Diverse Renal Phenotypes Observed in a Single Family with a Genetic Mutation in Paired Box Protein 2

Iwafuchi, Yoichi; Morioka, Toshio; Morita, Takashi; Yanagihara, Toshio; Oyama, Yoshihiro; Morisada, Naoya; Iijima, Kazumoto; Narita, Ichiei

doi:10.1159/000445679

Cited by 11 publications

(6 citation statements)

References 15 publications

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“…The phenotypic manifestations of the mutations were heterogeneous, with the same mutation showing different symptoms. For example, two of our cases possessed heterozygous c.76dupG mutation (p.Val26Glyfs*28) in exon 2, that had been reported previously (Iwafuchi et al, ) and was responsible for the animal model of human RCS (Porteous et al, ). Compared to patients previously reported, renal pathology in our patients ranged from oligomeganephronia to FSGS, with or without optic coloboma.…”

Section: Discussionsupporting

confidence: 68%

“…In a previous study, the onset of CKD Stage 5 was reported to occur up to the age of 79 years (Bower et al, ). The progression to ESRD differed, patient 3 in our study, progressed to ESRD at 11.2 years old with c.76dupG (p.Val26Glyfs*28), while a patient with the same mutation, reported by another group, had not progressed to ESRD at 52 years old (Iwafuchi et al, ). These results indicate that kidney dysfunction progressed variously even for patients with the same mutation.…”

Section: Discussionmentioning

confidence: 46%

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Diverse phenotypes in children with PAX2‐related disorder

Deng

Zhang

et al. 2019

Molec Gen & Gen Med

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Background The aim of this study was to analyze the diverse phenotypes of children with PAX2‐related disorder so as to improve our understanding of this disease. Methods The clinical data of ten children with PAX2 mutations, detected by targeted region capture sequencing or whole‐exome sequencing, were retrospectively analyzed. Family members of index cases were verified by Sanger sequencing and family segregation analysis was performed. Results The age of first symptom of 10 unrelated children (six girls and four boys) was 6.4 (ranged from postnatal day to 14.8) years old. Proteinuria, abnormal renal function, and structure were found in all patients. Renal hypoplasia and renal cysts were found in 10 of 10 and five of 10 cases, respectively. Three patients progressed to chronic kidney disease stage 5 and the onset age of end‐stage renal disease was 9.8–16.4 years old. PAX2‐related ocular abnormalities were found in five of seven cases and three patients were observed to have more than one ocular findings involved. In addition to diverse renal and ocular findings, new phenotypes including congenital ventricular septal defect, skeletal deformity (fourth metatarsal microsomia), ovarian teratoma, and relatively rare extrarenal manifestations such as growth retardation, gout, and microcephaly were also found. Three novel mutations were reported for the first time. De novo mutations occurred in all patients who were carried out segregation analysis. Patients with the same mutation had different manifestations. PAX2‐related disorder showed remarkable clinical variability and phenotypic heterogeneity. Conclusion We firstly reported skeletal deformity (fourth metatarsal microsomia), ovarian teratoma, and congenital ventricular septal defect as new phenotypes of PAX2‐related disorder which enlarged the phenotypic spectrum. Gout was firstly reported as the onset symptom of PAX2‐related disorder. The diagnosis of PAX2‐related disorder should be considered without family history due to a much higher percentage of De novo mutations.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 46%

Diverse phenotypes in children with PAX2‐related disorder

Deng

Zhang

et al. 2019

Molec Gen & Gen Med

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“…32,33 In contrast, in this study, some patients underwent detailed fundus examination after identifying genetic abnormalities, similar to previous studies. 34,35 Recently, genetic screening using TES or WES has become widely used in clinical practice. It is possible to re ne phenotypes based on genetic marker data, which is called reverse phenotyping.…”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype analysis in patients with PAX2 mutations: beyond renal coloboma syndrome

Kim

Ahn

Jang

et al. 2023

Preprint

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PAX2-related disorders encompass renal coloboma syndrome (RCS) and hereditary focal segmental glomerulosclerosis (FSGS)type 7. In this multicenter study on patients with PAX2 mutations, we explored genotype-phenotype correlations regarding kidney and ocular involvement and long-term clinical outcomes. Among 27 patients with PAX2 mutations detected from 2004–2022, 19 had RCS, 4 had FSGS, and 4 had isolated congenital anomalies of the kidneys and urinary tract (CAKUT). Based on genotypes, patients were classified into truncating (n=22) and missense (n=5) mutation groups. Truncating mutations were associated with RCS in 81.8% of cases, while missense mutations were linked to FSGS (n=2) and isolated CAKUT (n=2) in 80.0% of cases (P=0.034). Fourteen patients developed kidney failure at a median age of 14.5 years, with no difference in kidney survival between the truncating and missense mutation groups. However, mutations in the paired domain of PAX2 resulted in kidney failure more rapidly than mutations in other sites (P=0.025). Regarding ocular manifestations, the truncating mutation group exhibited more common, earlier onset and severe involvement compared to the missense mutation group. Our findings support genotype-phenotype correlations in ophthalmology field and emphasize the impact of the paired domain on kidney outcomes in patients with PAX2mutations.

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“…Briefly, the onset of CKD stage 5 requiring renal replacement therapy ranges from birth to 79 years ( 2 ). We list some of the reported family of PAX2 mutation in Table 3 ( 2 , 16 – 21 ), showing an enormous intra-familial heterogeneity on clinical manifestations, including onset age, renal morphology and pathology, age of progression to ESRD, and other extra-renal abnormalities. Further works on genetic investigations are warranted to delineate the relationship between the gene and the clinical presentations.…”

Section: Discussionmentioning

confidence: 99%

PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports

et al. 2022

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Paired box 2 (PAX2)-related disorder is an autosomal dominant genetic disorder associated with kidney and eye abnormalities and can result in end stage renal disease (ESRD). Despite reported low prevalence of PAX2 mutations, the prevalence of PAX2 related disorders may have been underestimated in past studies. With improved genetic sequencing techniques, more genetic abnormalities are being detected than ever before. Here, we report three patients from two families with PAX2 mutations identified within 1 year. Two patients were adults with chronic kidney disease and were followed for decades without correct diagnoses, including one with ESRD who had even undergone kidney transplant. The third patient was a neonate in whom PAX2-related disorder manifested as oligohydramnios, coloboma, and renal failure that progressed to ESRD within 1 year after birth. The phenotypes of PAX2 gene mutation were shown to be highly variable, even within the same family. Early detection promoted genetic counseling and guided clinical management. The appropriate time point for genetic study is an important issue. Clinicians must be more alert for PAX2 mutation when facing patients with congenital kidney and urinary tract anomalies, chronic kidney disease of unknown etiology, involvement of multiple systems, and/or a family history of renal disease.

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Diverse Renal Phenotypes Observed in a Single Family with a Genetic Mutation in Paired Box Protein 2

Cited by 11 publications

References 15 publications

Diverse phenotypes in children with PAX2‐related disorder

Diverse phenotypes in children with PAX2‐related disorder

Genotype-phenotype analysis in patients with PAX2 mutations: beyond renal coloboma syndrome

PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports

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