Diagnosis of a case of autosomal recessive polycystic kidney disease with combined prenatal imaging and genetic testing / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with renal abnormalities through whole exome sequencing and imaging examination.@*METHODS@#Clinical data and result of medical imaging of the fetus was collected. Amniotic fluid sample was collected for the extraction of fetal DNA. Whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Prenatal ultrasonography showed that the fetus had bilateral enlargement of the kidneys with hyperechogenicity and diffuse renal cysts. Whole exome sequencing revealed that the fetus carried compound heterozygous variants of the PKHD1 gene, namely c.5137G>T and c.2335_2336delCA, which were derived from its mother and father, respectively.@*CONCLUSION@#The fetus was diagnosed with autosomal recessive polycystic kidney disease through combined prenatal ultrasonography and whole exome sequencing. The compound heterozygous variants of the PKHD1 gene probably underlay the pathogenesis in the fetus. The results have enabled prenatal diagnosis and genetic counseling for its parents.

Clinical feature and genetic analysis of a fetus with autosomal recessive polycystic kidney disease / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a fetus with autosomal recessive polycystic kidney disease (ARPKD).@*METHODS@#Prenatal ultrasonography has revealed oligohydramnios and abnormal structure of fetal kidneys. After careful counseling, the couple opted induced abortion. With informed consent, genomic DNA was extracted from the muscle sample of the abortus and peripheral blood samples of the couple. High throughput whole exome sequencing was carried out to detect potential variants in relation with the disease. Suspected variants were verified by Sanger sequencing.@*RESULTS@#Prenatal ultrasound revealed increased size of fetal kidneys, with multiple hyperechos from the right kidney, and multiple hyperechos with anechoic masses within the left kidney. DNA sequencing revealed that the fetus has carried heterozygous variants of the PKHD1 gene, including c.7994T>C inherited from its father, and two heterozygous variants of the PKHD1 gene c.5681G>A from its mother.@*CONCLUSION@#The compound heterozygous c.7994T>C and c.5681G>A variants of the PKHD1 gene probably underlay the pathogenesis of ARPKD in this fetus. Above results can provide guidance for subsequent pregnancies of the couple.

Genetic diagnosis of Caroli syndrome with autosomal recessive polycystic kidney disease: a case report and literature review / 北京大学学报(医学版)

This case report is about one genetically specified diagnosed infant case of Caroli syndrome with autosomal recessive polycystic kidney disease (ARPKD) in China. The patient in this case report was an eight-month infant boy with an atypical onset and the main clinical manifestation was non-symptomatic enlargement of the liver and kidneys. The imaging study demonstrated a diffused cystic dilatation of intrahepatic bile ducts as well as polycystic changes in bilateral kidneys. The basic blood biochemical tests indicated a normal hepatorenal function. Four serum biomarkers of hepatic fibrosis were all elevated and the urine test for an early detection of the renal injury was positive. The genetic sequencing proved two heterozygous missense mutations of polycystic kidney and hepatic disease 1 (PKHD1) gene, c.9292G>A and c.2507T>C, inherited from each of his parents respectively. The former was a novel mutation that had been verified as disease causing through the predicting software while the latter had been reported from one recent case study on Chinese twins, which was possibly unique among Chinese population. The relations between the gene type and the clinical phenotype were not clarified yet. Up till a follow-up eleven months later after the discharge, the patient had a normal hepatorenal function without occurrence of any severe complication yet. The clinical symptoms of Caroli syndrome with ARPKD at infant stage were atypical and the enlargement of liver and kidney was usually the sole symptom. From the above systematic retrospective clinical analysis, as well as the relevant literature review, it's been concluded that the features of the hepatorenal images in patients with Caroli syndrome and ARPKD were distinctive. Genetic testing combined with the imaging study benefits a definite diagnosis as well as a differentiation from other hepatorenal fibrocystic diseases. Specific to the long-term management of this kind of patients, it's necessary to schedule a regular follow-up to monitor the hepatorenal function and the occurrence of various complications for an appropriate intervention, meantime to devote efforts to the genetic counseling work for the patients' family.

Doença renal policística do adulto: uma atualização / Adult polycystic kidney disease: an update

A doença renal policística do adulto é uma desordem genética de caráter autossômico dominante, caracterizada por progressivo desenvolvimento e crescimento de cistos renais, que culminam com a falência renal terminal na meia-idade. Outras manifestações clínicas associadas incluem cistos hepáticos e pancreáticos, hipertensão, aneurismas cerebrais e defeitos cardiovasculares. Aspectos celulares e moleculares dos mecanismos de cistogênese envolvem proliferação e apoptose celular, remodelamento da matriz extracelular, secreção e acúmulo de fluidos. Geneticamente heterogênea, na maioria dos casos (aproximadamente 85%) são mutações no gene PKD1, localizado no cromossomo 16p13.3, com o segundo gene, PKD2, localizado nos intervalos do cromossomo 4q13-q23, respondendo por 15% das mutações, ambos já seqüenciados e caracterizados. Existem evidências da interação comum das proteínas policistinas 1 e 2 em rotas de eventos de adesão extracelular e transporte iônico, possibilitando a regulação do fluxo de Ca++ transmembrana. Inúmeros trabalhos vêm tentando correlacionar o genótipo mutado ao fenótipo expresso em termos da progressão e severidade daautosomal dominant polycystic kidney disease. A análise das mutações autosomal dominant polycystic kidney disease é fundamental para a compreensão dos mecanismos de atuação envolvidos na doença. Métodos de detecção baseados na reação em cadeia da polimerase têm sido amplamente empregados, como a reação em cadeia da polimerase via transcriptase reversa, protein truncation test, single-strand conformational polymorphism e denaturing high performance liquid chromatography, importantes ferramentas que auxiliam no seqüenciamento e caracterização dessas mutações

Adult polycystic kidney disease is an autosomal dominant genetic disorder, characterized by progressive development and growth of renal cysts, which result in terminal renal failure in middle age. Other associated clinical manifestations include hepatic and pancreatic cysts, hypertension, cerebral aneurysms and cardiovascular disorders. Cellular and mononuclear aspects of the mechanisms of cytogenesis comprehend cellular proliferation and apoptosis, remodeling of the extracellular matrix, secretion and accumulation of fluids. This disease is genetically heterogeneous; in most cases (approximately 85%), the gene involved is PKD1, which is located on chromosome 16p13.3. In the remaining cases (15%), the disease is caused by mutational changes in another gene (PKD2), which is located at chromosome intervals 4q13-q23. Both genes have been sequenced and characterized. There is evidence of the common interaction of polycystins 1 and 2 in pathways of extracellular adhesion and ionic transportation events, which promotes the regulation of transmembrane Ca++ flow. Several studies have tried to correlate the mutant genotype with the phenotype expressed in terms of progression and severity of the autosomal dominant polycystic kidney disease. Analyzing mutations in the autosomal dominant polycystic kidney disease is crucial for understanding the action mechanisms involved in this disease. Detection methods based on the polymerase chain reaction have been widely used, such as the reverse transcriptase polymerase chain reaction, protein truncation test, single-strand conformational polymorphism, and denaturing high performance liquid chromatography. They are important tools that help sequencing and characterizing those mutations

Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disease characterized by a malformation complex which includes cystically dilated tubules in the kidneys and ductal plate malformation in the liver. The disorder is observed primarily in infancy and childhood, being responsible for significant pediatric morbidity and mortality. All typical forms of ARPKD are caused by mutations in a single gene, PKHD1 (polycystic kidney and hepatic disease 1). This gene has a minimum of 86 exons, assembled into multiple differentially spliced transcripts and has its highest level of expression in kidney, pancreas and liver. Mutational analyses revealed that all patients with both mutations associated with truncation of the longest open reading frame-encoded protein displayed the severe phenotype. This product, polyductin, is a 4,074-amino acid protein expressed in the cytoplasm, plasma membrane and primary apical cilia, a structure that has been implicated in the pathogenesis of different polycystic kidney diseases. In fact, cholangiocytes isolated from an ARPKD rat model develop shorter and dysmorphic cilia, suggesting polyductin to be important for normal ciliary morphology. Polyductin seems also to participate in tubule morphogenesis and cell mitotic orientation along the tubular axis. The recent advances in the understanding of in vitro and animal models of polycystic kidney diseases have shed light on the molecular and cellular mechanisms of cyst formation and progression, allowing the initiation of therapeutic strategy designing and promising perspectives for ARPKD patients. It is notable that vasopressin V2 receptor antagonists can inhibit/halt the renal cystic disease progression in an orthologous rat model of human ARPKD.

Análise do padrão de expressão do produto de PKHD1, o gene mutado na doença renal policística autossômica recessiva / Analysis of the expression pattern of the PKHD1 gene product, mutated in autosomal recessive polycistic kidney disease

O gene PKHD1, mutado na doença renal policística autossômica recessiva, apresenta um padrão de splicing complexo associado a múltiplos transcritos alternativos. Neste trabalho estudamos o perfil de expressão de seu produto, poliductina. Análises por western blot revelaram produtos putativos de membrana de >440 kDa e aproximadamente 230 kDa, e de aproximadamente 140 kDa em frações solúveis de rim, fígado e pâncreas. Estudos imunoistoquímicos mostraram marcação em ductos coletores renais e porção ascendente espessa da alça de Henle, em epitélios ductais biliar e pancreático e, no período embrionário, em broto ureteral, ductos biliar e pancreático e glândula salivar. /PKHD1, the gene mutated in autosomal recessive polycystic kidney disease, presents a complex splicing pattern, associated with multiple alternative transcripts. In this work we have studied the expression profile of its product, polyductin. Western blot analysis revealed putative membrane products of >440 kDa and 230 kDa, and of about 140 kDa in soluble fractions in kidney, liver and pancreas. Immunohistochemistry studies showed staining in renal collecting duct and thick ascending limb of Henle, in biliary and pancreatic ductal epithelia and, in the embryonic period, in ureteric bud, biliary and pancreatic ducts and salivary gland...