UNASSIGNED: Alport Syndrome (AS) is a progressive genetic condition characterized by chronic kidney disease (CKD), hearing loss, and eye abnormalities. It is caused by mutations in the genes COL4A3, COL4A4, and COL4A5. Heterozygous mutations in COL4A4 and COL4A3 cause autosomal dominant Alport Syndrome (ADAS), and a spectrum of phenotypes ranging from asymptomatic hematuria to CKD, with variable extra-renal features. In the past, heterozygous mutations in these genes were thought to be benign, however recent studies show that about 30% of patients can progress to CKD, and 15% can progress to end stage kidney disease (ESKD).
UNASSIGNED: We present a case of a woman who was noted to have microscopic hematuria pre-living kidney donation. Genetic testing revealed a heterozygous variant of uncertain significance (VUS) in the COL4A4 gene. VUSs are medically nonactionable findings and data show that VUSs can be detected in 41% of all patients who undergo clinical genetic testing. VUSs frustrate clinicians and patients alike. Although they cannot be used in medical decision-making, data suggest that reanalysis can result in the reclassification of a VUS over time.
UNASSIGNED: Post-donation, the index patient had a higher than anticipated rise in serum creatinine, raising a concern for possible intrinsic kidney disease. Kidney biopsy was deemed high risk in the setting of a unilateral kidney thereby limiting possible diagnostic intervention to determine the cause of disease.
UNASSIGNED: Re-evaluation of prior genetic testing results and reassessment of the previously identified VUS in COL4A4 was performed 5-years post-donation. These analyses, along with the addition of new phenotypic data and extended pedigree data, resulted in the reclassification of the previously identified VUS to a likely pathogenic variant.
UNASSIGNED: This case demonstrates the importance of structured, periodic re-evaluation of genetic testing results. With the ever-changing landscape of genetics in medicine, the interpretation of a VUS can be dynamic and therefore warrant caution in living kidney donor evaluations. Studies have shown that about 10% of VUSs can be upgraded to a pathogenic classification after an 18- to 36-month interval. Structured re-evaluation of genomic testing results has not yet been integrated into clinical practice and poses a unique challenge in living kidney donation.
UNASSIGNED: This case report highlights the variability of the ADAS phenotype caused by pathogenic heterozygous variants in the type 4 collagen genes. It supports the nomenclature change from a benign hematuria phenotype to ADAS, particularly when additional risk factors such as proteinuria, focal segmental glomerulosclerosis or glomerular basement membrane changes on kidney biopsy are present, or as in this case, evidence of disease in other family members.
UNASSIGNED: Le syndrome d’Alport (SA) est une maladie génétique progressive caractérisée par une insuffisance rénale chronique (IRC), une perte auditive et des anomalies oculaires. La maladie est causée par des mutations dans les gènes COL4A3, COL4A4 et COL4A5. Des mutations hétérozygotes dans les gènes COL4A4 et COL4A3 provoquent le syndrome d’Alport autosomique dominant (SAAD) et un specter de phénotypes allant de l’hématurie asymptomatique à l’IRC, avec des caractéristiques extrarénales variables. Dans le passé, les mutations hétérozygotes de ces gènes étaient considérées comme bénignes, mais des études récentes montrent qu’environ 30 % des patients peuvent progresser vers l’IRC et 15 % vers l’insuffisance rénale terminale (IRT).
UNASSIGNED: Nous présentons le cas d’une femme chez qui on avait observé une hématurie microscopique avant un don vivant de rein. Les tests génétiques ont révélé un variant hétérozygote de signification incertaine dans le gène COL4A4. Les variants de signification incertaine (VSI) sont des résultats qui ne peuvent être utilisés médicalement et les données montrent qu’ils peuvent être détectés chez 41 % des patients qui subissent des tests génétiques cliniques. Les VSI sont frustrants tant pour les cliniciens que pour les patients. Bien qu’ils ne puissent pas être utilisés dans la prise de décisions médicales, les données suggèrent que leur réanalyse pourrait entraîner leur reclassification au fil du temps.
UNASSIGNED: Après le don, ce cas index a présenté une élévation de la créatinine sérique plus importante que prévu, ce qui a soulevé une préoccupation quant à la présence d’une néphropathie intrinsèque. La biopsie rénale a été jugée à haut risque dans le contexte de rein unilatéral, ce qui a limité la possible intervention diagnostique pour déterminer la cause de la maladie.
UNASSIGNED: La réévaluation des résultats des tests génétiques antérieurs et du VSI précédemment identifié dans COL4A4 a été réalisée 5 ans après le don. Ces analyses, ainsi que l’ajout de nouvelles données phénotypiques et de données généalogiques étendues, ont abouti à la reclassification du VSI précédemment identifié en variant probablement pathogène.
UNASSIGNED: Ce cas illustre l’importance de réévaluer de façon structurée et périodique les résultats des tests génétiques. La génétique étant en constante évolution en médecine, l’interprétation d’un VSI peut être dynamique et, ainsi, justifier la prudence dans les évaluations des donneurs de reins vivants. Des études ont montré qu’environ 10 % des VSI peuvent être reclassés comme pathogènes après 18 à 36 mois. La réévaluation structurée des résultats des tests génomiques, qui n’a pas encore été intégrée dans la pratique clinique, pose un défi unique dans le contexte d’un don vivant de reins.
UNASSIGNED: Ce rapport de cas met en évidence la variabilité du phénotype du SAAD causé par des variants hétérozygotes pathogènes dans les gènes du collagène de type 4. Il soutient un changement de nomenclature du phénotype d’hématurie bénigne en SAAD, en particulier en présence de facteurs de risque supplémentaires tels que la protéinurie et la glomérulosclérose segmentaire et focale, de modifications de la membrane basale glomérulaire sur la biopsie rénale ou, comme dans ce cas, de preuves de la maladie chez d’autres membres de la famille.

UNASSIGNED: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder. The PKD1 gene is responsible for the majority of ADPKD cases, and the mutations in this gene exhibit high genetic diversity. This study aimed to investigate the association between genotype and phenotype in ADPKD patients with PKD1 gene mutations through pedigree analysis.
UNASSIGNED: Eight Chinese pedigrees affected by ADPKD were analyzed using whole-exome sequencing (WES) on peripheral blood DNA. The identified variants were validated using Sanger sequencing, and clinical data from the patients and their families were collected and analyzed.
UNASSIGNED: Nine novel mutation sites in PKD1 were discovered across the pedigrees, including c.4247T > G, c.3298_3301delGAGT, c.4798A > G, c.7567G > A, c.11717G > C, c.7703 + 5G > C, c.3296G > A, c.8515_8516insG, and c.5524C > A. These mutations were found to be associated with a range of clinical phenotypes, including chronic kidney disease, hypertension, and polycystic liver. The age of onset and disease progression displayed significant heterogeneity among the pedigrees, with some individuals exhibiting early onset and rapid disease progression, while others remained asymptomatic or had milder disease symptoms. Inheritance patterns supported autosomal dominant inheritance, as affected individuals inherited the mutations from affected parents. However, there were instances of individuals carrying the mutations who remained asymptomatic or exhibited milder disease phenotypes.
UNASSIGNED: This study highlights the importance of comprehensive genotype analysis in understanding the progression and prognosis of ADPKD. The identification of novel mutation sites expands our knowledge of PKD1 gene mutations. These findings contribute to a better understanding of the disease and may have implications for personalized therapeutic strategies.

UNASSIGNED: Due to next-generation sequencing, variants in new genes such as DNAJB11 are recently being identified as causing atypical autosomal dominant polycystic kidney disease (ADPKD). It is important to describe phenotypes associated with these variants in order to increase awareness among clinicians, especially since genetic variability affects ADPKD severity.
UNASSIGNED: We describe a 55-year-old female patient of Haitian origin who presented with slowly deteriorating kidney function, microscopic hematuria, proteinuria, enlarged kidneys with innumerable small cysts, and a family history of chronic kidney disease and cysts. The phenotype was atypical for ADPKD caused by PKD1 or PKD2 variants, since cysts were of small size, kidneys were only moderately enlarged, and the patient had no extra-renal involvement suggestive of typical ADPKD such as liver cysts, pancreatic cysts, cranial aneurysms, or cardiac abnormalities.
UNASSIGNED: A panel of genes was analyzed by next-generation massive sequencing techniques, including DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2, and PKHD1. Genetic testing revealed a heterozygous variant in the DNAJB11 gene (c.123 dup), which is predicted to result in premature protein termination (p. Lys42*) and was classified by the laboratory as likely pathogenic.
UNASSIGNED: She was treated with candesartan 16 mg once daily to address her proteinuria.
UNASSIGNED: At the time of the most recent follow-up, her proteinuria has increased, and her kidney function continues to slowly deteriorate.
UNASSIGNED: DNAJB11 variants are a rare cause of atypical ADPKD. It is important to recognize the clinical features that help distinguish DNAJB11 from PKD1 and PKD2 variants. Atypical ADPKD due to DNAJB11 variants is usually characterized by small cysts, normal kidney size, proteinuria, progressive chronic kidney disease, and phenotypic overlap with autosomal dominant tubulointerstitial kidney disease (ADTKD). It may, however, present itself with enlarged kidneys as was seen in our patient. Genetic testing should be offered whenever a patient presents atypical features of ADPKD, which also requires increased awareness among clinicians regarding the various phenotypes of atypical ADPKD.
UNASSIGNED: Grâce au séquençage de nouvelle génération, on a récemment identifié des variants de nouveaux gènes tels que DNAJB11 qui causeraient une forme atypique de polykystose rénale autosomique dominante (PKRAD). Afin de sensibiliser davantage les cliniciens, il est important de décrire les phénotypes associés à ces variants, d’autant plus qu’on sait que la variabilité génétique affecte la gravité de la PKRAD.
UNASSIGNED: Nous décrivons le cas d’une patiente de 55 ans d’origine haïtienne qui présentait une lente détérioration de la fonction rénale, une hématurie microscopique, une protéinurie et des reins avec d’innombrables petits kystes. La patiente avait également des antécédents familiaux de néphropathie et de kystes. Le phénotype était atypique pour une PKRAD causée par les variants PKD1 ou PKD2, car les kystes étaient petits, que la taille des reins n’était que modérément augmentée et qu’elle ne présentait aucune atteinte extra-rénale suggérant une PKRAD typique tels que des kystes hépatiques, des kystes pancréatiques, des anévrismes crâniens ou des anomalies cardiaques.
UNASSIGNED: Un groupe de gènes a été analysé par des techniques de séquençage massif de nouvelle génération, notamment les gènes DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2 et PKHD1. Le dépistage génétique a révélé un variant hétérozygote dans le gène DNAJB11 (c.123 dup), qui est prédite comme entraînant une terminaison protéique prématurée (p.Lys42*) et qui a été classé par le laboratoire comme étant probablement pathogène.
UNASSIGNED: La patiente a reçu 16 mg de candesartan une fois par jour pour traiter sa protéinurie.
UNASSIGNED: Lors du plus récent suivi, la protéinurie avait augmenté et la fonction rénale avait continué de se détériorer lentement.
UNASSIGNED: Les variants de DNAJB11 sont une cause rare de PKRAD atypique. Il est important de reconnaître les caractéristiques cliniques qui aident à distinguer les variants de DNAJB11 des variants PKD1 et PKD2. La PKRAD atypique due à des variants du gène DNAJB11 est généralement caractérisée par de petits kystes, des reins de taille normale, une protéinurie, une insuffisance rénale chronique progressive et un chevauchement phénotypique avec la néphropathie tubulo-interstitielle autosomique dominante. Elle peut cependant se présenter avec des reins de taille augmentée, comme on l’a vu chez cette patiente. Le dépistage génétique devrait être offert dès qu’un patient présente des caractéristiques de PKRAD atypique, ce qui nécessite également une sensibilisation accrue des cliniciens aux divers phénotypes de la PKRAD atypique.

Autosomal dominant tubulointerstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). An autosomal dominant inheritance is the general rule, but de novo UMOD mutations have been reported. It was reported that the median age of ESKD was 47 years (18-87 years) and men were at a much higher risk of progression to ESKD. Here, we reported a 13-year-old young girl with unexplained chronic kidney disease (CKD) (elevated serum creatine) and no positive family history. Non-specific clinical and histological manifestations and the absence of evidence for kidney disease of other etiology raised strong suspicion for ADTKD. Trio whole-exome sequencing confirmed that she carried a de novo heterozygous mutation c.280T > C (p.Cys94Arg) in the UMOD gene. The functional significance of the novel mutation was supported by a structural biology approach. With no targeted therapy, she was treated as CKD and followed up regularly. The case underscores the clinical importance of a gene-based unifying terminology help to identify under-recognized causes of CKD, and it demonstrates the value of whole-exome sequencing in unsolved CKD.

Familial renal glucosuria (FRG) is a rare genetic condition featured by isolated glucosuria without hyperglycemia or other kidney diseases. It is caused by pathogenic mutations of the SGLT2 (Sodium-Glucose Cotransporter 2) gene, whose protein product is responsible for reabsorbing the majority of glucose in the early proximal convoluted tubule. Hitherto, quite an array of variants of SGLT2 have been identified in patients of FRG. In this study, we performed whole exome sequencing on three Chinese pediatric patients with FRG and uncovered three compound heterozygous variants of SGLT2: c.1333C > T (p.Q445X) and c.1130-5 C > G; c.1438G > T (p.V480F) and c.346G > A (p.V116M); c.1175C > G (p.S392C) and c.1333C > T (p.Q445X). Among the total of five variants, c.1333C > T (p.Q445X), c.1438G > T (p.V480F) and c.1175C > G (p.S392C) represented novel variants that had not been reported in any genetic databases. All five variants had extremely low allele frequencies and the amino acids loci affected by missense variants were highly conserved in vertebrate species. Bioinformatic tools predicted that all five variants might disrupt the function of SGLT2, which were likely to be causal for FRG in these patients. Our findings expand the variant spectrum of SGLT2 associated with FRG and provide novel insights into mechanism of action of this transporter, which will aid in the development of novel SGLT2 inhibitors for treatment of type 2 diabetes and cardiovascular diseases.

Immunoglobulin A (IgA) nephropathy, in the presence of myeloid bodies, has been reported in Fabry disease (FD). In this case, we excluded the diagnosis of FD by demonstrating the absence of mutation in the α-galactosidase A（GLA）gene. Our patient also denied any history of use of cationic amphiphilic drugs. Interestingly, we identified a novel missense mutation for Coenzyme Q2（COQ2） , which is known to cause COQ2 mutation-associated nephropathy. We also found heteromorphic mitochondria and good treatment response in our patient following coenzyme Q10 supplementation. In light of our findings, our patient was diagnosed with COQ2 nephropathy and IgA nephropathy. To our knowledge, this is the first case report of COQ2 nephropathy with pathologic manifestations of myeloid bodies in podocytes.