Clinical characteristics.

Autosomal dominant tubulointerstitial kidney disease – MUC1 (ADTKD-MUC1) is characterized by slowly progressive tubulointerstitial disease that leads to end-stage renal disease (ESRD) and the need for dialysis or kidney transplantation. The rate of loss of kidney function for individuals is variable within and between families, with a median age of onset of end-stage renal disease (ESRD) of 46 years (range: ages 20-70 years). There are no other systemic manifestations.

Diagnosis/testing.

The diagnosis of ADTKD-MUC1 is established in a proband with suggestive clinical findings and molecular genetic testing that reveals a heterozygous pathogenic variant in MUC1 that results in the creation of a specific frameshift protein (MUC1fs) responsible for the pathogenic changes in this disorder.

Management.

Treatment of manifestations: Treatment follows standard guidelines for chronic kidney disease – based on the level of the serum creatinine and the estimated glomerular filtration rate (eGFR) – and its sequelae, which can include hypertension, anemia, and gout.

Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD-MUC1, by staying in optimal health (e.g., by exercising, avoiding obesity and tobacco usage, and maintaining strict control of hypertension, dyslipidemia, and other cardiovascular risk factors). Kidney transplantation is curative; the outcome is excellent.

Surveillance: Measurement of hemoglobin, serum concentrations of uric acid and creatinine and blood pressure annually prior to entering CKD Stage 3. Thereafter, follow up is determined by the treating nephrologist.

Agents/circumstances to avoid: Affected individuals should follow general recommendations for chronic kidney disease.

Pregnancy management: The use of ACE inhibitors should be avoided during pregnancy, as they can result in fetal damage and death. Women who are pregnant, planning a pregnancy, or not actively avoiding pregnancy should be transitioned to another antihypertensive medication. Allopurinol therapy should be stopped during pregnancy, if possible.

Evaluation of relatives at risk: For early diagnosis and treatment: It is appropriate to identify as early as possible apparently asymptomatic at-risk adult relatives who have the familial MUC1 variant in order to monitor their serum creatinine levels and promptly initiate treatment and awareness of agents/circumstances to avoid. For kidney donation: Any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the relative's genetic status so that only those who do not have the familial MUC1 pathogenic variant are evaluated further.

Genetic counseling.

ADTKD-MUC1 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the MUC1 pathogenic variant. Prenatal testing for MUC1 pathogenic variants is not available in the US at this time.

Suggestive Findings

ADTKD-MUC1 should be suspected in individuals with the following clinical, laboratory and imaging findings, and family history.

Establishing the Diagnosis

NOTE: Kidney biopsy should NOT be performed because it is an invasive procedure with some risk, and histopathologic findings are too nonspecific to reliably identify ADTKD-MUC1 (see Clinical Description). Molecular genetic testing, the gold standard for diagnosis, is safer and less expensive than kidney biopsy.

The diagnosis of ADTKD-MUC1 is established in a proband with suggestive clinical findings and molecular genetic testing that reveals a heterozygous pathogenic (or likely pathogenic) variant in MUC1 that results in the creation of a specific frameshift protein (MUC1fs) responsible for the pathogenic changes in this disorder [Kirby et al 2013] (see Table 1).

Note: (1) Per ACMG/AMP 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 [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous MUC1 variant of uncertain significance does not establish or rule out the diagnosis.

Because of the complex molecular genetics of ADTKD-MUC1, the following stepwise approach to testing is recommended.

Clinical Description

Autosomal dominant tubulointerstitial kidney disease – MUC1 (ADTKD-MUC1) is characterized by slowly progressive tubulointerstitial disease that leads to end-stage renal disease (ESRD) and the need for dialysis or kidney transplantation.

The rate of loss of kidney function for individuals is variable within and between families, with a median age of onset of ESRD of 46 years [Olinger et al 2020]; however, the age range of ESRD is extremely variable, with rare individuals developing ESRD before age 20 years and some affected individuals not having ESRD past age 70 years.

Onset. ADTKD-MUC1 rarely manifests in childhood. Abnormal serum creatinine concentration or reduced estimated glomerular filtration rate (eGFR) may initially appear in the late teens or early twenties (see Suggestive Findings).

Progression. With time, kidney function slowly worsens and serum creatinine concentration slowly rises from the normal range to the high normal range, and then to above normal.

As kidney function worsens, manifestations of chronic kidney disease (CKD) develop, including high blood pressure, gout, and anemia.

Gout in ADTKD-MUC1 is not a primary manifestation of the disease and is solely related to progressive CKD and the loss of ability to excrete uric acid. In one study, hyperuricemia was found in approximately 50% of individuals with ADTKD-MUC1 with CKD and in 81% of individuals with ESRD [Stavrou et al 2002]. Gout was reported in five of 75 affected individuals.

Kidney function progressively worsens until dialysis or kidney transplantation is required.

Post transplantation. Because ADTKD-MUC1 does not recur in the transplanted kidney, affected individuals are excellent transplant candidates [Cormican et al 2020].

Other. Kidney biopsy reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis. Biopsy findings are nonspecific.

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations.

Penetrance

Penetrance is complete.

Nomenclature

ADTKD-MUC1 was historically referred to as medullary cystic kidney disease type 1 (MCKD1). MCKD1 is a misnomer in that cysts in the renal medulla are not a common clinical characteristic, and the presence of medullary cysts is not a good predictor of the presence of ADTKD-MUC1.

According to the 2015 nomenclature [Eckardt et al 2015], the term "autosomal dominant tubulointerstitial kidney disease" (ADTKD) refers to disorders characterized by the following [Bleyer et al 2010]:

• Autosomal dominant inheritance
• Slowly progressive chronic tubulointerstitial kidney disease resulting in end-stage renal disease (ESRD) in the third through seventh decade of life
• Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
• Renal ultrasound examination that is normal early in the disease course

Prevalence

ADTKD-MUC1 is estimated to affect one to four individuals per million population [Devuyst et al 2019]; however, this is likely an underestimate, as diagnosis is difficult due to unremarkable clinical findings and the inability to include MUC1 molecular genetic testing in multigene panels. It is estimated that 1% of individuals with ESRD harbor heterozygous UMOD pathogenic variants; the prevalence of ADTKD-UMOD and of ADTKD-MUC1 is believed to be similar [Devuyst et al 2019].

Urinalysis

If blood and protein are present, consider evaluation for inherited glomerulonephritis. If the urine sediment is bland (trace or no blood and protein <500 mg/24 h), obtain a family history to determine the likely inheritance pattern. If autosomal recessive (i.e., only sibs are affected), consider autosomal recessive polycystic kidney disease or the group of disorders termed "nephronophthisis" (see Table 2).

Renal Imaging

Renal imaging should always be performed. Ultrasound examination is typically performed first. If numerous cortical and medullary cysts and enlarged kidneys are present, consider autosomal dominant polycystic kidney disease (ADPKD).

If the number of cysts is fewer than required for a diagnosis of ADPKD, the family history suggests autosomal dominant inheritance, the urine is bland, the kidneys are normal or reduced in size with or without medullary cysts, and renal histology (if performed) has shown interstitial fibrosis, consider screening for pathogenic variants in UMOD, REN, or MUC1.

The most common condition in the differential will be autosomal dominant tubulointerstitial kidney disease – UMOD (ADTKD-UMOD) [Bleyer et al 2010]. Gout occurs in approximately 50% of individuals with ADTKD-UMOD and develops before the onset of chronic kidney disease [Kidd et al 2020]. However, many individuals and families with ADTKD-UMOD may not have gout, and their presentation is identical to that of ADTKD-MUC1 [Bleyer et al 2010].

If family members have a history of anemia in childhood and mildly elevated serum potassium concentrations, consider autosomal dominant tubulointerstitial kidney disease – REN [Živná et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADTKD-MUC1, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Care by a nephrologist is recommended.

Treatment follows standard guidelines for chronic kidney disease – based on the level of the serum creatinine and estimated glomerular filtration rate (eGFR) – and its sequelae, which can include hypertension, anemia, and gout.

Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD-MUC1, by staying in optimal health (e.g., by exercising, avoiding obesity and tobacco usage, and maintaining strict control of hypertension, dyslipidemia, and other cardiovascular risk factors).

Affected individuals should be referred for evaluation for kidney transplantation when their eGFR declines to <19 mL/min/1.73m². (See Evaluation of Relatives at Risk for kidney donation.)

Kidney transplantation is curative; the outcome is excellent [Cormican et al 2020].

Surveillance

Monitor the following annually, starting at the time of diagnosis and continuing until chronic kidney disease (CKD) Stage 3:

• Hemoglobin concentration
• Serum concentrations of uric acid and creatinine
• Blood pressure

After CKD Stage 3, follow up is determined by the treating nephrologist.

Agents/Circumstances to Avoid

Affected individuals should follow general recommendations for chronic kidney disease.

Evaluation of Relatives at Risk

For early diagnosis and treatment. It is appropriate to identify as early as possible apparently asymptomatic at-risk adult relatives who have the familial MUC1 variant in order to monitor their serum creatinine levels and promptly initiate treatment and awareness of Agents/Circumstances to Avoid. (Note: Normal kidney function in and of itself does not exclude ADTKD-MUC1 in at-risk family members.) See Related Genetic Counseling Issues for discussion of testing of children.

For kidney donation. Any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the relative's genetic status so that only those who do not have the familial MUC1 pathogenic variant are evaluated further.

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

Pregnancy Management

Pregnancies in women with ADTKD tend to have better outcomes for themselves and their children compared to women with other kidney diseases who have similar levels of kidney function: about 20% of women develop hypertension during pregnancy, about 10% deliver before 38 weeks' gestation, and the rate of cæsarean section is not increased. Fetal outcomes are in general excellent [Authors, unpublished data].

Women of childbearing age who are taking medications such as an angiotensin-converting enzyme (ACE) inhibitor or allopurinol should discuss their medication regimen with their physician. Ideally, women should avoid taking either an ACE inhibitor or allopurinol during pregnancy.

• ACE inhibitors. The use of ACE inhibitors during pregnancy can result in fetal damage and death. Women who are pregnant, planning a pregnancy, or not actively avoiding pregnancy should be transitioned to another antihypertensive medication.
• Allopurinol. Published data on the fetal risk associated with use of allopurinol during pregnancy is limited. While a number of pregnancies in which allopurinol was used resulted in the birth of healthy infants, the rare occurrence of a pattern of malformations similar to what is observed in women who use mycophenolate mofetil during pregnancy was reported in two infants born to women who took allopurinol throughout pregnancy [Kozenko et al 2011, Hoeltzenbein et al 2013].
  This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of de novo purine biosynthesis).

The acute treatment of gout may require the use of other medications, such as prednisone or colchicine.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Of note, basic science and animal studies have identified a potential therapy for the small molecule BRD4780, which was found to clear MUC1 frameshift protein deposits in cells in culture, organoids, and a mouse model of ADTKD-MUC1. This compound is anticipated to enter clinical trials within the next two to five years [Dvela-Levitt et al 2019].

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

By definition, autosomal dominant tubulointerstitial kidney disease – MUC1 (ADTKD-MUC1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Most individuals diagnosed with ADTKD-MUC1 have an affected parent.

• A proband with ADTKD-MUC1 may have the disorder as the result of a de novo pathogenic variant. Because only a few simplex cases (i.e., a single occurrence in a family) have been identified, the proportion of ADTKD-MUC1 caused by a de novo pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of an individual with ADTKD-MUC1 may appear to be negative because of early death of the parent before the onset of symptoms, a milder phenotypic presentation, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the MUC1 pathogenic variant identified in the proband.

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

• If a parent of the proband has the MUC1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Although the penetrance of ADTKD-MUC1 is complete, the rate of progression of kidney disease varies among heterozygous sibs.
• If the proband has a known MUC1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the MUC1 pathogenic variant but are clinically asymptomatic, sibs are still presumed to be at increased risk for ADTKD-MUC1 because of the possibility of later onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with ADTKD-MUC1 has a 50% chance of inheriting the MUC1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MUC1 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 adult relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the MUC1 pathogenic variant in the family. Such testing is helpful in predicting the future development of chronic kidney disease and should be performed if the family member is considering becoming a kidney donor.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• In general, predictive testing of minors for adult-onset disorders is considered inappropriate unless such testing has a compelling medical benefit. Concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For parents desiring closer surveillance of their children, blood pressure can be monitored and serum creatinine can be tested on an annual basis.
  • It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD-MUC1 and the child may develop worsening kidney function with age.
  • For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
• Genetic testing may be considered in children when affected family members have an earlier age of onset of kidney disease and end-stage renal disease.
• Bleyer et al [2019] describe high levels of personal satisfaction reported by seven individuals who underwent predictive ADTKD-MUC1 testing as children.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of ADTKD-MUC1, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• Women with ADTKD-MUC1 who are considering pregnancy should be advised that, if appropriate, pregnancy should not be deferred but considered at younger ages when kidney function is better (as the decline in eGFR occurs during child-bearing years) and there is less chance of complications.
• 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

Prenatal testing for the MUC1 pathogenic variant is not available in the US at this time.

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. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

Mucin-1, encoded by MUC1, a membrane-anchored mucoprotein found in breast, respiratory tract, sebaceous gland, salivary gland, and kidney tubules, is important in signal transduction. Mucin-1 provides (among other functions) a protective barrier that prevents pathogens from accessing the cell surface.

MUC1 pathogenic variants causing ADTKD-MUC1 always result in the creation of the same frameshift protein (MUC1fs) (see MUC1-specific laboratory technical considerations). This protein accumulates within the endoplasmic reticulum Golgi intermediate compartment (ERGIC) [Dvela-Levitt et al 2019]. In individuals with ADTKD-MUC1, MUC1fs is found in all cell types normally expressing MUC1 (including breast, gastric mucosa, and lung); however, clinical manifestations of disease only occur in the kidney, where its deposition leads to accelerated apoptosis [Staubach et al 2018], tubular cell death, nephron dropout, and progressive chronic kidney disease.

Mechanism of disease causation. Gain of function. All affected individuals harbor pathogenic variants creating the same MUC1fs protein; no person with this disorder has had truncating variants or other variants that would result in loss of function [Olinger et al 2020].

MUC1-specific laboratory technical considerations

• MUC1 contains within the coding region a domain of multiple variable-number tandem repeats (VNTRs), called the "VNTR domain."
• Each VNTR is an oligonucleotide comprising 60 nucleotides (also referred to as a "60-mer"). Each 60-nucleotide repeat includes a sequence of seven cytosines (also called "a 7-cytosine tract").
• The normal number of 60-mer VNTRs comprising a VNTR domain ranges from 20 to 125.

In most MUC1 disease-causing variants an additional nucleotide inserted within a seven-cytosine sequence causes a frameshift that encodes an abnormal MUC1 protein called a "frameshift protein," known as MUC1fs. The most commonly inserted nucleotide is cytosine; less commonly, it is a different nucleotide (e.g., adenosine).

The additional nucleotide can either be within the VNTR [Kirby et al 2013] or immediately before the VNTR [Yamamoto et al 2017]; however, in approximately 95% of cases, MUC1fs results from insertion of a cytosine in the seven-cytosine sequence within the VNTR [Authors, personal observations based on 196 families with ADTKD-MUC1]. See Figure 2.

Figure 2.

Illustration of the mechanism by which the MUC1fs protein is encoded within a 60-mer block of repeated sequence that forms a MUC1 variable-number tandem repeat (VNTR). In this figure of a hypothetic coding sequence of ten 60-mer blocks of repeated sequence, (more...)

Clinical testing issues. Due to the high guanosine-cytosine content and the repetitive nature of the 60-mer VNTR sequences, variants within a VNTR cannot be identified by commonly used sequencing methods (e.g., exome sequencing, Sanger sequencing).

The CLIA-certified Broad Institute of Harvard and MIT laboratory performs targeted analysis for the common MUC1 frameshift variant (i.e., insertion of a cytosine within the 7-cytosine sequence) and the less common frameshift variant (insertion of an adenine in a 7-cytosine sequence). (See Author Notes regarding testing available at no cost to families with autosomal dominant tubulointerstitial kidney disease.)

Other published test methods for detecting variants not identified by standard genetic sequencing techniques include the following:

• Long-read single-molecule real-time (SMRT) sequencing can identify the insertion of a cytosine within the seven-cytosine sequence as well as many (but not all) other disease-causing MUC1 variants. This method also determines the length and structure of the MUC1 VNTR and the exact position of the variant within the VNTR [Wenzel et al 2018, Knaup et al 2018, Wang et al 2020].
• Illumina-based sequencing of MUC1 VNTR amplicons can identify the cytosine insertion as well as many (but not all) other disease-causing variants [Živná et al 2018].

Author Notes

Dr Stanislav Kmoch (zc.inuc.1fl@hcomks) and Dr Anthony Bleyer (ude.htlaehekaw@reyelba) are actively involved in clinical research regarding individuals with ADTKD-MUC1 and other forms of inherited kidney disease and would be happy to communicate with individuals who have any questions regarding diagnosis or other considerations.

MUC1 molecular genetic testing is available at several commercial laboratories in Europe. Clinical MUC1 genetic testing is available free of charge through the Broad Institute of Harvard and MIT. Contact Dr Bleyer (ude.htlaehekaw@reyelba) to inquire about testing or to review MUC1 variants of uncertain significance.

Dr Bleyer is also interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.

Revision History

• 21 October 2021 (bp) Comprehensive update posted live
• 30 June 2016 (ha) Comprehensive update posted live
• 15 August 2013 (me) Review posted live
• 30 April 2013 (ab) Original submission

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