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1.
J Am Soc Nephrol ; 34(6): 1105-1119, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36995132

RESUMO

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.


Assuntos
Hidronefrose , Obstrução Ureteral , Refluxo Vesicoureteral , Humanos , Variações do Número de Cópias de DNA , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Refluxo Vesicoureteral/diagnóstico , Refluxo Vesicoureteral/genética , Pelve Renal/patologia
2.
Childs Nerv Syst ; 39(3): 633-645, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36180597

RESUMO

PURPOSE: Gut microbiota has recently been recognized to be influenced by a broad range of pathologies. Alterations of gut microbiota are known as dysbiosis and have found to be related to chronic constipation, a condition which affects also pediatric patients with spina bifida (SB). METHODS: In this study, gut microbiota richness and composition were investigated by 16S rRNA sequencing and bioinformatic analysis in 48 SB patients (mean age, 11.9 ± 4.8 years) with secondary neurogenic constipation and 32 healthy controls (mean age, 18.0 ± 9.6 years). The study also aimed at exploring eventual effects of laxatives and transanal irrigation (TAI) adopted by SB subjects to get relief from the symptoms of neurogenic constipation. RESULTS: Collected data demonstrated that the microbiota richness of SB patients was significantly increased compared to healthy controls, with a higher number of dominant bacteria rather than rare species. The absence of SB condition was associated with taxa Coprococcus 2, with the species C. eutactus and Roseburia, Dialister, and the [Eubacterium] coprostanoligenes group. On the other hand, the SB patients displayed a different group of positively associated taxa, namely, Blautia, Collinsella, Intestinibacter, and Romboutsia genera, the [Clostridium] innocuum group, and Clostridium sensu stricto 1. Bifidobacterium and the [Eubacterium] hallii group were also found to be positively associated with SB gut microbiome. CONCLUSIONS: Among SB patients, the administration of laxatives and TAI did not negatively affect gut microbiota diversity and composition, even considering long-term use (up to 5 years) of TAI device.


Assuntos
Microbioma Gastrointestinal , Intestino Neurogênico , Disrafismo Espinal , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Intestino Neurogênico/etiologia , Intestino Neurogênico/terapia , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , Laxantes , Disrafismo Espinal/complicações , Constipação Intestinal/complicações
3.
Cureus ; 15(10): e47772, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38021820

RESUMO

Hourglass bladder is a definition used to describe a particular configuration of the urinary bladder, divided into two compartments, upper and lower, communicating through a narrowed segment resembling an hourglass. It may be due to various conditions, such as bladder diverticula, bladder neck obstruction, neurogenic bladder, or other abnormalities. Congenital hourglass bladder is an extremely rare anomaly. To the best of our knowledge, only 24 cases have been reported. We present the case of a 2-year-old male, probably the youngest patient with congenital hourglass bladder ever recorded. We aim to increase knowledge about the incidence of this likely underdiagnosed condition and its management and stress the importance of long-term follow-up.

5.
Nat Genet ; 51(1): 117-127, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578417

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.


Assuntos
Variações do Número de Cópias de DNA/genética , Rim/anormalidades , Sistema Urinário/anormalidades , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Deleção Cromossômica , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino
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