X-linked Alport syndrome is a form of progressive renal failure caused by pathogenic variants in the
COL4A5
gene. More than 700 variants have been described and a further 400 are estimated to be ...known to individual laboratories but are unpublished. The major genetic testing laboratories for X-linked Alport syndrome worldwide have established a Web-based database for published and unpublished
COL4A5
variants (
https://grenada.lumc.nl/LOVD2/COL4A/home.php?select_db=COL4A5
). This conforms with the recommendations of the Human Variome Project: it uses the Leiden Open Variation Database (LOVD) format, describes variants according to the human reference sequence with standardized nomenclature, indicates likely pathogenicity and associated clinical features, and credits the submitting laboratory. The database includes non-pathogenic and recurrent variants, and is linked to another
COL4A5
mutation database and relevant bioinformatics sites. Access is free. Increasing the number of
COL4A5
variants in the public domain helps patients, diagnostic laboratories, clinicians, and researchers. The database improves the accuracy and efficiency of genetic testing because its variants are already categorized for pathogenicity. The description of further
COL4A5
variants and clinical associations will improve our ability to predict phenotype and our understanding of collagen IV biochemistry. The database for X-linked Alport syndrome represents a model for databases in other inherited renal diseases.
MYH9 Associated nephropathy Furlano, Mónica; Arlandis, Rosa; del Prado Venegas, María ...
Nefrología,
03/2019, Letnik:
39, Številka:
2
Journal Article
Recenzirano
Odprti dostop
MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the ...nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided. Resumen: Las enfermedades relacionadas con mutaciones del gen MYH9 son un grupo de patologías genéticas raras. Su herencia sigue un patrón autosómico dominante en donde el gen MYH9, codifica la cadena pesada de la miosina IIA no muscular que se expresa en diferentes tejidos pero especialmente en los podocitos y en las células mesangiales. Este trastorno se caracteriza por la presencia de macrotrombocitopenia, inclusiones leucocitarias y un riesgo variable de desarrollar insuficiencia renal, hipoacusia y cataratas en edad juvenil o adulta. Describimos el caso de una mujer de 27 años, de raza caucásica, diagnosticada inicialmente de púrpura trombocitopénica idiopática. Tras una detallada historia familiar y el desarrollo de síntomas clínicos posteriores con afectación renal e hipoacusia, se le realizó un estudio genético que nos permitió el diagnóstico de nefropatía asociada a la mutación en el gen MYH9. Este caso destaca el retraso del diagnóstico y la utilidad del estudio genético en pacientes con enfermedades muy poco frecuentes. Se procede a la revisión de la enfermedad en este artículo. Keywords: MYH9 nephropathy, Hearing loss, Thrombocytopenia, Alport syndrome, Epstein syndrome, May-Hegglin anomaly, Palabras clave: Nefropatía MYH9, Hipoacusia, Trombocitopenia, Síndrome de Alport, Síndrome de Epstein, Anomalía de May-Hegglin, Sindrome de Sebastián
Autosomal dominant polycystic kidney disease is a systemic disorder with a wide range of extrarenal involvement. The scope of this study was to analyze the prevalence of seminal cysts and to ...correlate these findings with the sperm parameters in patients with autosomal dominant polycystic kidney disease.
A prospective study enrolled 30 adult men with autosomal dominant polycystic kidney disease. Of these 30 patients, 22 agreed to provide a semen sample for analysis, and 28 of 30 agreed to undergo an ultrasound rectal examination. Data obtained from the semen tests and from the ultrasound study were compared.
Cysts in the seminal tract were present in 10 (43.47%) of 28 individuals. Twenty of 22 patients showed abnormal semen parameters, with asthenozoospermia as the most common finding. No correlation between ultrasound findings and sperm abnormalities was observed.
The presence of cysts in the seminal tract is remarkably high (43.47%); however, this finding does not correlate with sperm abnormalities, which are also a frequent finding, especially asthenozoospermia. This semen abnormality is probably related to the abnormal function of polycystins. More attention should be paid to reproductive aspects in the initial evaluation of patients with autosomal dominant polycystic kidney disease before their ability to conceive is further impaired by uremia.
Background
Genetic diagnosis of autosomal recessive polycystic kidney disease (ARPKD) is challenging due to the length and allelic heterogeneity of the
PKHD1
gene. Mutations appear to be clustered at ...specific exons, depending on the geographic origin of the patient. We aimed to identify the
PKHD1
exons most likely mutated in Spanish ARPKD patients.
Methods
Mutation analysis was performed in 50 ARPKD probands and nine ARPKD-suspicious patients by sequencing
PKHD1
exons arranged by their reported mutation frequency. Haplotypes containing the most frequent mutations were analyzed. Other PKD genes (
HNF1B, PKD1, PKD2
) were sequenced in
PKHD1
-negative cases.
Results
Thirty-six different mutations (concentrated in 24
PKHD1
exons) were detected, giving a mutation detection rate of 86 %. The screening of five exons (58, 32, 34, 36, 37) yielded a 54 % chance of detecting one mutation; the screening of nine additional exons (3, 9, 39, 61, 5, 22, 26, 41, 57) increased the chance to 76 %. The c.9689delA mutation was present in 17 (34 %) patients, all of whom shared the same haplotype. Two
HNF1B
mutations and one
PKD1
variant were detected in negative cases.
Conclusions
Establishing a
PKHD1
exon mutation profile in a specific population and starting the analysis with the most likely mutated exons might significantly enhance the efficacy of genetic testing in ARPKD. Analysis of other PKD genes might be considered, especially in suspicious cases.
Nefropatía asociada a mutación del gen MYH9 Furlano, Mónica; Arlandis, Rosa; Venegas, María del Prado ...
Nefrología/Nefrología,
March-April 2019, 2019-03-00, 2019-03-01, Letnik:
39, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Las enfermedades relacionadas con mutaciones del gen MYH9 son un grupo de patologías genéticas raras. Su herencia sigue un patrón autosómico dominante en donde el gen MYH9, codifica la cadena pesada ...de la miosina IIA no muscular que se expresa en diferentes tejidos pero especialmente en los podocitos y en las células mesangiales. Este trastorno se caracteriza por la presencia de macrotrombocitopenia, inclusiones leucocitarias y un riesgo variable de desarrollar insuficiencia renal, hipoacusia y cataratas en edad juvenil o adulta. Describimos el caso de una mujer de 27 años, de raza caucásica, diagnosticada inicialmente de púrpura trombocitopénica idiopática. Tras una detallada historia familiar y el desarrollo de síntomas clínicos posteriores con afectación renal e hipoacusia, se le realizó un estudio genético que nos permitió el diagnóstico de nefropatía asociada a la mutación en el gen MYH9. Este caso destaca el retraso del diagnóstico y la utilidad del estudio genético en pacientes con enfermedades muy poco frecuentes. Se procede a la revisión de la enfermedad en este artículo.
MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided.
Objective To test the efficiency of 6 mRNA bladder markers in staging urothelial cell carcinoma (UCC) and monitoring UCC dissemination from blood samples. Methods From 2002 to 2009, 347 blood samples ...were collected from 150 patients with UCC and 29 healthy controls. Sequential blood sampling was performed in patients undergoing cystectomy at surgery and 6, 12, 18, and 24 months postoperatively. The median follow-up was 33 months. The presence of KRT20, FXYD3, C10orf116, UPK2, AGR2, and KRT19 markers in blood was evaluated in all patients and controls by measuring the gene expression using preamplified cDNA and reverse transcriptase quantitative polymerase chain reaction. Gene expression data were correlated with the tumor risk, follow-up, and outcomes data. Results Expression of C10orf116 and KRT19 genes differed between patients and controls ( P < .001). KRT20 , C10orf116, and AGR2 differentiated between low- and high-risk nonmuscle-invasive bladder cancer ( P = .001, P = .011, and P = .001, respectively). FXYD3 differentiated between patients with high-risk nonmuscle-invasive bladder cancer and those with muscle-invasive bladder cancer ( P = .009). In contrast, the 6 markers showed no differences in gene expression between metastatic and patients without metastases who had not undergone cystectomy ( P = NS). None of the markers were significantly increased in the metastatic patients at 6, 12, 18, or 24 months after surgery. Conclusion The gene expression of bladder-specific mRNA markers in blood was different among the various tumor risk groups of patients with UCC. However, this gene expression analysis is not suitable for predicting metastases or monitoring UCC hematogenous dissemination in patients who have undergone cystectomy.
In recent years there has been a reclassification of hereditary tubulointerstitial renal diseases. The old concepts of nephronoptisis or medullary cystic disease have been reordered based on the ...discovery of new genes. The 2015 KDIGO guidelines proposed a unification of terminology, diagnostic criteria and monitoring. So far 4 genes causing autosomal dominant tubulointerstitial kidney disease have been described: MUC1, UMOD, HNF1B and REN. Although the mutation in each of them causes distinctive features in how they present, all have in common the progressive tubulointerstitial damage and renal fibrosis. In this article, we present a review of the guidelines and the literature, and some practical recommendations for dealing with this disease.
Some 7-10% of patients on replacement renal therapy (RRT) are receiving it because of autosomal dominant polycystic kidney disease (ADPKD). The age at initiation of RRT is expected to increase over ...time.
Clinical data of 1,586 patients (7.9%) with ADPKD and 18,447 (92.1%) patients with other nephropathies were analysed from 1984 through 2009 (1984-1991, 1992-1999 and 2000-2009).
The age at initiation of RRT remained stable over the three periods in the ADPKD group (56.7 ± 10.9 (mean ± SD) vs 57.5 ± 12.1 vs 57.8 ± 13.3 years), whereas it increased significantly in the non-ADPKD group (from 54.8 ± 16.8 to 63.9 ± 16.3 years, p < 0.001). The ratio of males to females was higher for non-ADPKD than for ADPKD patients (1.6-1.8 vs 1.1-1.2). The prevalence of diabetes was significantly lower in the ADPKD group (6.76% vs 11.89%, p < 0.001), as were most of the co-morbidities studied, with the exception of hypertension. The survival rate of the ADPKD patients on RRT was higher than that of the non-ADPKD patients (p < 0.001).
Over time neither changes in age nor alterations in male to female ratio have occurred among ADPKD patients who have started RRT, probably because of the impact of unmodifiable genetic factors in the absence of a specific treatment.
Abstract Background Routine histologic analysis of lymph nodes (LN) for detecting disseminated bladder urothelial carcinoma (BUC) lacks sensitivity. Objective To identify and test potential mRNA ...markers of BUC dissemination in LN that has been missed by histological analysis, and to compare the performance of selected markers with patients’ clinical outcome. Design, setting, and participants Microarray data and a literature search were used to identify potential markers expressed in BUC but absent in LN. Five genes were finally selected to be studied by quantitative real-time RT-PCR (qRT-PCR) in 181 and 29 LN from 102 BUC patients and 29 controls, respectively, collected from 2002 to 2004 (median follow-up of 35 mo). Measurements The three most expressed genes plus two additional markers selected from the literature were finally evaluated by qRT-PCR. Gene expression values were statistically compared with histologic results and clinical outcome. Results and limitations A discriminant analysis showed that the combination of FXYD3 and KRT20 genes yielded a 100% sensitivity and specificity differentiating LN with BUC dissemination from controls. Combined, the expression of both genes allowed the identification of urothelial cells in LN in 20.5% of patients with previous histologically negative LN. These patients did not have a significantly worse survival than those who were negative by qRT-PCR. Conclusions Using molecular markers it was possible to improve the sensitivity of LN histologic analysis. However, since 20.5% of patients that reclassified as positive by qRT-PCR did not have a significantly worse survival, we assume lymphadenectomy was important to remove residual disease.
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