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 Table of Contents  
Year : 2023  |  Volume : 3  |  Issue : 2  |  Page : 117-121

Genotype–Phenotype Characteristics of Children with Distal Renal Tubular Acidosis Caused by WDR72 Mutations: A Systematic Review of Case Reports

Department of Pediatrics, AIIMS, Bhopal, Madhya Pradesh, India

Date of Submission13-Apr-2023
Date of Decision14-Apr-2023
Date of Acceptance14-Apr-2023
Date of Web Publication24-May-2023

Correspondence Address:
Girish Chandra Bhatt
Department of Pediatrics, AIIMS, Bhopal, Madhya Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_86_23

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Background: Distal renal tubular acidosis (dRTA) can be acquired or inherited. Hereditary types of dRTA are mostly seen in the pediatric population, whereas acquired forms predominate in adults. The diagnosis of hereditary dRTA can be confirmed by genetic testing. Five genes are known to cause the disease: ATP6V1B1, ATP6V0A4, FOXI1, SLC4A1, and WDR72. Most of the children with autosomal dominant forms carry mutations in the SLC4A1 gene, whereas the most common mutation in autosomal recessive type is ATP6V0A4 and ATP6V1B1 genes. Objective: In this systematic review of case reports, we discuss the clinical features and mutation variants of hereditary dRTA due to homozygous pathogenic variations in the WDR72 gene, which has been recently identified. Methods: The PubMed and Google Scholar databases were searched with defined search terms and eligibility criteria independently by different authors. Results: Of five full-text articles retrieved, four were finally included which provided data of 14 individuals, all of which had specific mutations in WDR72 gene. The majority of cases were attributed to individuals of Asian descent (71%) with equal distribution of males and females. The mean age of onset was 4.42 years. Amelogenesis imperfecta (AI) was described in 90% of patients, nephrocalcinosis in 62.5%, polyuria in 55.5%, proximal muscle weakness in 55.5%, and rickets in two patients. Conclusion: In patients exhibiting features such as metabolic acidosis, hypokalemia, AI, polyuria, nephrocalcinosis, and growth retardation, genetic analysis for WDR72 mutation should be considered.

Keywords: Amelogenesis imperfecta, distal renal tubular acidosis, genetic analysis, metabolic acidosis

How to cite this article:
Todkar M, Harshitha S, Bhatt GC. Genotype–Phenotype Characteristics of Children with Distal Renal Tubular Acidosis Caused by WDR72 Mutations: A Systematic Review of Case Reports. Indian Pediatr Case Rep 2023;3:117-21

How to cite this URL:
Todkar M, Harshitha S, Bhatt GC. Genotype–Phenotype Characteristics of Children with Distal Renal Tubular Acidosis Caused by WDR72 Mutations: A Systematic Review of Case Reports. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Sep 26];3:117-21. Available from:

Distal renal tubular acidosis (dRTA) is a rare disease with an estimated incidence <1: 100,000,[1] in which urinary acidification is impaired, resulting in hyperchloremic metabolic acidosis. The condition may be acquired or inherited. While in adults, dRTA is mostly due to acquired causes, in children hereditary forms predominate resulting from mutations in genes responsible for encoding or regulating the channels involved in urinary acidification at the level of distal and collecting tubules.

The typical features seen in dRTA include hypokalemia, hypercalciuria, and nephrocalcinosis.[2] Children with this condition present with short stature, vomiting, diarrhea and/or constipation, loss of appetite, polydipsia, polyuria, nephrocalcinosis, nephrolithiasis, osteomalacia, and rickets. Essentially, the diagnosis of dRTA relies on clinical and laboratory findings. At the distal tubular level, mutations in genes that encode transporters or enzymes responsible for regulating acid-base balance are the cause of hereditary dRTA. These transporters or enzymes play a role in renal bicarbonate (HCO3) reabsorption or hydrogen (H+) secretion. These forms of the disease typically present during infancy or early childhood.[3]

The diagnosis of hereditary dRTA can be confirmed through genetic testing of five genes that are known to cause the disease: ATP6V1B1, ATP6V0A4, FOXI1, SLC4A1, and WDR72.[4] Autosomal dominant forms are usually caused by mutations in the SLC4A1 gene, whereas autosomal recessive forms are mostly associated with mutations in ATP6V0A4 and ATP6V1B1 genes. Performing a molecular diagnosis enables the patient and their family to receive appropriate genetic counseling, to obtain a better understanding of the patient's prognosis, and to establish correlations between their genotype and phenotype.

In this systematic review of case reports, we discuss hereditary dRTA due to homozygous pathogenic variations in the WDR72 gene, which has been recently identified. This gene is thought to play a role in intracellular trafficking, impacting the orientation of acid-base regulating proteins such as the AE1 transporter isoform or V-ATPase, and resulting in their retention or misdirection within the cell.[5] WDR72 mutations have also been linked to amelogenesis imperfecta (AI), a group of inherited conditions that impact the development of dental enamel.[6] One possible hypothesis connecting AI and renal tubular acidosis (RTA) suggests that certain dental proteins previously considered to only exist in dental tissue may also be present in other tissues such as the kidneys. This includes DLX3, a type of homeobox protein, which has been found to be expressed in both dental and renal tissues. Additional investigation into the functions of these proteins is needed to determine whether they have a significant impact on the development of renal tubular disorders.[7]

While case reports may not be able to establish causal relationships, they can offer detailed clinical information, and systematic reviews of case reports can be valuable in collating all clinical presentations and comorbidities, in such rare diseases.

The main aim of conducting this descriptive systematic review of case reports is to provide a comprehensive account of the clinical comorbidities and presentations of dRTA due to WDR72 mutation, a newly recognized genetic mutation.

  Methods Top

The relevant articles were examined to gather information on the mutations and clinical manifestations of patients, which were then summarized.

Search strategy and information sources

We searched PubMed and Google Scholar using the following search strategy “(((distal renal tubular acidosis) OR (incomplete distal renal tubular acidosis)) OR (hereditary distal renal tubular acidosis)) AND (((wdr72) OR (WDR1 protein, human)) OR (wdr72 renal)).” We also noted references included in the study to avoid omissions.

Eligibility criteria

Articles that satisfied the following conditions were considered eligible for inclusion: (1) patients had a confirmed diagnosis of dRTA, (2) molecular genetic techniques were used to confirm the presence of mutations in WDR72, and (3) the clinical data of the patients were reported. The articles involving a series of patients with genetic analysis but without specific WDR72 mutations were excluded from the study.

Data extraction

Two authors (MT and HS) independently extracted the data pertaining to patients meeting the inclusion criteria were gathered, including information such as (1) the country of origin, (2) gender, (3) age at which symptoms first appeared, (4) details regarding the specific genetic mutation, (5) observed clinical symptoms, and (6) results of laboratory tests conducted during the time of diagnosis.

Data analysis

As this review is descriptive in nature, we utilized descriptive statistics to present information about the demographics and clinical features.

  Results Top

Of the 143 citations retrieved, full texts of five articles were assessed for eligibility. Of these five articles, four were finally included which provided data of 14 individuals. A detailed flow diagram is shown in [Figure 1]. Clinical details were not provided in one article which reported a case of dRTA and for a few cases in another article.[4],[8]
Figure 1: PRISMA flow diagram

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There were a total of 14 cases of dRTA-associated WDR72 mutations, in all of which specific mutations have been described [Table 1].
Table 1: Variant in information of the WDR72 mutations reported in the case studies

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Four cases had Turkish descent,[9] but majority of cases were attributed to individuals of Asian descent (10/14; 71%), of which seven were Indians[4],[10],[11] and three of Thai descent.[4] Gender distribution was female in (7/14) 50% versus male in (7/14) 50%. The age of onset ranged from 6 months to 10 years, with a mean of 4.42 years. AI was described in 10/11 (90.0%) patients, nephrocalcinosis was reported in 5/8 (62.5%) patients, polyuria in 5/9 (55.5%) patients, proximal muscle weakness in 4 (55.5%) patients, and rickets in 2 patients. While acidic urine pH (<6.5) was reported in 8/14 patients, acidosis was present in all, and hypokalemia was reported in 9/14 (64.3%) patients. The phenotype–genotype correlations of the cases are depicted in [Table 2].
Table 2: Genotype–phenotype correlations of the cases diagnosed with WDR72 mutations

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  Discussion Top

In this work, we summarized the mutation spectrum and clinical characteristics in patients with dRTA with WDR72 mutation.

The WDR72 gene consists of 19 coding exons ranging up to 250 kb, encoding a protein of 1102 amino acids. As per studies, it is the closest human homolog and a possible paralog is WDR7.[5] Although functions of WDR72 are not fully known, previous studies speculated that WDR72 may regulate endocytosis in a manner similar to WDR7, which is its closest human homolog.[12] It is an intracellular protein and is predicted to have a two β-propeller structure. It is composed of WD40 repeat domains in its N-terminus and an α-solenoid tail in its C-terminus. The above-mentioned domain organization is characteristic of certain vesicle coat proteins that regulate intracellular vesicle trafficking.[13],[14] The role of WDR72 mutations in AI has been studied previously. Recently, genetic variations of WDR72 are found to be associated with dRTA. In 2013, a case of a 10-year-old girl with dRTA and AI was reported.[15]

In 2019, Rungroj et al. reported compound heterozygous pathogenic variations in WDR72 in three affected siblings of a family with hereditary dRTA.[4] All of them having low arterial blood pH, low serum HCO3, low serum potassium, high serum chloride, alkaline urine pH, and no acidification of urine after acid loading. Out of these, one of the affected family members had nephrolithiasis and localized enamel hypoplasia. This study also reported AI and dRTA in a 13-year-old Indian girl.[4] Furthermore, another study in 2019 identified homozygous mutations in the gene WDR72 in two additional dRTA families.[10] Further, in 2020, Khandelwal et al. described four patients from three families with pathogenic variants of WDR72 associated with AI, dRTA, hypokalemia, and nephrocalcinosis.[13] The dRTA reported was found to be rate dependent as mild metabolic acidosis was documented with ability to acidify urine upon acid loading but was unable to increase urinary pCO2 after alkalizing urine. Another feature found in this study was that some features of Fanconi syndrome were present in these patients which resolved after therapy with alkali.

In this review, 66% of individuals were of Asian descent, out of which seven were Indians and three of Thai descent. There are few other studies done in India, which showed association between AI and dRTA, but genetic analysis in these patients was not done.[11] Further, no sex preponderance was found; both males and females were equally affected. The age of onset ranged from 6 months to 10 years, the mean age being 4.42 years, which is comparable to those with previous studies.

Mutations in WDR72 identified are illustrated in [Table 1]. With the available data, clinical features were described in 9 out of the 15 patients. Ten out of 11 patients with dRTA with WDR72 mutation were found to have AI. No data have been reported in other four cases. This uplifts the importance of screening for WDR72 mutations as part of the genetic testing in patients with dRTA, particularly if associated with dental defects, and need for evaluation for dRTA in patients with AI.

Our review of the clinical characteristics of these patients revealed certain differences. Nephrocalcinosis was found in 62% (5 out of 8) patients with available data and no data regarding the seven other patients were available. Further, hypokalemia was found in 81.8% (9 out of 11), out of which 55.5% presented with proximal muscle weakness. Hypokalemia can lead to life-threatening complications such as arrhythmias and paralysis. Further, hypercalciuria and nephrocalcinosis may lead to progression to chronic kidney disease and end-stage renal disease in patients with dRTA. Thus, early diagnosis and intervention for acid-base and electrolyte imbalance are essential to prevent life-threatening complications and also to reduce morbidity and mortality.

All the reported cases were found to have acidosis, all of them showing mild acidosis. The value of pH of three patients was not available. Ability to acidify urine after furosemide test was found to be preserved in four patients; all of these were unable to increase urinary pCO2 after alkalizing urine. However, distal acidification was found to be impaired in five patients, whereas no data were available in six patients.

Growth retardation was described in more than half of the children (55% patients), further reiterating the need for early recognition of acid-base imbalances and prompt correction to improve growth in these children, prevent skeletal deformities, and improve the quality of life of these patients.

  Conclusion Top

To sum up, our study provided a summary of both clinical characteristics and mutations associated with dRTA that are caused by WDR72 mutations. A genetic test should be promptly conducted for patients exhibiting metabolic acidosis, hypokalemia, AI, polyuria, nephrocalcinosis, and growth retardation. Conducting a molecular diagnosis holds great significance as it allows for better genetic counseling for the patients and their relatives, facilitates comprehension of the patient's prognosis, and establishes associations between their genotype and phenotype.


Funding support for collaborative research studies tubular disorders by ICMR file no F. no 33/12/2019-TF/Rare/BMS.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Lopez-Garcia SC, Emma F, Walsh SB, et al. Treatment and long-term outcome in primary distal renal tubular acidosis. Nephrol Dial Transplant 2019;34:981-91.  Back to cited text no. 1
Vallés PG, Batlle D. Hypokalemic distal renal tubular acidosis. Adv Chronic Kidney Dis 2018;25:303-20.  Back to cited text no. 2
Ferraro PM, D'Addessi A, Gambaro G. When to suspect a genetic disorder in a patient with renal stones, and why. Nephrol Dial Transplant 2013;28:811-20.  Back to cited text no. 3
Rungroj N, Nettuwakul C, Sawasdee N, et al. Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations. Clin Genet 2018;94:409-18.  Back to cited text no. 4
El-Sayed W, Parry DA, Shore RC, et al. Mutations in the beta propeller WDR72 cause autosomal-recessive hypomaturation amelogenesis imperfecta. Am J Hum Genet 2009;85:699-705.  Back to cited text no. 5
Rodríguez Soriano J. Renal tubular acidosis: The clinical entity. J Am Soc Nephrol 2002;13:2160-70.  Back to cited text no. 6
Misgar RA, Hassan Z, Wani AI, et al. Amelogenesis imperfecta with distal renal tubular acidosis: A novel syndrome? Indian J Nephrol 2017;27:225-7.  Back to cited text no. 7
[PUBMED]  [Full text]  
Sinha R, Pradhan S, Banerjee S, et al. Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: The East India tubulopathy gene study. Pediatr Nephrol 2022;37:1811-36.  Back to cited text no. 8
Zhang H, Koruyucu M, Seymen F, et al. WDR72 Mutations associated with amelogenesis imperfecta and acidosis. J Dent Res 2019;98:541-8.  Back to cited text no. 9
Jobst-Schwan T, Klämbt V, Tarsio M, et al. Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis. Kidney Int 2020;97:567-79.  Back to cited text no. 10
Khandelwal P, Mahesh V, Mathur VP, et al. Phenotypic variability in distal acidification defects associated with WDR72 mutations. Pediatr Nephrol 2021;36:881-7.  Back to cited text no. 11
Frontiers | Mutations and Clinical Characteristics of dRTA Caused by SLC4A1 Mutations: Analysis Based on Published Patients. Available from: 2023.1077120/full. [Last accessed on 2023 Mar 30].  Back to cited text no. 12
Katsura K, Nakano Y, Zhang Y, et al. WDR72 regulates vesicle trafficking in ameloblasts. Sci Rep 2022;12:2820.  Back to cited text no. 13
Katsura KA, Horst JA, Chandra D, et al. WDR72 models of structure and function: A stage-specific regulator of enamel mineralization. Matrix Biol 2014;38:48-58.  Back to cited text no. 14
Jain M, Agarwal MP, Wasir JS, et al. Amelogenesis imperfecta and distal renal tubular acidosis presenting as hypokalemic periodic paralysis. J Assoc Physicians India 1999;47:1205-6.  Back to cited text no. 15


  [Figure 1]

  [Table 1], [Table 2]


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