagnosis
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pproximately 10% of adults and nearly all children who undergo renal replacement therapy have an inherited kidney disease. Because of advances in technology, the diagnosis of genetic disorders has improved, enabling better understanding of the genetic causes of renal and other syndromic diseases. Renal disorders are unique in that patients are likely to reproduce, and therefore, it is important that they are aware of the potential to avoid or prevent transmission of genetic disorders to their children by using genetic testing. Despite recent advances in genetic testing, studies have shown that use of genetic testing is not as high as it can be, suggesting that awareness is lower than in other fields of medicine. This may be the result of several factors, including the perception that establishing the genetic cause will not affect management of the disorder.1–3 To make options available to patients, accurate diagnosis of the precise genetic cause of the disorder is essential. Genetic disorders involving the kidneys are diverse and include chromosomal, monogenic, and multifactorial or polygenic causes. Patterns of inheritance are detailed in Table 1. In this article, we review common genetic etiologies and commonly used genetic tests, and provide a guide to genetic counseling and reproductive options *
Division of Medical Genetics, Department of Genetics and Genomic Sciences/Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY. † Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY. Financial disclosure and conflict of interest statements: none. Address reprint requests to Lakshmi Mehta, MD, Division of Medical Genetics, Department of Genetics and Genomic Sciences/Pediatrics, Icahn School of Medicine, Mount Sinai Medical Center, Box 1497, New York, NY 10029. E-mail: [email protected] 0270-9295/ - see front matter & 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2017.05.007
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for couples at risk to have a child with a genetic renal disorder. We also describe pregnancy outcomes of the best-studied inherited renal diseases.
CHROMOSOMAL DISORDERS AND COPY NUMBER VARIANTS Chromosomal abnormalities or aneuploidy refer to abnormal dosage of genes, either in the form of whole-chromosome monosomies or trisomies, or partial monosomies/trisomies in the form of deletions and duplications. Such abnormalities generally present with syndromic or dysmorphic features, growth problems, birth defects, and developmental disabilities. Genomewide scans for such imbalance, through the use of chromosomal microarrays, are used routinely for diagnosis to detect subtle microdeletions or duplications, termed copy number variants (CNVs), providing an additional yield of 10% to 15% if routine karyotype is normal. Renal structural anomalies are common in chromosome abnormalities. It is routine to screen individuals for renal anomalies by ultrasound in the setting of a chromosome abnormality. Examples of common chromosome abnormalities and recurrent microdeletions with renal involvement are provided in Table 2. For example, microdeletion of chromosome 17q12 along with deletion of the HNF1B gene, as well as mutations in this gene, are a cause of structural renal abnormalities.4 Furthermore, the detection of several recurrent CNVs by microarrays, with variable expression and reduced penetrance for features such as birth defects, has led to the theory that these variants may represent susceptibility alleles that require other genetic hits or triggers before they are expressed.
MONOGENIC DISORDERS Monogenic disorders, or genetic disorders caused by mutations in a single gene, typically follow an Seminars in Nephrology, Vol 37, No 4, July 2017, pp 354–361
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Table 1. Patterns of Inheritance Type of Disorder
Chance of Inheritance in Each Pregnancy
Autosomal dominant Autosomal recessive X-linked in a woman
50% 25% 25% for affected son 25% for carrier daughter 25% for healthy son 25% for noncarrier healthy daughter 100% for daughters who are obligate carriers; sons will not be affected 50%
X- linked in a man De novo dominant
autosomal-dominant, recessive, or X-linked inheritance pattern. In such disorders, genetic testing to establish the causative mutation can be complicated owing to allelic heterogeneity (many mutations in the same gene) or locus heterogeneity (many genes may be implicated for a phenotype). Molecular diagnostics for establishing a monogenic cause has evolved from the sequencing of an individual gene suspected to be the cause based on clinical suspicion, to sequencing many genes simultaneously using nextgeneration sequencing technology to accommodate a broad differential diagnosis. In recent years, wholeexome sequencing has led to the identification of novel genes for renal disease and expansion of the phenotypes and natural history of rare disorders. Table 3 illustrates the use of sequencing technologies. Multiple additional technologies are available to enhance gene identification, such as homozygosity mapping using microarray technology. Identification of the precise genetic cause enables accurate genetic counseling and prediction of risks for affected children; furthermore, it allows for reproductive options such as prenatal diagnosis or pre-implantation genetic diagnosis (PGD). Several common monogenic renal disorders are reviewed briefly later, with regard to their genetics and inheritance patterns, as well as pregnancy outcomes.
Autosomal dominant polycystic kidney disease Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases in human beings and may be caused by mutations either in the PKD1 or PKD2 gene, which encodes the polycystin-1 and polcystin-2 proteins, respectively. In approximately 90% of patients, the condition is inherited with a positive family history, whereas in 10% the disorder appears to be owing to a de novo mutation. ADPKD occurs with an incidence ranging from 1 in 400 to 1 in 1,000 persons.5 The average age of onset of ESRD for PKD1 mutation is earlier than for PKD2 mutation, with an average age of 54.3 versus 74 years.6 In patients with ADPKD, 85% are caused by mutations in PKD1 whereas 15% are caused by mutations in PKD2. A rare contiguous deletion of the PKD1 gene together with the tuberous sclerosis gene TSC2 causes a combination of features of both diseases. The current testing strategy would be to sequence both genes simultaneously. Mutations are detectable in approximately 90% of patients who are tested, making it a viable diagnostic option when imaging studies and family histories are equivocal. Pregnancy outcomes in women with ADPKD are varied. One study showed a higher incidence of hypertensive disorders of pregnancy in women with
Table 2. Renal Involvement in Chromosomal Abnormalities and Copy Number Variants Disease
Chromosomal Anomaly
Renal Findings
Down syndrome Turner syndrome
Trisomy 21 Monosomy X
Williams syndrome
Deletion 7q11
DiGeorge/velocardiofacial Syndrome CAKUT
22q11.2 microdeletion 17q12 deletion (HNF1B)
Hydronephrosis, multicystic kidneys, obstructive lesions, renal agenesis Structural: horseshoe kidney, duplication Vascular: hypertension, hypoplastic vessels, or aortic arch Asymmetric kidneys, solitary kidney, reflux, bladder diverticulae, nephrocalcinosis Absent, dysplastic, multicystic kidneys, obstructive uropathy, reflux Multicystic, dysplastic, hypoplastic kidneys, renal agenesis, ectopic kidney, reflux, hydronephrosis
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Table 3. Gene Sequencing Options Single Gene
Gene Panel
Exome Sequencing
Heterogeneous disorder with well-defined disease-associated genes
Extreme heterogeneity or unknown diagnosis
Pros and Minimal VUS cons No incidental findings
NGS with Sanger sequencing to fill in for 100% coverage, complementary deletion/duplication analysis Fewer VUS Unlikely incidental findings
Examples ADPKD genes
Alport panel, Ciliopathies
NGS, all 20,000 genes examined No Sanger fill in and coverage varies Certain mutation types not detected Large number of VUS Possible identification of mutations in genes with unknown function Incidental findings Undiagnosed diseases or unclear phenotype with broad differential diagnosis
Indication Specific disorder with specific diseasecausing gene Test Sanger sequencing
NOTE. In undiagnosed diseases, complementary tests also include microarray, exon CNV analysis, and homozygosity mapping. Abbreviations: NGS, next-generation sequencing; VUS, variants of uncertain significance. Adapted from Xue et al53 with permission.
ADPKD as compared with the control group, although multiple pregnancies did not appear to increase the risk of renal failure.7 A large study of ADPKD in pregnancy showed that in a group of 235 women with ADPKD with 605 pregnancies as compared with 108 unaffected family members with 244 pregnancies, fetal complication rates were similar.8 However, there were higher rates of maternal complications, including new or worsening hypertension and preeclampsia in women with ADPKD as compared with unaffected family members (35% versus 19%; P o .001), with pre-existing hypertension being the most important risk factor.8 Furthermore, among women with ADPKD and hypertension, those with four or more pregnancies had a lower age-adjusted creatinine clearance as compared with women with fewer than four pregnancies (49 ⫾ 5 versus 66 ⫾ 3 mL/min per 1.73 m2; P o .01). This observation suggests that women with ADPKD should be counseled that multiple consecutive pregnancies might increase the risk for progression. This study also suggested that women with ADPKD who were normotensive generally had successful uncomplicated pregnancies, but that women with hypertension had higher rates of fetal and maternal complications. Autosomal recessive polycystic kidney disease Autosomal-recessive polycystic kidney disease (ARPKD) is rare, with an incidence of 1 in 20,000. It can be identified either prenatally or neonatally by the presence of enlarged echogenic kidneys on ultrasound.9 In extreme cases, severe oligohydramnios leads to Potter’s phenotype, which consists of pulmonary hypoplasia, characteristic facies, and deformations. These severe findings can cause neonatal deaths in up to 30% of cases.10 ARPKD is caused by
mutations in the PKHD1 gene, which encodes for the protein fibrocystin. There is a high level of allelic heterogeneity of PKHD1, however recently, common mutations have been identified in the Ashkenazi Jewish population.11 Molecular diagnosis is necessary to confirm the diagnosis especially in nonsevere cases, and to enable future reproductive options for the family in severe cases. Alport syndrome Alport syndrome is a familial nephritis that is caused by defects in type IV collagen, which is composed of a heterotrimer of α chains 3, 4, and 5. Type IV collagen is the predominant network of basement membranes of the glomerular basement membrane, the cochlea, cornea, lens capsule, and retina, which explains much of the phenotype.12 The majority of patients (85%) inherit the disease as an X-linked trait because of a mutation in the COL4A5 gene.13 Mutations in the COL4A3 or COL4A4 genes encoding the α3 and α4 chains of type IV collagen cause the autosomalrecessive and rarely the autosomal-dominant forms of Alport syndrome. The disease presents as hematuria, progressive renal failure, sensorineural hearing loss, and ocular lesions such as anterior lenticonus and retinal thinning. Pathologic ultrastructural changes include irregular thinning, thickening, and splitting of the glomerular basement membrane. The X-linked form of this disease shows progression to ESRD by the second and third decades of life. Although most of Alport syndrome is diagnosed in males, X-linked diseases affect twice as many women. Although women commonly are undiagnosed, up to 30% of women with X-linked Alport syndrome may develop renal failure by 60 years of age.14 This severe
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outcome probably is owing to the phenomenon of X-chromosome inactivation.15 Autosomal-recessive Alport syndrome in both sexes behaves similarly to that of X-linked disease in males. Expert guidelines presently recommend genetic testing as the gold standard for the diagnosis of Alport syndrome to show its mode of inheritance, enable pre-implantation diagnosis, and to identify and closely follow up affected family members. Genetic testing is performed as a panel of these three genes: COL4A3, COL4A, and COL4A5. Along with the underdiagnosis of women with Alport syndrome, there is even less information on how it affects the kidney in pregnancy. In a case series of two women who carried the missense mutations in the α5 chain of type IV collagen, it was found that proteinuria had increased above their abnormal baseline throughout the pregnancy, one into the nephrotic range, despite normal renal function.16 The more severely proteinuric patient developed hypertension, prompting delivery at 33 weeks of gestation. Upon follow-up evaluation at 22 months postpartum, the patient with nephrotic range proteinuria decreased her creatinine clearance to 42 mL/min from normal, whereas the patient with subnephrotic proteinuria maintained her normal renal function. Conversely, a woman with X-linked Alport syndrome who experienced two consecutive pregnancies with normal blood pressure, mild proteinuria, and normal renal function had good obstetric and renal outcomes.17 It is difficult to adequately counsel affected women with this scarcity of data, however, control of blood pressure (and proteinuria) is recommended as good general obstetric practice, and as in other chronic renal diseases, those with preserved renal function can be expected to have better outcomes. Fabry disease Fabry disease is yet another rare X-linked lysosomal storage disorder that results from the deficiency of lysosomal enzyme α-galactosidase A (α-gal A) that affects 1 in 40,000 to 1 in 117,000 live births.18 Many heterozygote females show similar manifestations as males. Deficiency of this enzyme results in the storage of globotriaosylceramide and other glycosphingolipids in multiple cell types throughout the body, leading to multi-organ pathology in the nervous system, kidney, heart, gastrointestinal tract, and skin. Neurologic manifestations include chronic pain, acroparesthesias, hearing loss, tinnitus, hypohidrosis or hyperhidrosis, and strokes.19 Cardiac manifestations include hypertrophic cardiomyopathy, dysrhythmias, coronary ischemia, and valvular dysfunction. Renal disease presents with proteinuria, renal insufficiency, and possibly ESRD. Gastrointestinal involvement causes abdominal
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cramping and diarrhea. Psychological symptoms such as depression affect up to 50% of women.20,21 The diagnosis of Fabry disease is made by clinical suspicion followed by enzyme assay or mutation analysis (sequencing) of the α galactosidase A gene.22 It is unclear how Fabry disease affects pregnancy because there are only a handful of case reports mostly denoting successful pregnancy outcomes with use of enzyme replacement therapy during pregnancy.23,24 Preconception counseling should include retinal and audiologic testing, brain magnetic resonance imaging, electrocardiogram, echocardiogram, serum electrolytes, and a 24-hour urine collection for creatinine clearance and protein excretion. Prenatal diagnosis on amniocytes or chorionic villi of at-risk pregnancies may be offered25 because the offspring of affected women will have a 50% chance of having the disease. Treatment, even in pregnancy, consists of enzyme replacement with agalsidase alfa (α-galactosidase A) along with symptomatic management of complications such as neuropathic pain and cardiac and renal dysfunction.19,23,24 The medication currently is labeled as category B in pregnancy, and is administered with no dose adjustment. In terms of whether pregnancy impacts Fabry disease, a retrospective survey of 41 women indicated that several Fabryrelated symptoms such as gastrointestinal symptoms, acroparesthesias, proteinuria, headaches, and depression may worsen with increased frequency of hypertension in pregnancy.26 Fortunately, there is no documented increase in the incidence of strokes, ESRD, or other life-threatening complications. Bartter and Gitelman syndromes Bartter and Gitelman syndromes share similar modes of transmission, clinical manifestations, and treatment strategies. Bartter syndrome is an autosomal-recessive disorder owing to defects in the Na-K-2Cl co-transporter in the luminal membrane,27 the renal outer medullary K channel in the luminal membrane,28,29 the chloride channel Kb in the basolateral membrane of the ascending limb in the loop of Henle,30,31 the chloride channels in both the kidney and the inner ear, and the calcium-sensing receptor in the basolateral membrane of the thick ascending limb.32 Gitelman syndrome is an autosomal-recessive disorder as well that involves the apical distal convoluted tubule sodium chloride co-transporter. Patients with both of these syndromes present with hypokalemia, metabolic alkalosis, and hypocalcuria, but for Gitelman syndrome, they also present with hypomagnesemia in late childhood or adulthood.33 Given the rarity of this disease in the overall population, only a few case reports have described pregnancy outcomes. For both syndromes, the requirements for potassium and magnesium replacement increase
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Table 4. Rare Hereditary Disorders Involving the Kidneys Group
Disease
Ciliopathies ARPKD Bardet Biedl CAKUT Renal– coloboma Branchio-otorenal Tumors Von Hippel Lindau Tuberous sclerosis
Gene
Inheritance Renal Features
PKHD1 AR BBS1-17 AR PAX2 AD EYA1
AD
VHL
AD
TSC1/ TSC2
AD
Cystic or complex Hypoplasia Dysplasia Hypoplasia Clear cell RCC, cysts
Extrarenal Features Hepatic fibrosis, retinal, short stature, obesity, polydactyly Optic coloboma Branchial, ear Hemangioblastoma pheochromocytoma
Angiomyolipoma, RCC, cysts, Skin findings FSGS Seizures SEGA
AD, autosomal dominant; AR, autosomal recessive; FSGS, focal segmental glomerulosclerosis; RCC, renal cell carcinoma; SEGA, subependymal giant cell astrocytoma. Adapted from Joly et al2 with permission.
dramatically during pregnancy. Case reports of pregnancy with Bartter syndrome have shown increases of potassium supplementation of up to 480 mEq/d, along with the need for amiloride.34–37 In Gitelman syndrome, a case series of five Italian women showed four uneventful pregnancies, while one was complicated by tetanic seizures (of unclear etiology).38 These women were managed primarily with potassium and magnesium salts, whereas one patient required amiloride. The pregnancies were successful and resulted in four neonates who were born at term and two near-term with appropriate body weight.38 Other potassium-sparing diuretics such as spironolactone and eplerenone also have been used successfully.39,40 A review of the literature showed that 78 pregnancies associated with Bartter and Gitelman syndrome resulted in a favorable outcome, with 63 pregnancies delivering between 37 and 40 weeks of gestation.38 Again, aggressive supplementation was required, as well as additional medications such as spironolactone or amiloride with no adverse fetal effects. However, in general, we do not recommend the use of spironolactone because of its
Table 5. Types of CAKUT Disorders Ureteropelvic junction obstruction Kidney agenesis Multicystic dysplastic kidneys Kidney dysplasia Kidney hypoplasia Hydronephrosis Vesicoureteral reflux Megaureter Ectopic ureter Horseshoe kidney Duplex collecting system Posterior urethral valves CAKUT: Congenital anomalies of the kidney and urinary tract
potential antiandrogenic effects on male fetuses.41 As noted, amiloride also may be considered in difficult-tomanage cases. Furthermore, adequate repletion of the potassium and magnesium losses often will require hospitalization for intravenous administration because oral doses either may not suffice or may have intolerable side effects (eg, severe diarrhea from high doses of magnesium).42 Other rare hereditary renal disorders with a known genetic basis are illustrated in Table 4.
COMPLEX OR MULTIFACTORIAL DISORDERS Conditions currently believed to be caused by polygenic susceptibilities or gene–environment interactions are termed complex or multifactorial disorders. Congenital anomalies of the kidney and urinary tract (CAKUT) refers to a group of structural abnormalities initiated during embryonic kidney development of complex etiology. CAKUTs comprise up to 30% of all congenital abnormalities with a prevalence ranging between 3 and 6 per 1,000 births.43,44 Malformations such as ureteropelvic junction obstruction (most common), kidney agenesis, multicystic dysplastic kidneys, kidney dysplasia, kidney hypoplasia, vesicoureteral reflux, and duplex collecting system are included (Table 5). Prenatal detection of these malformations has improved dramatically with the quality and availability of ultrasonography, although many still may remain undetected until after birth when infants or children become symptomatic. These anomalies are believed to cause 40% to 50% of pediatric ESRD and an unknown percentage of adult ESRD. CAKUT may be associated in syndromic form with other anomalies when caused by chromosomal abnormalities, rare CNVs, or monogenic disorders such as the branchiooto-renal syndrome. More than 20 single-gene causes
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Table 6. Examples of Autosomal-Recessive Diseases With Renal Involvement Tested Through Expanded Carrier Screening Disease
Gene
Ethnicity
Carrier Frequency
Pubmed ID
Alport Bardet Biedl Joubert 2 ARPKD Renal tubular acidosis, deafness Cystinosis Congenital nephrosis
COL4A3 BBS2 TMEM216 PKHD1 ATP6V1B1 CTNS NPHS1
Ashkenazi Ashkenazi Ashkenazi Ashkenazi Moroccan/Syrian Moroccan Finnish
1:192 1:140 1:110 1:106 1:140 1:100 1:45
23927549 and 27415407 23829372 20036350 27415407 * Personal communication 10767171 938078
*Personal communication from Mount Sinai Genetic Testing Laboratory, New York.
of CAKUT have been described.44–47 These anomalies also may cluster with other birth defects, as in the vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects association. Mutations in the ZIC3 and FOXF1 genes have been implicated in vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects, the cluster of birth defects known as VACTERL association.48 HNF1B mutations, the 17q12 microdeletion CNV and PAX2 mutations, which cause renal dysplasia of the renal coloboma syndrome, may account for 15% of CAKUT.49
GENETIC EVALUATION In practical terms, genetic testing is best performed after genetic counseling. A genetics evaluation is helpful to define the phenotype and choose the appropriate testing. Choice of test, cost, benefits, and limitations of testing are part of pretest genetic counseling. Sequence variants of uncertain significance continue to be the biggest challenge in interpretation of results. For an individual with a genetic disorder who is considering a pregnancy, the ideal time to review options is during the preconception period. Pediatric referrals to geneticists are generally to identify the genetic basis of a renal disease. Adults are referred because of their own personal history of a hereditary disorder or because they have a partner, child, or family member with a genetic or suspected genetic condition. The American College of Obstetrics and Gynecology recommends that women with genetic disorders, such as ADPKD, be referred to genetics specialists and relevant subspecialists in the preconception period to optimize maternal health, review maternal and neonatal morbidities, and to be offered genetic counseling to review reproductive options.50 The genetics evaluation includes a review of personal history, family history, and supporting investigations to help establish the details of the phenotype and natural history. The causative genetic mutation first must be identified in an affected individual. The choice of test can become complex because of availability, insurance
coverage, detection rates, and turnaround time. An integral part of the genetic testing process is obtaining informed consent, which must review possible test results such as limitations of a negative result, implications of a positive result, and the detection of variants of uncertain significance. Patients may have concerns related to privacy and discrimination, particularly in the setting of presymptomatic testing. Currently, the Genetic Information Non-Discrimination Act protects individuals from employer and health insurer discrimination (https://www.eeoc.gov/laws/stat utes/gina.cfm). Today, a wide range of screening tests routinely are available to couples considering a pregnancy. These include carrier screening for recessive disorders. Although there is inconsistency in what panel of testing is offered, several hereditary renal disorders have been included in such panels because of the identification of recurrent mutations. Table 6 shows some genes for recessive disorders affecting the kidneys made available through carrier screening panels. In an already established pregnancy, genetic testing of cell-free fetal DNA is offered as a screening test for common chromosomal trisomies, such as Down syndrome. In the future, this may well extend to testing for other genetic abnormalities. Once a genetic basis for a disorder is identified, couples may wish to discuss options. These include testing for the targeted mutations in an established pregnancy through chorionic villus sampling at 10 to 12 weeks’ gestation or amniocentesis at 16 weeks’ gestation or later. The pros and cons of these invasive procedures that carry a small risk of miscarriage must be weighed against the actionability of diagnosing a fetus with a genetic disorder. In general, it is our experience that although there is demand for establishing causative mutations in an adult with a condition such as ADPKD or Alport syndrome, demand for testing an established pregnancy is low. Couples may prefer to defer testing until their child is at an age when monitoring is recommended. Finally, couples may choose to use preimplantation genetic diagnosis
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(PGD) to avoid the birth of a child with a genetic disorder. The goal of PGD is to select out the unaffected embryos after genetic analysis, before transfer into the woman to establish pregnancy. The PGD option avoids the difficult decision to possibly terminate a pregnancy when a genetic diagnosis is made after conception. There is limited published literature exploring the demand for PGD for renal disorders such as ADPKD; most of the literature focuses on severe childhood-onset disorders, adult-onset neurodegenerative disorders such as Huntington disease, or hereditary cancer susceptibility. We have anecdotal experience of couples seeking PGD for potentially fatal recessive conditions such as ARPKD. To date, short-term follow-up evaluation of singletons born after PGD have not been found to be different compared with spontaneous conceptions in terms of congenital malformation, postnatal linear growth, or cognitive impairment.51,52
SUMMARY The general strategy for nephrologists with regard to patients with hereditary disorders or a family history of such conditions should be to refer the patient for genetic counseling and testing early after diagnosis to establish a genetic cause. An affected patient must be tested first to establish the causative mutation(s). The choice of test, cost, and benefits and limitations of testing are part of pretest genetic counseling. Sequence variants of uncertain significance continue to be a challenge in the interpretation of results. As data sharing and testing continue to develop, the hope is that knowledge of the genetic cause will help in not just reproductive options for the patient and their family, but also in improving the understanding of genotype–phenotype correlations, modifiers of outcome, and eventually the development of therapeutics.
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L. Mehta and B. Jim 6. Hateboer N, v Dijk MA, Bogdanova N, et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet. 1999;353:103-7. 7. Milutinovic J, Fialkow PJ, Agodoa LY, Phillips LA, Bryant JI. Fertility and pregnancy complications in women with autosomal dominant polycystic kidney disease. Obstet Gynecol. 1983;61:566-70. 8. Chapman AB, Johnson AM, Gabow PA. Pregnancy outcome and its relationship to progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1994;5:1178-85. 9. Harris PC, Torres VE. Polycystic kidney disease. Ann Rev Med. 2009;60:321-37. 10. Guay-Woodford LM, Desmond RA. Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics. 2003;111:1072-80. 11. Shi L, Webb BD, Birch AH, et al. Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease-causing variants. Clin Genet. 2017;91:599-604. 12. Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med. 2003;348:2543-56. 13. Artuso R, Fallerini C, Dosa L, et al. Advances in Alport syndrome diagnosis using next-generation sequencing. Eur J Hum Genet. 2012;20:50-7. 14. Savige J, Colville D, Rheault M, et al. Alport Syndrome in women and girls. Clin J Am Soc Nephrol. 2016;11:1713-20. 15. Rheault MN. Women and Alport syndrome. Pediatr Nephrol. 2012;27:41-6. 16. Alessi M, Fabris A, Zambon A, et al. Pregnancy in Alport syndrome: a report of two differently-evolving cases. J Obstet Gynaecol. 2014;34:98-100. 17. Matsubara S, Muto S. Good obstetric outcome of consecutive pregnancies in a woman with Alport syndrome. Arch Gynecol Obstet. 2012;286:261-2. 18. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34:236-42. 19. Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008;372: 1427-35. 20. Bouwman MG, Rombach SM, Schenk E, et al. Prevalence of symptoms in female Fabry disease patients: a case-control survey. J Inherit Metab Dis. 2012;35:891-8. 21. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007;9: 34-45. 22. Laney DA, Bennett RL, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2013;22:555-64. 23. Kalkum G, Macchiella D, Reinke J, Kolbl H, Beck M. Enzyme replacement therapy with agalsidase alfa in pregnant women with Fabry disease. Eur J Obstet Gynecol Reprod Biol. 2009;144:92-3. 24. Wendt S, Whybra C, Kampmann C, Teichmann E, Beck M. Successful pregnancy outcome in a patient with Fabry disease receiving enzyme replacement therapy with agalsidase alfa. J Inherit Metab Dis. 2005;28:787-8. 25. Desnick RJ. Prenatal diagnosis of Fabry disease. Prenat Diagn. 2007;27:693-4. 26. Holmes A, Laney D. A retrospective survey studying the impact of Fabry disease on pregnancy. JIMD Rep. 2015;21: 57-63. 27. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet. 1996;13:183-8.
Hereditary renal diseases 28. Simon DB, Karet FE, Rodriguez-Soriano J, et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the Kþ channel, ROMK. Nat Genet. 1996;14:152-6. 29. Lorenz JN, Baird NR, Judd LM, et al. Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter’s syndrome. J Biol Chem. 2002;277:37871-80. 30. Simon DB, Bindra RS, Mansfield TA, et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nat Genet. 1997;17:171-8. 31. Konrad M, Vollmer M, Lemmink HH, et al. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol. 2000;11:1449-59. 32. Watanabe S, Fukumoto S, Chang H, et al. Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet. 2002;360:692-4. 33. Bettinelli A, Bianchetti MG, Girardin E, et al. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr. 1992;120:38-43. 34. Almeida OD Jr, Spinnato JA. Maternal Bartter’s syndrome and pregnancy. Am J Obstet Gynecol. 1989;160:1225-6. 35. Klajnbard A, Thomsen JK. Bartter’s syndrome and pregnancy. Acta Obstet Gynecol Scand. 2000;79:81-2. 36. Clode N, Mendonca E, Stone R, et al. Bartter’s syndrome and pregnancy. Eur J Obstet Gynecol Reprod Biol. 1999;82:17-8. 37. Peregrin-Alvarez I, Rodriguez-Casares J, Lucena-Herrera C, Arribas F, Castro D. Bartter’s syndrome and pregnancy. Eur J Obstet Gynecol Reprod Biol. 2005;121:118-9. 38. Mascetti L, Bettinelli A, Simonetti GD, et al. Pregnancy in inherited hypokalemic salt-losing renal tubular disorder. Obstet Gynecol. 2011;117:512-6. 39. Daskalakis G, Marinopoulos S, Mousiolis A, Mesogitis S, Papantoniou N, Antsaklis A. Gitelman syndrome-associated severe hypokalemia and hypomagnesemia: case report and review of the literature. J Matern Fetal Neonatal Med. 2010;23:1301-4. 40. de Arriba G, Sanchez-Heras M, Basterrechea MA. Gitelman syndrome during pregnancy: a therapeutic challenge. Arch Gynecol Obstet. 2009;280:807-9. 41. Groves TD, Corenblum B. Spironolactone therapy during human pregnancy. Am J Obstet Gynecol. 1995;172:1655-6.
361 42. McCarthy FP, Magee CN, Plant WD, Kenny LC. Gitelman’s syndrome in pregnancy: case report and review of the literature. Nephrol Dial Transplant. 2010;25:1338-40. 43. Queisser-Luft A, Stolz G, Wiesel A, Schlaefer K, Spranger J. Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990-1998). Arch Gynecol Obstet. 2002;266:163-7. 44. Sanna-Cherchi S, Caridi G, Weng PL, et al. Genetic approaches to human renal agenesis/hypoplasia and dysplasia. Pediatr Nephrol. 2007;22:1675-84. 45. Chen F. Genetic and developmental basis for urinary tract obstruction. Pediatr Nephrol. 2009;24:1621-32. 46. Renkema KY, Winyard PJ, Skovorodkin IN, et al. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT). Nephrol Dial Transplant. 2011;26:3843-51. 47. Weber S. Novel genetic aspects of congenital anomalies of kidney and urinary tract. Curr Opin Pediatr. 2012;24:212-8. 48. Hilger AC, Halbritter J, Pennimpede T, et al. Targeted resequencing of 29 candidate genes and mouse expression studies implicate ZIC3 and FOXF1 in human VATER/VACTERL association. Hum Mutat. 2015;36:1150-4. 49. Nicolaou N, Renkema KY, Bongers EM, Giles RH, Knoers NV. Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol. 2015;11:720-31. 50. Genetics Co. Identification and referral of maternal genetic conditions in pregnancy. Am Coll Obstet Gynecol. 2015;643:1. 51. Desmyttere S, De Schepper J, Nekkebroeck J, et al. Two-year auxological and medical outcome of singletons born after embryo biopsy applied in preimplantation genetic diagnosis or preimplantation genetic screening. Hum Reprod. 2009;24: 470-6. 52. Winter C, Van Acker F, Bonduelle M, Desmyttere S, De Schrijver F, Nekkebroeck J. Cognitive and psychomotor development of 5- to 6-year-old singletons born after PGD: a prospective case-controlled matched study. Hum Reprod. 2014;29:1968-77. 53. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17: 444-51.
Summary: Hereditary kidney disease comprises approximately 10% of adults and nearly all children who require renal replacement therapy. Technologic advances have improved our ability to perform genetic diagnosis and enhanced our understanding of renal and syndromic diseases. In this article, we review the genetics of renal diseases, including common monogenic diseases such as polycystic kidney disease, Alport syndrome, and Fabry disease, as well as complex disorders such as congenital anomalies of the kidney and urinary tract. We provide the nephrologist with a general strategy to approach hereditary disorders, which includes a discussion of commonly used genetic tests, a guide to genetic counseling, and reproductive options such as prenatal diagnosis or pre-implantation genetic diagnosis for at-risk couples. Finally, we review pregnancy outcomes in certain renal diseases. Semin Nephrol 37:354-361 C 2017 Elsevier Inc. All rights reserved. Keywords: Hereditary renal disease, genetic counseling, pre-implantation genetic diagnosis
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pproximately 10% of adults and nearly all children who undergo renal replacement therapy have an inherited kidney disease. Because of advances in technology, the diagnosis of genetic disorders has improved, enabling better understanding of the genetic causes of renal and other syndromic diseases. Renal disorders are unique in that patients are likely to reproduce, and therefore, it is important that they are aware of the potential to avoid or prevent transmission of genetic disorders to their children by using genetic testing. Despite recent advances in genetic testing, studies have shown that use of genetic testing is not as high as it can be, suggesting that awareness is lower than in other fields of medicine. This may be the result of several factors, including the perception that establishing the genetic cause will not affect management of the disorder.1–3 To make options available to patients, accurate diagnosis of the precise genetic cause of the disorder is essential. Genetic disorders involving the kidneys are diverse and include chromosomal, monogenic, and multifactorial or polygenic causes. Patterns of inheritance are detailed in Table 1. In this article, we review common genetic etiologies and commonly used genetic tests, and provide a guide to genetic counseling and reproductive options *
Division of Medical Genetics, Department of Genetics and Genomic Sciences/Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY. † Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY. Financial disclosure and conflict of interest statements: none. Address reprint requests to Lakshmi Mehta, MD, Division of Medical Genetics, Department of Genetics and Genomic Sciences/Pediatrics, Icahn School of Medicine, Mount Sinai Medical Center, Box 1497, New York, NY 10029. E-mail: [email protected] 0270-9295/ - see front matter & 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2017.05.007
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for couples at risk to have a child with a genetic renal disorder. We also describe pregnancy outcomes of the best-studied inherited renal diseases.
CHROMOSOMAL DISORDERS AND COPY NUMBER VARIANTS Chromosomal abnormalities or aneuploidy refer to abnormal dosage of genes, either in the form of whole-chromosome monosomies or trisomies, or partial monosomies/trisomies in the form of deletions and duplications. Such abnormalities generally present with syndromic or dysmorphic features, growth problems, birth defects, and developmental disabilities. Genomewide scans for such imbalance, through the use of chromosomal microarrays, are used routinely for diagnosis to detect subtle microdeletions or duplications, termed copy number variants (CNVs), providing an additional yield of 10% to 15% if routine karyotype is normal. Renal structural anomalies are common in chromosome abnormalities. It is routine to screen individuals for renal anomalies by ultrasound in the setting of a chromosome abnormality. Examples of common chromosome abnormalities and recurrent microdeletions with renal involvement are provided in Table 2. For example, microdeletion of chromosome 17q12 along with deletion of the HNF1B gene, as well as mutations in this gene, are a cause of structural renal abnormalities.4 Furthermore, the detection of several recurrent CNVs by microarrays, with variable expression and reduced penetrance for features such as birth defects, has led to the theory that these variants may represent susceptibility alleles that require other genetic hits or triggers before they are expressed.
MONOGENIC DISORDERS Monogenic disorders, or genetic disorders caused by mutations in a single gene, typically follow an Seminars in Nephrology, Vol 37, No 4, July 2017, pp 354–361
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Table 1. Patterns of Inheritance Type of Disorder
Chance of Inheritance in Each Pregnancy
Autosomal dominant Autosomal recessive X-linked in a woman
50% 25% 25% for affected son 25% for carrier daughter 25% for healthy son 25% for noncarrier healthy daughter 100% for daughters who are obligate carriers; sons will not be affected 50%
X- linked in a man De novo dominant
autosomal-dominant, recessive, or X-linked inheritance pattern. In such disorders, genetic testing to establish the causative mutation can be complicated owing to allelic heterogeneity (many mutations in the same gene) or locus heterogeneity (many genes may be implicated for a phenotype). Molecular diagnostics for establishing a monogenic cause has evolved from the sequencing of an individual gene suspected to be the cause based on clinical suspicion, to sequencing many genes simultaneously using nextgeneration sequencing technology to accommodate a broad differential diagnosis. In recent years, wholeexome sequencing has led to the identification of novel genes for renal disease and expansion of the phenotypes and natural history of rare disorders. Table 3 illustrates the use of sequencing technologies. Multiple additional technologies are available to enhance gene identification, such as homozygosity mapping using microarray technology. Identification of the precise genetic cause enables accurate genetic counseling and prediction of risks for affected children; furthermore, it allows for reproductive options such as prenatal diagnosis or pre-implantation genetic diagnosis (PGD). Several common monogenic renal disorders are reviewed briefly later, with regard to their genetics and inheritance patterns, as well as pregnancy outcomes.
Autosomal dominant polycystic kidney disease Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases in human beings and may be caused by mutations either in the PKD1 or PKD2 gene, which encodes the polycystin-1 and polcystin-2 proteins, respectively. In approximately 90% of patients, the condition is inherited with a positive family history, whereas in 10% the disorder appears to be owing to a de novo mutation. ADPKD occurs with an incidence ranging from 1 in 400 to 1 in 1,000 persons.5 The average age of onset of ESRD for PKD1 mutation is earlier than for PKD2 mutation, with an average age of 54.3 versus 74 years.6 In patients with ADPKD, 85% are caused by mutations in PKD1 whereas 15% are caused by mutations in PKD2. A rare contiguous deletion of the PKD1 gene together with the tuberous sclerosis gene TSC2 causes a combination of features of both diseases. The current testing strategy would be to sequence both genes simultaneously. Mutations are detectable in approximately 90% of patients who are tested, making it a viable diagnostic option when imaging studies and family histories are equivocal. Pregnancy outcomes in women with ADPKD are varied. One study showed a higher incidence of hypertensive disorders of pregnancy in women with
Table 2. Renal Involvement in Chromosomal Abnormalities and Copy Number Variants Disease
Chromosomal Anomaly
Renal Findings
Down syndrome Turner syndrome
Trisomy 21 Monosomy X
Williams syndrome
Deletion 7q11
DiGeorge/velocardiofacial Syndrome CAKUT
22q11.2 microdeletion 17q12 deletion (HNF1B)
Hydronephrosis, multicystic kidneys, obstructive lesions, renal agenesis Structural: horseshoe kidney, duplication Vascular: hypertension, hypoplastic vessels, or aortic arch Asymmetric kidneys, solitary kidney, reflux, bladder diverticulae, nephrocalcinosis Absent, dysplastic, multicystic kidneys, obstructive uropathy, reflux Multicystic, dysplastic, hypoplastic kidneys, renal agenesis, ectopic kidney, reflux, hydronephrosis
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Table 3. Gene Sequencing Options Single Gene
Gene Panel
Exome Sequencing
Heterogeneous disorder with well-defined disease-associated genes
Extreme heterogeneity or unknown diagnosis
Pros and Minimal VUS cons No incidental findings
NGS with Sanger sequencing to fill in for 100% coverage, complementary deletion/duplication analysis Fewer VUS Unlikely incidental findings
Examples ADPKD genes
Alport panel, Ciliopathies
NGS, all 20,000 genes examined No Sanger fill in and coverage varies Certain mutation types not detected Large number of VUS Possible identification of mutations in genes with unknown function Incidental findings Undiagnosed diseases or unclear phenotype with broad differential diagnosis
Indication Specific disorder with specific diseasecausing gene Test Sanger sequencing
NOTE. In undiagnosed diseases, complementary tests also include microarray, exon CNV analysis, and homozygosity mapping. Abbreviations: NGS, next-generation sequencing; VUS, variants of uncertain significance. Adapted from Xue et al53 with permission.
ADPKD as compared with the control group, although multiple pregnancies did not appear to increase the risk of renal failure.7 A large study of ADPKD in pregnancy showed that in a group of 235 women with ADPKD with 605 pregnancies as compared with 108 unaffected family members with 244 pregnancies, fetal complication rates were similar.8 However, there were higher rates of maternal complications, including new or worsening hypertension and preeclampsia in women with ADPKD as compared with unaffected family members (35% versus 19%; P o .001), with pre-existing hypertension being the most important risk factor.8 Furthermore, among women with ADPKD and hypertension, those with four or more pregnancies had a lower age-adjusted creatinine clearance as compared with women with fewer than four pregnancies (49 ⫾ 5 versus 66 ⫾ 3 mL/min per 1.73 m2; P o .01). This observation suggests that women with ADPKD should be counseled that multiple consecutive pregnancies might increase the risk for progression. This study also suggested that women with ADPKD who were normotensive generally had successful uncomplicated pregnancies, but that women with hypertension had higher rates of fetal and maternal complications. Autosomal recessive polycystic kidney disease Autosomal-recessive polycystic kidney disease (ARPKD) is rare, with an incidence of 1 in 20,000. It can be identified either prenatally or neonatally by the presence of enlarged echogenic kidneys on ultrasound.9 In extreme cases, severe oligohydramnios leads to Potter’s phenotype, which consists of pulmonary hypoplasia, characteristic facies, and deformations. These severe findings can cause neonatal deaths in up to 30% of cases.10 ARPKD is caused by
mutations in the PKHD1 gene, which encodes for the protein fibrocystin. There is a high level of allelic heterogeneity of PKHD1, however recently, common mutations have been identified in the Ashkenazi Jewish population.11 Molecular diagnosis is necessary to confirm the diagnosis especially in nonsevere cases, and to enable future reproductive options for the family in severe cases. Alport syndrome Alport syndrome is a familial nephritis that is caused by defects in type IV collagen, which is composed of a heterotrimer of α chains 3, 4, and 5. Type IV collagen is the predominant network of basement membranes of the glomerular basement membrane, the cochlea, cornea, lens capsule, and retina, which explains much of the phenotype.12 The majority of patients (85%) inherit the disease as an X-linked trait because of a mutation in the COL4A5 gene.13 Mutations in the COL4A3 or COL4A4 genes encoding the α3 and α4 chains of type IV collagen cause the autosomalrecessive and rarely the autosomal-dominant forms of Alport syndrome. The disease presents as hematuria, progressive renal failure, sensorineural hearing loss, and ocular lesions such as anterior lenticonus and retinal thinning. Pathologic ultrastructural changes include irregular thinning, thickening, and splitting of the glomerular basement membrane. The X-linked form of this disease shows progression to ESRD by the second and third decades of life. Although most of Alport syndrome is diagnosed in males, X-linked diseases affect twice as many women. Although women commonly are undiagnosed, up to 30% of women with X-linked Alport syndrome may develop renal failure by 60 years of age.14 This severe
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outcome probably is owing to the phenomenon of X-chromosome inactivation.15 Autosomal-recessive Alport syndrome in both sexes behaves similarly to that of X-linked disease in males. Expert guidelines presently recommend genetic testing as the gold standard for the diagnosis of Alport syndrome to show its mode of inheritance, enable pre-implantation diagnosis, and to identify and closely follow up affected family members. Genetic testing is performed as a panel of these three genes: COL4A3, COL4A, and COL4A5. Along with the underdiagnosis of women with Alport syndrome, there is even less information on how it affects the kidney in pregnancy. In a case series of two women who carried the missense mutations in the α5 chain of type IV collagen, it was found that proteinuria had increased above their abnormal baseline throughout the pregnancy, one into the nephrotic range, despite normal renal function.16 The more severely proteinuric patient developed hypertension, prompting delivery at 33 weeks of gestation. Upon follow-up evaluation at 22 months postpartum, the patient with nephrotic range proteinuria decreased her creatinine clearance to 42 mL/min from normal, whereas the patient with subnephrotic proteinuria maintained her normal renal function. Conversely, a woman with X-linked Alport syndrome who experienced two consecutive pregnancies with normal blood pressure, mild proteinuria, and normal renal function had good obstetric and renal outcomes.17 It is difficult to adequately counsel affected women with this scarcity of data, however, control of blood pressure (and proteinuria) is recommended as good general obstetric practice, and as in other chronic renal diseases, those with preserved renal function can be expected to have better outcomes. Fabry disease Fabry disease is yet another rare X-linked lysosomal storage disorder that results from the deficiency of lysosomal enzyme α-galactosidase A (α-gal A) that affects 1 in 40,000 to 1 in 117,000 live births.18 Many heterozygote females show similar manifestations as males. Deficiency of this enzyme results in the storage of globotriaosylceramide and other glycosphingolipids in multiple cell types throughout the body, leading to multi-organ pathology in the nervous system, kidney, heart, gastrointestinal tract, and skin. Neurologic manifestations include chronic pain, acroparesthesias, hearing loss, tinnitus, hypohidrosis or hyperhidrosis, and strokes.19 Cardiac manifestations include hypertrophic cardiomyopathy, dysrhythmias, coronary ischemia, and valvular dysfunction. Renal disease presents with proteinuria, renal insufficiency, and possibly ESRD. Gastrointestinal involvement causes abdominal
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cramping and diarrhea. Psychological symptoms such as depression affect up to 50% of women.20,21 The diagnosis of Fabry disease is made by clinical suspicion followed by enzyme assay or mutation analysis (sequencing) of the α galactosidase A gene.22 It is unclear how Fabry disease affects pregnancy because there are only a handful of case reports mostly denoting successful pregnancy outcomes with use of enzyme replacement therapy during pregnancy.23,24 Preconception counseling should include retinal and audiologic testing, brain magnetic resonance imaging, electrocardiogram, echocardiogram, serum electrolytes, and a 24-hour urine collection for creatinine clearance and protein excretion. Prenatal diagnosis on amniocytes or chorionic villi of at-risk pregnancies may be offered25 because the offspring of affected women will have a 50% chance of having the disease. Treatment, even in pregnancy, consists of enzyme replacement with agalsidase alfa (α-galactosidase A) along with symptomatic management of complications such as neuropathic pain and cardiac and renal dysfunction.19,23,24 The medication currently is labeled as category B in pregnancy, and is administered with no dose adjustment. In terms of whether pregnancy impacts Fabry disease, a retrospective survey of 41 women indicated that several Fabryrelated symptoms such as gastrointestinal symptoms, acroparesthesias, proteinuria, headaches, and depression may worsen with increased frequency of hypertension in pregnancy.26 Fortunately, there is no documented increase in the incidence of strokes, ESRD, or other life-threatening complications. Bartter and Gitelman syndromes Bartter and Gitelman syndromes share similar modes of transmission, clinical manifestations, and treatment strategies. Bartter syndrome is an autosomal-recessive disorder owing to defects in the Na-K-2Cl co-transporter in the luminal membrane,27 the renal outer medullary K channel in the luminal membrane,28,29 the chloride channel Kb in the basolateral membrane of the ascending limb in the loop of Henle,30,31 the chloride channels in both the kidney and the inner ear, and the calcium-sensing receptor in the basolateral membrane of the thick ascending limb.32 Gitelman syndrome is an autosomal-recessive disorder as well that involves the apical distal convoluted tubule sodium chloride co-transporter. Patients with both of these syndromes present with hypokalemia, metabolic alkalosis, and hypocalcuria, but for Gitelman syndrome, they also present with hypomagnesemia in late childhood or adulthood.33 Given the rarity of this disease in the overall population, only a few case reports have described pregnancy outcomes. For both syndromes, the requirements for potassium and magnesium replacement increase
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Table 4. Rare Hereditary Disorders Involving the Kidneys Group
Disease
Ciliopathies ARPKD Bardet Biedl CAKUT Renal– coloboma Branchio-otorenal Tumors Von Hippel Lindau Tuberous sclerosis
Gene
Inheritance Renal Features
PKHD1 AR BBS1-17 AR PAX2 AD EYA1
AD
VHL
AD
TSC1/ TSC2
AD
Cystic or complex Hypoplasia Dysplasia Hypoplasia Clear cell RCC, cysts
Extrarenal Features Hepatic fibrosis, retinal, short stature, obesity, polydactyly Optic coloboma Branchial, ear Hemangioblastoma pheochromocytoma
Angiomyolipoma, RCC, cysts, Skin findings FSGS Seizures SEGA
AD, autosomal dominant; AR, autosomal recessive; FSGS, focal segmental glomerulosclerosis; RCC, renal cell carcinoma; SEGA, subependymal giant cell astrocytoma. Adapted from Joly et al2 with permission.
dramatically during pregnancy. Case reports of pregnancy with Bartter syndrome have shown increases of potassium supplementation of up to 480 mEq/d, along with the need for amiloride.34–37 In Gitelman syndrome, a case series of five Italian women showed four uneventful pregnancies, while one was complicated by tetanic seizures (of unclear etiology).38 These women were managed primarily with potassium and magnesium salts, whereas one patient required amiloride. The pregnancies were successful and resulted in four neonates who were born at term and two near-term with appropriate body weight.38 Other potassium-sparing diuretics such as spironolactone and eplerenone also have been used successfully.39,40 A review of the literature showed that 78 pregnancies associated with Bartter and Gitelman syndrome resulted in a favorable outcome, with 63 pregnancies delivering between 37 and 40 weeks of gestation.38 Again, aggressive supplementation was required, as well as additional medications such as spironolactone or amiloride with no adverse fetal effects. However, in general, we do not recommend the use of spironolactone because of its
Table 5. Types of CAKUT Disorders Ureteropelvic junction obstruction Kidney agenesis Multicystic dysplastic kidneys Kidney dysplasia Kidney hypoplasia Hydronephrosis Vesicoureteral reflux Megaureter Ectopic ureter Horseshoe kidney Duplex collecting system Posterior urethral valves CAKUT: Congenital anomalies of the kidney and urinary tract
potential antiandrogenic effects on male fetuses.41 As noted, amiloride also may be considered in difficult-tomanage cases. Furthermore, adequate repletion of the potassium and magnesium losses often will require hospitalization for intravenous administration because oral doses either may not suffice or may have intolerable side effects (eg, severe diarrhea from high doses of magnesium).42 Other rare hereditary renal disorders with a known genetic basis are illustrated in Table 4.
COMPLEX OR MULTIFACTORIAL DISORDERS Conditions currently believed to be caused by polygenic susceptibilities or gene–environment interactions are termed complex or multifactorial disorders. Congenital anomalies of the kidney and urinary tract (CAKUT) refers to a group of structural abnormalities initiated during embryonic kidney development of complex etiology. CAKUTs comprise up to 30% of all congenital abnormalities with a prevalence ranging between 3 and 6 per 1,000 births.43,44 Malformations such as ureteropelvic junction obstruction (most common), kidney agenesis, multicystic dysplastic kidneys, kidney dysplasia, kidney hypoplasia, vesicoureteral reflux, and duplex collecting system are included (Table 5). Prenatal detection of these malformations has improved dramatically with the quality and availability of ultrasonography, although many still may remain undetected until after birth when infants or children become symptomatic. These anomalies are believed to cause 40% to 50% of pediatric ESRD and an unknown percentage of adult ESRD. CAKUT may be associated in syndromic form with other anomalies when caused by chromosomal abnormalities, rare CNVs, or monogenic disorders such as the branchiooto-renal syndrome. More than 20 single-gene causes
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Table 6. Examples of Autosomal-Recessive Diseases With Renal Involvement Tested Through Expanded Carrier Screening Disease
Gene
Ethnicity
Carrier Frequency
Pubmed ID
Alport Bardet Biedl Joubert 2 ARPKD Renal tubular acidosis, deafness Cystinosis Congenital nephrosis
COL4A3 BBS2 TMEM216 PKHD1 ATP6V1B1 CTNS NPHS1
Ashkenazi Ashkenazi Ashkenazi Ashkenazi Moroccan/Syrian Moroccan Finnish
1:192 1:140 1:110 1:106 1:140 1:100 1:45
23927549 and 27415407 23829372 20036350 27415407 * Personal communication 10767171 938078
*Personal communication from Mount Sinai Genetic Testing Laboratory, New York.
of CAKUT have been described.44–47 These anomalies also may cluster with other birth defects, as in the vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects association. Mutations in the ZIC3 and FOXF1 genes have been implicated in vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects, the cluster of birth defects known as VACTERL association.48 HNF1B mutations, the 17q12 microdeletion CNV and PAX2 mutations, which cause renal dysplasia of the renal coloboma syndrome, may account for 15% of CAKUT.49
GENETIC EVALUATION In practical terms, genetic testing is best performed after genetic counseling. A genetics evaluation is helpful to define the phenotype and choose the appropriate testing. Choice of test, cost, benefits, and limitations of testing are part of pretest genetic counseling. Sequence variants of uncertain significance continue to be the biggest challenge in interpretation of results. For an individual with a genetic disorder who is considering a pregnancy, the ideal time to review options is during the preconception period. Pediatric referrals to geneticists are generally to identify the genetic basis of a renal disease. Adults are referred because of their own personal history of a hereditary disorder or because they have a partner, child, or family member with a genetic or suspected genetic condition. The American College of Obstetrics and Gynecology recommends that women with genetic disorders, such as ADPKD, be referred to genetics specialists and relevant subspecialists in the preconception period to optimize maternal health, review maternal and neonatal morbidities, and to be offered genetic counseling to review reproductive options.50 The genetics evaluation includes a review of personal history, family history, and supporting investigations to help establish the details of the phenotype and natural history. The causative genetic mutation first must be identified in an affected individual. The choice of test can become complex because of availability, insurance
coverage, detection rates, and turnaround time. An integral part of the genetic testing process is obtaining informed consent, which must review possible test results such as limitations of a negative result, implications of a positive result, and the detection of variants of uncertain significance. Patients may have concerns related to privacy and discrimination, particularly in the setting of presymptomatic testing. Currently, the Genetic Information Non-Discrimination Act protects individuals from employer and health insurer discrimination (https://www.eeoc.gov/laws/stat utes/gina.cfm). Today, a wide range of screening tests routinely are available to couples considering a pregnancy. These include carrier screening for recessive disorders. Although there is inconsistency in what panel of testing is offered, several hereditary renal disorders have been included in such panels because of the identification of recurrent mutations. Table 6 shows some genes for recessive disorders affecting the kidneys made available through carrier screening panels. In an already established pregnancy, genetic testing of cell-free fetal DNA is offered as a screening test for common chromosomal trisomies, such as Down syndrome. In the future, this may well extend to testing for other genetic abnormalities. Once a genetic basis for a disorder is identified, couples may wish to discuss options. These include testing for the targeted mutations in an established pregnancy through chorionic villus sampling at 10 to 12 weeks’ gestation or amniocentesis at 16 weeks’ gestation or later. The pros and cons of these invasive procedures that carry a small risk of miscarriage must be weighed against the actionability of diagnosing a fetus with a genetic disorder. In general, it is our experience that although there is demand for establishing causative mutations in an adult with a condition such as ADPKD or Alport syndrome, demand for testing an established pregnancy is low. Couples may prefer to defer testing until their child is at an age when monitoring is recommended. Finally, couples may choose to use preimplantation genetic diagnosis
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(PGD) to avoid the birth of a child with a genetic disorder. The goal of PGD is to select out the unaffected embryos after genetic analysis, before transfer into the woman to establish pregnancy. The PGD option avoids the difficult decision to possibly terminate a pregnancy when a genetic diagnosis is made after conception. There is limited published literature exploring the demand for PGD for renal disorders such as ADPKD; most of the literature focuses on severe childhood-onset disorders, adult-onset neurodegenerative disorders such as Huntington disease, or hereditary cancer susceptibility. We have anecdotal experience of couples seeking PGD for potentially fatal recessive conditions such as ARPKD. To date, short-term follow-up evaluation of singletons born after PGD have not been found to be different compared with spontaneous conceptions in terms of congenital malformation, postnatal linear growth, or cognitive impairment.51,52
SUMMARY The general strategy for nephrologists with regard to patients with hereditary disorders or a family history of such conditions should be to refer the patient for genetic counseling and testing early after diagnosis to establish a genetic cause. An affected patient must be tested first to establish the causative mutation(s). The choice of test, cost, and benefits and limitations of testing are part of pretest genetic counseling. Sequence variants of uncertain significance continue to be a challenge in the interpretation of results. As data sharing and testing continue to develop, the hope is that knowledge of the genetic cause will help in not just reproductive options for the patient and their family, but also in improving the understanding of genotype–phenotype correlations, modifiers of outcome, and eventually the development of therapeutics.
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