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Genetics and pathogenesis of nephronophthisis

Genetics and pathogenesis of nephronophthisis
Literature review current through: Sep 2023.
This topic last updated: Feb 12, 2023.

INTRODUCTION — Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disorder that typically progresses to end-stage kidney disease (ESKD). It is caused by variants in a large number of genes that encode proteins involved in the function of primary cilia, basal bodies, and centrosomes resulting in renal disease and extra-renal manifestations, including retinal degeneration, cerebellar ataxia, and liver fibrosis.

The genetics and pathogenesis of NPHP will be reviewed here. The clinical manifestations and management of NPHP are discussed separately. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis".)

OVERVIEW — Patients with NPHP have variants in genes that encode components of the ciliary apparatus [1,2]. Although variants in NPHP1 gene account for 20 percent of cases, at least 20 different genes have been associated with NPHP. All the genes encode proteins that are localized to the primary cilia, basal bodies, and centrosomes.

These gene defects result in the characteristic findings of NPHP:

Autosomal recessive inheritance

Impaired urinary concentrating ability and sodium reabsorption

Bland urinalysis (absence of proteinuria, hematuria and cellular elements)

Chronic tubulointerstitial nephritis and progression to end-stage kidney disease (ESKD) generally before the age of 20 years

Three clinical variants have been described based upon the median age of onset of ESKD [3].

Infantile − one year of age

Juvenile − 13 years of age

Adolescent − 19 years of age

These clinical variants are associated with specific gene defects. In addition, abnormalities in extra-renal organs including hepatic fibrosis and retinal defects are often present and are usually also associated with a specific gene defect.

NPHP is included in the NPHP/medullary cystic kidney disease complex (MCKD). In contrast to NPHP, MCKD is an autosomal dominant disorder that generally progresses to ESKD later in life during adulthood. A discussion on medullary cystic kidney disease is found elsewhere. (See "Autosomal dominant tubulointerstitial kidney disease".)

EPIDEMIOLOGY — NPHP is an uncommon condition equally distributed in males and females. The juvenile form, in which patients develop end-stage kidney disease (ESKD) during childhood or adolescence, is the most common variant. Cases of juvenile NPHP have been reported worldwide [4]. Estimated prevalence for this variant varies from 0.1 to 0.2 per 10,000 live births in reports from Finland and Canada [3,4].

NPHP is the most frequent genetic cause of ESKD in the first three decades of life. It has been estimated that NPHP is responsible for approximately 2.4 percent of cases of ESKD in children in the United States [5]. This may be an underestimate, since studies from Europe have revealed a higher frequency of 15 percent [6].

GENETICS

Overview — Patients with NPHP have variants in genes that encode components of the ciliary apparatus, which are expressed in primary cilia, basal bodies, or centrosomes (table 1) [1-3,7-22].

Variants of the NPHP1 gene are the most common, being reported in approximately 20 percent of cases [2,3,23]. Variants in each of the other genes contribute less than 3 percent each [3]. The gene involved remains unknown in 30 percent of patients with NPHP [24].

Clinical correlation and gene variant — The clinical findings vary with the involved gene [22]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Clinical manifestations'.)

Juvenile NPHP is associated with variants in all the NPHP genes except NPHP2, including NPHP1, the most commonly affected gene.

Variants in NPHP2 and NPHP3 result in infantile and adolescent NPHP, respectively [17,25].

Variants in NPHP5 are associated with retinitis pigmentosa (also referred to as tapetoretinal degeneration) and the Senior-Loken syndrome.

Variants in NPHP6 and NPHP8 are associated with retinal degeneration and cerebellar vermis aplasia in the Joubert syndrome or Meckel-Gruber syndrome.

Variants in NPHP7 and NPHP9 are rare causes of NPHP [20,21].

NPHP1 gene — The first gene, NPHP1, was identified via the use of positional cloning in consanguineous affected families and is located on chromosome 2q12.3 [8-10]. NPHP1 encodes for nephrocystin-1, which is located at the cell-cell junction (adherens junction) and the cell-matrix interface (focal adhesion) and is expressed primarily in the collecting duct [3,26,27]. It interacts with other NPHP proteins and participates in multiple intracellular signaling pathways that involve ciliary function. (See 'Pathogenesis' below.)

The major NPHP1 gene defect is a large homozygous 290 kb deletion found in approximately 80 percent of the patients [28,29]. Heterozygous deletions may be associated with concomitant point variant of the NPHP1 gene on the second allele [3].

Patients with NPHP1 gene variants generally present with juvenile NPHP. NPHP1 gene deletions or variants have also been described in association with moderate retinitis pigmentosa, Cogan syndrome with oculomotor apraxia, and a subset of individuals with Joubert syndrome [27,30-33]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Clinical manifestations'.)

Although most patients with NPHP1 gene variants present in childhood and progress to ESKD before age 20, in a large series of 5606 patients adult-onset ESKD, homozygous NPHP1 deletions were detected in 26 patients (0.5 percent) [34].

NPHP2 gene — NPHP2, located on chromosome 9q21-22, encodes for the protein inversin (also called nephrocystin-2) [16]. Inversin is critical for the normal development of left-right patterning [16,35] and is thought to be involved in the signaling mechanisms of planar cell polarity [36,37]. Inversin is located in several different subcellular compartments including the primary cilia of the renal tubule where it interacts with both nephrocystin-1, nephrocystin-3, and beta-tubulin, a major component of primary cilia [3,16]. Defects in this gene are responsible for the infantile form of NPHP with and without situs inversus [16].

In patients with NPHP2 gene variants, histologic changes seen on renal biopsy consist of diffuse chronic tubulo-interstitial nephritis and microcystic dilatation of proximal tubules and Bowman’s space [28,38]. Partial deletion of this gene in a mouse model results in large renal cysts, situs inversus, and hepatobiliary duct malformations [39].

Twenty-eight families with NPHP have been identified as having variants of the NPHP2 gene [22,40]. The age of onset of end-stage kidney disease (ESKD) was less than four years in all patients and less than 24 months in most of them [16]. Hypertension is a constant finding. Other findings include situs inversus, heart valve or septal defects, liver disease, recurrent bronchitis, and optic nerve atrophy.

NPHP3 gene — NPHP3, located on chromosome 3q22, encodes a protein with a tubulin-tyrosine ligase domain, which interacts with nephrocystin-I [17]. In a mouse model, complete loss of the NPHP3 protein function may be associated with a very severe phenotype with embryonic lethality [41]. In humans, there is a broad clinical spectrum of early embryonic patterning defects that include situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract [41]. NPHP3 gene variants have been described in families with renal disease alone, as well as in families with renal disease associated with hepatic fibrosis, heart valve or septal defects, cone-shaped epiphysis, central nervous system anomalies, or retinitis pigmentosa [17,22,40,42].

NPHP3 gene variants are associated with the adolescent variant of NPHP (with a reported median age of 19 at the time of ESKD) [43]. NPHP3 gene variants have also been observed in patients with the infantile form of NPHP and early-onset ESKD [40].

NPHP4 gene — The NPHP4 gene, located on chromosome 1p36, encodes nephrocystin-4 (also referred to as nephroretinin), which localizes to primary cilia, basal bodies, and centrosomes, interacts with nephrocystin-1, and is involved with the same intracellular signaling pathway [15]. NPHP4 has been identified as a negative regulator of the Hippo pathway, which is involved in tumor suppression and the control of cell proliferation [44]. In one study of 250 patients, 23 different NPHP4 gene variants were detected in 26 unrelated cases of juvenile NPHP [45]. These cases included 13 of 190 patients with isolated NPHP, 8 of 50 with retinitis pigmentosa, and 2 of 10 with oculomotor apraxia. (See "Retinitis pigmentosa: Clinical presentation and diagnosis".)

Nephrocystin-4 localizes to the connecting cilium of photoreceptor cells and interacts with a cone and rod receptor protein, RPGRIP1L (retinitis pigmentosa GTPase regulator interacting protein 1) [46].

NPHP5 gene — The NPHP5 gene (also referred to as IQCB1 gene) is located on chromosome 3q21 and encodes nephrocystin-5 [18]. Nephrocystin-5 interacts with calmodulin and the retinitis pigmentosa GTPase regulator (RPGR) [3]. Since variants in RPGR cause X-linked retinitis pigmentosa, the eye disorder resulting from defects in the NPHP5 gene is likely due to a common functional pathway that involves the two proteins. Both nephrocystin-5 and retinitis pigmentosa GTPase regulator are expressed in the connecting cilia of photoreceptor and primary cilia of renal epithelial cells [18]. (See "Retinitis pigmentosa: Clinical presentation and diagnosis" and 'Pathogenesis' below.)

All patients with variants of the NPHP5 gene have retinitis pigmentosa, and disruption of this gene appears to be the most frequent cause of Senior-Loken syndrome, in which retinitis pigmentosa accompanies NPHP. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Senior-Loken syndrome and retinitis pigmentosa'.)

NPHP6 gene — The NPHP6 gene, also known as CEP290, is located on chromosome 12q21 and encodes a centrosomal protein that interacts with ATF4, a transcription factor involved in the control of the cell cycle [19,47]. Variants of the ATF4 gene are associated with cAMP-dependent renal cyst formation.

Several variants in the NPHP6 gene were reported in families with Joubert syndrome with and without renal involvement, Senior-Loken syndrome, Bardet-Biedl syndrome, and Meckel-Gruber syndrome [19,47-49]. In addition, in two case series, NPHP6 gene variants were one of the most common causes of Leber's congenital amaurosis (LCA), a recessive disorder of congenital severe vision impairment or blindness due to the abnormal development of photoreceptors without renal disease. NPHP6 gene variants accounted for 20 percent of LCA cases [50,51]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Clinical manifestations'.)

NPHP7 gene — Variants in the NPHP7 gene, also known as GLIS2, located on chromosome 16p, is a rare cause of NPHP. The gene product is a Kruppel-like zinc finger protein, which, unlike other NPHP proteins, appears to be a transcriptional repressor without involvement in ciliary function. Variants of this gene were reported in a single family with three affected children who developed ESKD by eight years of age [20]. However, no variants of this gene were identified in a cohort of 470 individuals with clinical features suggesting NPHP. In a mouse model, NPHP7 gene variant resulted in severe premature renal atrophy and fibrosis, suggesting that the gene product plays a role in the maintenance of renal tissue architecture by preventing apoptosis [20,52].

NPHP8 gene — Variants in the NPHP8 gene (also referred to as the RPGRIP1L gene) located on chromosome 16q, have been reported in a few families with Joubert syndrome (missense variants) and Meckel-Gruber syndrome (truncating variants) [53,54]. Variants in the NPHP8 gene may also cause retinal degeneration [55]. Inactivation of the mouse orthologue recapitulated the cerebral, renal, and hepatic findings associated with these two disorders [53]. The gene product colocalizes to the basal body and centrosomes with nephrocystin-4 and -6 [53,56].

RPGRIP1L participates in sonic hedgehog (Shh) signaling and plays a critical role in patterning of the developing neural tube and limb [57].

NPHP9 gene — Variants in the NPHP9 gene (also called the NEK8 gene) are rare causes of NPHP.

In one cohort of 588 patients diagnosed with NPHP, three patients from different families had missense variants in the Nek8 gene [21]. One patient with homozygous variant developed infantile NPHP, while in the other two patients, only one recessive variant was identified. In one of them, an additional variant of the NPHP5 gene was present.

NEK8 gene variants were also observed in a third-degree consanguineous multiplex pedigree with three affected fetuses who presented with a multisystemic phenotype, which included enlarged cystic kidneys, liver, and pancreas and developmental heart disease [58].

A third case report described two brothers who presented in the newborn period with cardiac (hypertrophic cardiomyopathy), hepatic (bile duct hypoplasia), and renal anomalies (renal cystic dysplasia) [59].

NEK8 is a member of the NIMA (never in mitosis A)-related kinase (NEK) family, which is thought to coordinate the regulation of cilia and cell cycle progression. NEK8 localizes to the primary cilia of renal epithelial cells.

NPHP10 gene — Variants of the gene that encodes SDCCAG8 (serologically defined colon cancer antigen 8, also known as the centrosomal colon cancer autoantigen protein [CCCAP]) have been identified in 10 families with retinitis pigmentosa and NPHP [60]. SDCCAG8 is localized at the centrioles of both renal epithelial and retinal photoreceptor cells. This finding supports the role of the cilia-centrosome-mitotic spindle complex for single-gene disorders that affect both the kidney and retina.

NPHP11 gene — The NPHP11 gene at 8q22 is also known as the MKS3 and TMEM67 gene [22]. It encodes meckelin, which is located at the base of primary cilia [22]. Patients with this gene defect have clinical features of Joubert syndrome, an autosomal recessive neurologic disorder characterized by cerebellar vermis hypoplasia resulting in ataxia, polydactyly, hypotonia, developmental delay, neonatal respiratory dysregulation, and abnormal eye movements or Meckel-Gruber syndrome, an autosomal recessive lethal disorder characterized by central nervous system malformation (eg, occipital encephalocele), bilateral renal cystic dysplasia, cleft palate, polydactyly, and ductal proliferation in the portal area of the liver. Compound heterozygous variants have been identified in two brothers with the RHYNS syndrome characterized by retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia [61]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Joubert syndrome' and "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Meckel-Gruber syndrome'.)

NPHP12 gene — The NPHP12 gene, also known as the TTC21B, JBS11, SRTD4, or ATD4 gene, on chromosome 2 encodes IFT139, a subunit of the intraflagellar transport-A complex, which regulates the retrograde trafficking in the primary cilium [62]. Variants in this gene have been reported in patients with isolated NPHP, in patients with NPHP with hepatic fibrosis or bone anomalies, and in patients with asphyxiating thoracic dystrophy (also known as Jeune syndrome) or Joubert syndrome [63,64]. A homozygous missense variant, p.P209L, in this gene has been reported in seven families from North Africa or Portugal with proteinuria and focal and segmental glomerulosclerosis [65]. Tubular basement membrane thickening, similar to that observed in patients with NPHP, was also noted. These patients had late-onset proteinuria and high blood pressure, and progressed to end-stage renal failure between 15 and 32 years. This observation shows that ciliary genes may also be involved in glomerular diseases.

NPHP13 gene — The NPHP13 gene, also known as WRD19, SRDT5, ATD5, or CED4, encodes IFT144, another subunit of the intraflagellar transport-A complex. Variants in this gene have been identified in patients with isolated NPHP, NPHP and hepatic fibrosis, Senior-Loken syndrome, Caroli disease, Sensenbrenner syndrome, Joubert syndrome, Jeune syndrome, and Mainzer-Saldino syndrome [24,66-70].

Other genes — Patients with defects in genes that affect components important for ciliary function may also present with NPHP. These include the following:

Variants in the gene SRDT9 encoding IFT140, another subunit of the intraflagellar transport-A complex, are responsible for Saldino-Mainzer syndrome and Jeune syndrome [71,72].

Variants in genes encoding proteins of the intraflagellar transport-B complex involved in the anterograde transport in the primary cilium, IFT27, IFT80, IFT172/NPHP17, have been reported in patients with Jeune syndrome, Saldino-Mainzer syndrome, and Bardet-Biedl syndrome [24,73,74].

The CEP83/NPHP18 gene encodes one of the distal appendages (DAPs) of centrioles, which anchor cilia to the plasma membrane. Biallelic variants of CEP83 have been identified in seven families, with early onset NPHP and rapid progression to ESKD, associated with central nervous system abnormalities in half of the patients [75].

Variants of ANKS6/NPHP16, which encodes a protein that localizes to the proximal compartment of the ciliary axoneme and connects NEK8 (gene product of NPHP9) to inversin (gene product of NPHP2) and NPHP3, have been reported in six families affected with infantile onset of NPHP, severe cardiovascular abnormalities, liver fibrosis, and situs inversus [76].

Variants of genes that encode for proteins within the DNA damage response pathway (ie, MRE11, ZNF423/NPHP14, and CEP164/NPHP15 genes) result in NPHP-related ciliopathies [77].

Variants in the gene TRAF3IP1, encoding the IFT-B subunit, IFT54, were observed in eight individuals from five unrelated families [78]. Patients presented with tubulointerstitial nephritis, leading to end-stage kidney disease (ESKD) between 3 and 16 years and the Senior-Loken syndrome. Four patients had liver defects and six had skeletal anomalies.

Variants in the IFT81 gene, encoding an IFT-B core protein, have been reported as a very rare cause of ciliopathy dysfunction [79]. One of the patients presented with NPHP and polydactyly.

Variants of the DCDC2/NPHP19 gene were detected in two patients from consanguineous families [80]. One patient presented with hepatic fibrosis at 11 months and ESKD at 14 years from NPHP, while the second patient presented with early liver fibrosis, requiring liver transplantation at two years. An isolated neonatal sclerosing cholangitis has been found to be related to recessive variants of the DCDC2 gene [81,82]. DCDC2 interacts with the mediator of Wnt signaling, thus demonstrating a central role of Wnt signaling in the pathogenesis of NPHP.

Variants in the gene MAPKBP1/NPHP20, encoding a scaffolding protein for the JNK signaling pathway, were detected in eight individuals from five families presenting with late-onset NPHP with massive renal fibrosis but no extra-renal manifestations [83]. Interestingly, MAPKBP1 is not located in the primary cilium but in the mitotic spindle pole and may represent a group of new gene products resulting in NPHP, which are not involved in cilia-associated functions.

Defects in the genes AHI1 and CC2D2A are also associated with NPHP and are discussed separately. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Associated syndromes'.)

Variants in the gene ADAMTS9 encoding a secreted extracellular metalloproteinase has been identified in patients with nephronophthisis-related ciliopathy [84]. In this study, ADAMTS9 was found localized near the basal bodies of the primary cilia in the cytoplasm.

Oligogenic inheritance — Oligogenic inheritance has been reported in individuals with NPHP, in whom variants in different NPHP genes occur. In a study of 94 families, patients from six families had two or more variants in the NPHP1, NPHP3, and NPHP4 genes [85]. Oligogenic inheritance was also noted in some patients with Joubert syndrome who had mutations in both the NPHP1 and NPHP6 genes [33].

The number of patients with oligogenic variants is too low to draw any conclusions on genotype/phenotype correlation, such as whether the presence of multiple variants or the type of variants (truncating versus missense variant) increase the severity of clinical findings.

PATHOGENESIS

Although it is uncertain exactly how the defects in the various NPHP genes lead to renal disease, the proposed common mechanism is ciliary dysfunction. This hypothesis is based upon the observation that most proteins associated with various forms of human renal cystic disease, including the nephrocystin proteins, localize to primary cilia, basal bodies, and centrosomes [18,19,86-88].

Nephrocystins interact with one another and with other proteins (such as tensin, filamins, and tubulins) that are involved with cell-cell and cell-matrix signaling [15,16,88]. It is thought that mutations in the NPHP genes alter cilia function via defects in intracellular signaling pathways, resulting in the inability of the ciliary mechanosensors to correctly sense luminal flow rates [3,89]. The inability of renal tubular cells to perceive luminal fluid flow due to dysfunctional ciliary function results in dysregulated tissue growth and subsequent development of renal cysts. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth".)

Gene products of some of the NPHP genes are found in the cilia of other organs. Variants of these genes result in the nonrenal manifestations of NPHP, such as retinitis pigmentosa, which occurs in 20 percent of all cases of NPHP. (See "Retinitis pigmentosa: Clinical presentation and diagnosis".)

With the identification of causative genes for NPHP, a genotype-phenotype correlation is becoming more apparent. Additional insight into the pathogenesis and clinical manifestations of the different forms of NPHP is provided by studies in animal models that replicate the mutations of the different genes. The following observations illustrate some of the findings:

Histology of the kidneys of mice without functional NPHP2 genes reveals tubular cysts and interstitial fibrosis, similar to the renal pathology seen in humans with NPHP2 gene mutations [39,90,91].

Mice with homozygous missense variants in the murine homolog of NPHP3 have similar renal pathology to that observed in patients with adolescent NPHP [92]. In the mouse, NPHP3 is expressed in those organs and tissue sites known to be affected in this disorder, including renal tubules, retina, liver, biliary tract, and neural tissues [17].

The renal, retinal, and cerebellar phenotype of Joubert syndrome can be reproduced by eliminating the function of the NPHP6 gene in zebrafish [19].

In animal models, variants in several genes (NPHP10, ZNF423, CEP164, NEK8 [77,93,94]) that cause NPH have been implicated in DNA damage response (DDR) signaling. Apoptosis antagonizing transcription factor (AATF) is a central modulator of DDR signaling. Mice with deletion of the AATF gene have ciliary defects and an accumulation of DNA double strand breaks and develop a progressive renal disease with histological lesions similar to those observed in the human NPH, suggesting a linkage between DDR and the development of nephronophthisis [95].

Renal inflammation has been identified as a prominent feature of human NPHP. Specific mediators of this process are common to NPHP mouse models and patients, suggesting inflammation as a potential therapeutic target [96].

PATHOLOGY

Juvenile and adolscent variant — In the juvenile and adolescent variants of NPHP, the kidneys are grossly normal or shrunken in appearance with small corticomedullary cysts up to 1.5 cm in size (image 1). Histologic changes include initial interstitial fibrosis and limited signs of inflammation, followed by severe tubular damage characterized by atrophic tubules with thickened and multilayered basement membranes [2]. The glomeruli are often normal, but secondary segmental sclerosis is not uncommon in advanced disease. In the later stages of the disease, light microscopy demonstrates that groups of dilated or collapsed tubules alternate with the atrophied damaged tubules (picture 1). This is often accompanied by collapsed glomeruli with severe periglomerular fibrosis.

On electron microscopy, homogeneous or multilayered thickening of tubular basement membranes is prominent along with duplication [97]. Disintegration of the basement membrane also can occur.

Infantile variant — In the infantile variant, due to variants of the inversin/NPHP2 gene, histologic changes include a diffuse chronic tubulointerstitial injury (or nephropathy), microcystic dilatations of cortical tubules, and minimal tubular basement membrane changes [2,38,40]. In contrast, patients with infantile NPHP due to mutations of the NPHP3 gene have similar pathology as those who present with the juvenile variant of NPHP.

SUMMARY AND RECOMMENDATIONS — Nephronophthisis (NPHP) is an autosomal recessive disorder that is characterized by a reduced urinary concentrating ability with a bland urinary sediment, chronic tubulointerstitial nephritis, and progression to end-stage kidney disease (ESKD) at an early age (generally before the age of 20 years).

Variants of several genes whose protein products are expressed in primary cilia, basal bodies, or centrosomes, have been identified in patients with NPHP. The gene products are thought to have roles in cell-cell and cell-matrix signaling, which involve sensing luminal flow rates within the renal tubules via ciliary mechanosensors. Genetic defects lead to dysregulation of tissue growth and cyst formation as a consequence of the abnormal renal cells’ attempt to compensate for a perceived lack of fluid flow. (See 'Genetics' above and 'Pathogenesis' above.)

Three clinical variants have been described based upon the median age of onset of ESKD. These variants are associated with specific gene defects. (See 'Genetics' above.)

The juvenile form (median onset of ESKD is 13 years of age) is the most common variant and is associated with variants in all the NPHP genes except NPHP2. In particular, patients with mutations of the NPHP1 gene, the most commonly affected gene, present with juvenile NPHP.

The infantile (median onset of ESKD by one year of age) form is associated with mutations in the NPHP2 gene and the adolescent form with mutations of the NPHP3 gene.

Characteristic pathologic features include severe tubular damage of atrophic tubules with thickened basement membranes alternating with groups of dilated or collapsed tubules demonstrated on light microscopy with normal appearing glomeruli (picture 1). (See 'Pathology' above.)

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Topic 6136 Version 26.0

References

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