Clinical characteristics.

WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT) and gonadoblastoma. While various combinations of renal and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past, those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful.

Diagnosis/testing.

The diagnosis of a WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing.

Management.

Treatment of manifestations: SRNS: Avoid immunosuppressants; consider renin-angiotensin-aldosterone system (RAAS) inhibition. Disorder of testicular development: Management is often by a multidisciplinary team (medical geneticist, endocrinologist, urologist, and psychologist). Treat Wilms tumor with standard oncology protocols and, when applicable, nephron-sparing surgery. Treat CAKUT as per standard care. Prevent whenever possible gonadoblastoma by prophylactic gonadectomy.

Surveillance: Monitor for first appearance of the following: (1) proteinuria every six months until age ten years, yearly thereafter; (2) Wilms tumor every three months until age seven years. For ongoing issues with disorder of testicular development as per treating multidisciplinary team and for CAKUT as per treating nephrologist and/or urologist.

Agents/circumstances to avoid: Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with a WT1 disorder in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance.

Genetic counseling.

WT1 disorder is inherited in an autosomal dominant manner. Most individuals diagnosed with WT1 disorder have the disorder as the result of an apparent de novo WT1 pathogenic variant; in rare instances, a parent of an individual with WT1 disorder is heterozygous for the WT1 pathogenic variant. If a parent of the proband is affected and/or is known to have the WT1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the WT1 pathogenic variant is 50%. If the proband's WT1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Once the WT1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

A WT1 disorder should be suspected in an individual with the following clinical findings.

Establishing the Diagnosis

The diagnosis of a WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in WT1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous WT1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of WT1 disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

A WT1 disorder is characterized by congenital/infantile- or childhood-onset of a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT) and gonadoblastoma (see Table 2). While various combinations of renal and other findings associated with a WT1 pathogenic variant have in the past been designated as certain syndromes, those combinations are now recognized to be part of a phenotypic continuum and their designations are no longer clinically helpful (see Nomenclature) [Chernin et al 2010, Lipska et al 2014, Lehnhardt et al 2015, Ahn et al 2017].

Genotype-Phenotype Correlations

Recent developments have allowed delineation of genotype-phenotype correlations for the following subgroups of WT1 variants.

Truncating pathogenic variants (all nonsense, frameshift, or splice-site variants that are not KTS intron variants; see Molecular Genetics) are associated with the following [Lipska et al 2014, Lehnhardt et al 2015]:

• Glomerulopathy. Proteinuria is typically diagnosed in the second decade of life in individuals who underwent unilateral or partial nephrectomy for Wilms tumor. The course of SRNS is slower.
• Genital anomalies secondary to a 46,XY DSD affect the vast majority of phenotypic males; 46,XY CGD is unlikely.
• The risk for bilateral Wilms tumor is the highest (odds ratio = 18.4).
• One in five individuals has congenital anomalies of the kidney and urinary tract.

Missense variants affecting nucleotides coding for amino acid residues in the DNA-binding region in exons 8 and 9 (see Molecular Genetics) are associated with the following [Lipska et al 2014]:

• The highest risk for congenital nephrotic syndrome or early-onset rapidly progressive SRNS. By age two and a half years, 50% of affected children have ESRD.
• Of 46,XY individuals, approximately 80% had 46,XY DSD and 20% 46,XY CGD [Author, personal observation].

Missense pathogenic variants in exons 8 and 9 outside the DNA-binding region are associated with an intermediate glomerulopathy phenotype that manifests before age five years and progresses to ESRD by about age ten years [Lipska et al 2014].

Certain donor splice-site pathogenic variants in intron 9 (see Molecular Genetics) are associated with the following [Chernin et al 2010, Lipska et al 2014, Lehnhardt et al 2015]:

• Later-onset and relatively slow progression of glomerulopathy that typically leads to ESRD in adolescence
• 46,XY CGD in the majority of (but not all) 46,XY individuals and 46,XY DSD in a few individuals

Penetrance

The penetrance of WT1 disorder is high. It is age dependent, reaching about 90% by the end of puberty.

A few asymptomatic parents heterozygous for the same germline WT1 variant in their affected offspring have been reported [Fencl et al 2012, Lipska et al 2014, Kaneko et al 2015, Boyer et al 2017]. The penetrance appears to depend on the sex of the affected parent, with higher penetrance associated with paternal origin of the WT1 variant [Kaneko et al 2015]. However, current data on penetrance are limited because the variable expressivity of WT1 pathogenic variants was not recognized until recently, as the asymptomatic parents of a child with a WT1 pathogenic variant were not routinely tested.

Nomenclature

Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome were originally described as distinct disorders on the basis of clinical findings but are now understood to represent a continuum of features caused by a WT1 heterozygous pathogenic variant. Given the extensive clinical overlap between these clinical diagnoses and molecular characterization of their shared genetic etiology, Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome are no longer useful clinical diagnoses. However, these terms may still be used in the medical literature to refer to the following general phenotypic constellations:

• Frasier syndrome. SRNS, 46,XY CGD, and gonadoblastoma
• Denys-Drash syndrome. SRNS with diffuse mesangial sclerosis on renal biopsy, Wilms tumor, and 46,XY DSD
• Meacham syndrome. Diaphragmatic hernia, pulmonary dysplasia, complex congenital heart defects, and genitourinary abnormalities including ambiguous genitalia and gonadal dysgenesis; in most reports, the condition was lethal early in infancy prior to development of other possible manifestations of WT1 disorder, such as SRNS or Wilms tumor. So far, none of the reported individuals with a confirmed WT1 pathogenic variant and a diaphragmatic defect had a complex congenital heart defect. A multigenic cause of this syndrome, with another as-yet-unknown gene responsible for the more severe cardio-pulmonary phenotype, has been suggested [Suri et al 2007].

Male pseudohermaphroditism. The spectrum of clinical manifestations related to 46,XY disorders of testicular development with a WT1 pathogenic variant was previously referred to using outdated terms such as "male pseudohermaphroditism."

Prevalence

The prevalence of WT1 disorder is not known. Fewer than 500 affected individuals have been reported to date.

There are no WT1 founder variants or biased geographic distribution in specific populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a WT1 disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual with a WT1 disorder in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because renal disease may progress during pregnancy, a pregnant woman with a WT1 disorder should be referred promptly to a perinatal center experienced in the care of pregnant women with chronic kidney disease.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

WT1 disorder is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a WT1 disorder have the disorder as the result of an apparent de novo WT1 pathogenic variant.
• In rare cases, a parent of an individual with WT1 disorder is heterozygous for the pathogenic variant identified in the proband. Intrafamilial clinical variability is observed in WT1 disorder and a heterozygous parent may be asymptomatic or have clinical manifestations of the disorder.
  • Fencl et al [2012] describe monozygotic twins presenting with congenital nephrotic syndrome born to an asymptomatic father age 41 years with the same WT1 pathogenic variant.
  • Guaragna et al [2013] describe two families with vertical transmission of isolated WT1-related steroid-resistant nephrotic syndrome from an affected parent to an affected child.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo WT1 pathogenic variant.
• If the WT1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Parental mosaicism has been reported [Beltcheva et al 2016].
• The family history of some individuals diagnosed with a WT1 disorder may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
  Note: If the parent is the individual in whom the WT1 pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected or asymptomatic [Beltcheva et al 2016].

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the WT1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the WT1 pathogenic variant is 50%. Although a sib who inherits a pathogenic variant is likely to have clinical manifestations of WT1 disorder, the phenotype in a heterozygous sib cannot be reliably predicted because both intrafamilial clinical variability and reduced penetrance are observed in WT1 disorder (see Penetrance) [Fencl et al 2012, Kaneko et al 2015, Boyer et al 2017].
• If the proband has a known WT1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Beltcheva et al 2016].
• If the parents have not been tested for the WT1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a WT1 disorder because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a WT1 disorder has a 50% chance of inheriting the WT1 pathogenic variant. It should be noted however, that most individuals with a disorder of testicular development are infertile.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the WT1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternative paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption may also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the WT1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

WT1 encodes a regulatory protein comprising a proline- and glutamine-rich interaction domain and four zinc fingers (exons 7-9) which determine the sequence specificity of this critical transcription factor [Wang et al 2018]. Expression of WT1 occurs for the most part in kidney progenitors and podocytes; in the urogenital ridge and gonadal progenitors [Wilm & Muñoz-Chapuli 2016]. More than 30 WT1 isoforms are derived from alternative splicing as well as alternative translation start sites and RNA editing; their relative ratios regulate particular processes of urogenital differentiation.

WT1 is a major transcription factor involved in cell differentiation and survival in the developing kidney, urinary tract, and gonads. WT1 regulates the expression of numerous target genes, including many genes encoding proteins that localize to the slit diaphragm of the glomeruli such as nephrin and podocin. WT1 controls the polarity of podocytes, cytoskeleton arrangement, and cell-matrix adhesion of the podocytes. It has a tumor-suppressor as well as an oncogenic role in tumor formation [Dong et al 2015].

Mechanism of disease causation

• Dominant-negative mechanism. WT1 disorder is caused by a dominant-negative mechanism. For example, missense, nonsense, and frameshift variants that affect the zinc finger region may result in the loss, reduction, or altered specificity of WT1 isoforms to bind target DNAs. The numerous WT1 isoforms, derived from alternative splicing, alternative translation start sites, and RNA editing likely have varying effects in different tissues during development. For example, two common pathogenic variants with intron splice-site nucleotide changes (see Table 6) alter the ratio of alternative transcripts. Physiologically, an alternative donor splice site in intron 9 of WT1 results in addition of three amino acid residues – lysine (K), threonine (T) and serine(S), referred to as the KTS splice variant – between the third and fourth zinc finger domains. Disruption of this splice site due to single-nucleotide variants at positions +4 or +5 of intron 9 alters the ratio of the WT1 isoforms with and without the KTS insert (+KTS/-KTS, respectively). Affected individuals have significantly fewer +KTS splice variants, resulting in a decreased ratio of +KTS/-KTS isoforms, a regulatory factor involved in proper testicular development in 46,XY individuals.
• Tumor suppressor mechanism. Consistent with the Knudson two-hit model of tumorigenesis and previous observations, children with a germline loss-of-function WT1 variant are at very high risk for Wilms tumor (see Wilms Tumor Predisposition). See also Cancer and Benign Tumors.

WT1-specific laboratory technical considerations. Because of high GC content, the sequencing of exon 1 of WT1 is problematic. The numerous transcripts and their isoforms resulting from alternative splicing and translation start sites result in a single variant having many HGVS-approved names depending on the reference sequence. As there is no consensus in the literature or databases as to the "canonic" protein sequence, care must be taken when interpreting numbers of residues. In this chapter, amino acid positions are given according to NP_077742.3 (see Table 6).

Notable WT1 variants. Variants discussed in the Genotype-Phenotype Correlations section include the following:

• Missense variants affecting nucleotides coding for DNA-binding helices of Zinc fingers 2 and 3 (residues: 439-454[RSDQLKRHQRRHTGVK]) from exon 8 and 467-474(RSDHLKTH) from exon 9 (reference sequence NP_077742.3)
• Certain splice site pathogenic single-nucleotide variants in the splice donor site of intron 9 change the ratio of +KTS/-KTS isoforms (See Table 6.)

Note: Originally, WT1 pathogenic variants were subclassified as exon variants (presumably Denys-Drash syndrome-type) and KTS intron variants (presumably Frasier syndrome-type) (see Nomenclature).

A few recurrent pathogenic variants, both exon and intron, have been identified (see Table 6).

Cancer and Benign Tumors

Somatic WT1 variants have been described in sporadic Wilms tumors as well as in a significant proportion of other cancers, in particular desmoplastic small round cell tumor of childhood and leukemia.

Loss-of-function WT1 variants are reported in about 15% of sporadic Wilms tumors.

In hematologic malignancies, somatic WT1 variants are noted in about 6% to 15% of de novo acute myeloid leukemia (AML) and are associated with poor prognosis.

The EWS-WT1 gene fusion is pathognomonic for desmoplastic small round cell tumor, an extremely rare aggressive soft tissue malignancy [Charlton & Pritchard-Jones 2016].

Author Notes

Beata S Lipska-Ziętkiewicz is the genetic coordinator at PodoNet (www.escapenet.eu/researchers/beata-lipska-zietkiewicz), one of the largest international registries of the steroid-resistant nephrotic syndrome. She is a member of the Molecular Diagnostics Task Force for the European Rare Kidney Disease Reference Network (ErkNet; www.erknet.org).

Revision History

• 29 April 2021 (blz) Revision: references added: Trautmann et al [2020], Boyer et al [2021]
• 30 April 2020 (bp) Review posted live
• 2 October 2019 (blz) Original submission

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