Studies of genetic linkage between adult polycystic kidney disease and three markers on chromosome 16.

Adult polycystic kidney disease (APKD) is a common genetic disorder that is inherited as an autosomal dominant trait. Recent reports show that, in some families, the APKD gene shows close genetic linkage to two chromosome 16 specific genetic markers. We have been conducting a genetic linkage study using 29 polymorphic isoenzyme and antigenic markers in 184 members of 12 APKD families. We present here the results of linkage analysis using three of these markers which have also been reported to be located on chromosome 16: phosphoglycolate phosphatase (PGP), glutamate pyruvate transaminase (GPT), and haptoglobin (HP). The results show that APKD is closely linked to the PGP locus on the short arm of chromosome 16 (16p13----p12), which is consistent with the previously reported linkage both to PGP and to the alpha globin locus. The genetic distance between PGP and APKD shows a maximum likelihood value of the recombination fraction at zero with a lod score of 5 X 5. There is no evidence of linkage between APKD and either GPT or HP. The PGP polymorphism potentially provides a useful predictive test to complement the use of alpha globin probes in genetic counselling. These tests should provide an efficient means of primary screening of family members at risk, as well as introducing the possibility of prenatal diagnosis.     

Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling

Few reports are available on the age-related risk of relatives of affected persons to manifest adult polycystic kidney disease (APKD). For 371 persons in 17 kindreds, at risk for APKD by virtue of having an affected first degree relative, we calculated the estimated probability of clinical diagnosis of APKD to be 0.011 by age 20, 0.041 by age 30, 0.115 by age 40, 0.299 by age 50, and 0.404 by age 60 years (expected = 0.50). Ultrasonographic examination of 172 asymptomatic persons at risk showed definite APKD in 60. The probability of ultrasonographic detection of asymptomatic APKD is estimated as 0.222, 0.657, and 0.855 at age 5, 15, and 25 years, respectively. The probability of having APKD following normal ultrasonogram results (conservatively assuming 90% specificity) is estimated as 0.46, 0.28, and 0.14 for persons at 50% risk in their first, second, or third decade. The marginal benefit of ultrasound as a diagnostic test for APKD for persons in the second or third decade is estimated as 0.37 and 0.41, respectively for a "positive" test and 0.22 and 0.37 for a "negative" test.     

Exaggerated natriuresis in adult polycystic kidney disease

Angiotensin II (AII), aldosterone (Aldo) arginine vasopressin (AVP) in plasma, serum osmolality (Sosm), and renal sodium excretion (UNaV) were studied before and after infusion of hypertonic sodium chloride solution in 20 patients with adult polycystic kidney disease (PKD) with normal or moderately reduced creatinine clearance (Ccr) and in 10 healthy control subjects. UNaV increased after sodium loading in all, significantly more in the PKD patients. AII and Aldo were normal before sodium loading and suppressed after saline in PKD patients and controls. The increase in VNaV correlated with Aldo in patients but not in controls. AVP before loading was increased in hypertensive PKD patients with reduced Ccr, but not in normotensive patients with normal Ccr. After hypertonic saline, Sosm increased to the same degree both in PKD and control subjects, but AVP increased more in those with PKD. The exaggerated natriuresis of PKD is probably not explained by a change in the activity of the renin-angiotensin-aldosterone system. The enhanced response of AVP to osmotic stimuli in PKD may be a compensatory reaction to a reduced renal tubular effect of AVP.     

Genetic counseling in adult polycystic kidney disease

We evaluated 22 patients with end-stage renal disease (ESRD) due to adult polycystic kidney disease (APKD) to assess their knowledge of the hereditary nature of the condition and to determine whether they received adequate genetic counseling. Patients were evaluated by means of a questionnaire and a review of their medical records. Only 5 of 22 (23%) knew their disorder was hereditary at the time of diagnosis, and in only 4 (18%) was genetic counseling suggested. In no instance had proband and spouse received genetic counseling together. Diagnostic studies of children at risk were rarely suggested. We also evaluated the children of 9 probands for APKD. Of 26 children evaluated, 17 had APKD (65%). Sixteen had no children at the time of testing. All but two of the 26 were less than 25 years old. Of the probands' children over 15 years of age, 55% knew the name of the condition in the family but only 9% knew they should be tested. Our study demonstrated inadequacy of genetic counseling and follow-up in this group of patients; we suggest that referral for counseling become a routine part of their management. Early diagnosis and effective counseling has the potential benefit for the individuals of making rational reproductive decisions appropriate for their situation. Counseling may have to be repeated during the course of the patients' disease, as their perception of risk may change with time. With advances in dialysis and transplantation, ESRD may not be as devastating in years to come as it is now.     

Prenatal ultrasonographic findings of dominant polycystic kidney disease and postnatal renal evolution

Autosomal dominant polycystic kidney disease (ADPKD) is a relatively common genetic disorder, and its prenatal diagnosis has been reported with increasing frequency. Nevertheless, no data are available on the significance of prenatal ultrasound (US) patterns in predicting postnatal renal function and outcome. We report on one case of ADPKD diagnosed prenatally by US, and on two cases diagnosed immediately after birth, with different prenatal US and renal outcomes. Data on prenatal US findings and postnatal renal evolution are scanty and largely incomplete. Apparently, none of the prenatal findings are consistently different in cases with and without normal postnatal renal function and blood pressure. More complete information on prenatal US findings and postnatal renal evolution is urgently needed. © 1996 Wiley-Liss, Inc.     

Frequency of hepatic cysts in adult polycystic kidney disease

The frequency of hepatic cysts in patients with adult polycystic kidney disease (APKD) is usually considered to average about 33%, but with great, and hitherto largely unexplained, variations between different studies. Sixty-six consecutive patients with APKD were all subjected to CT scanning of the liver and of the kidneys. In confirmation of one previous study, a clearcut correlation was found between age (= duration of disease) and the frequency of hepatic cysts. It was furthermore found that cysts in the liver, as opposed to cysts in the kidneys, continue to grow and appear de novo even after institution of renal replacement therapy.     

Trichosporon loubieri infection in a patient with adult polycystic kidney disease

A 45-year-old man from Nepal with a 13-year history of polycystic kidney disease was diagnosed as suffering from chronic renal failure with end-stage renal disease. After receiving empirical antituberculosis treatment, he was treated with broad-spectrum antibiotics. A left nephrectomy was performed, and after 4 months, he received a kidney transplant. The left kidney was grossly enlarged, with multiple cystic spaces filled with blackish material. Histologic examination of the excised left kidney tissue stained with hematoxylin and eosin and Gomori's methenamine silver stains showed numerous hyaline, septate, fungal hyphae of various lengths, many broken into rectangular arthroconidia in the cystic spaces. Culture of the kidney tissue yielded white, glabrous, yeast-like colonies. Based on its micromorphology, growth at 42 degrees C, and ribosomal DNA (rDNA) sequence analysis, and also sequence analysis of the internal-transcribed-spacer and D1/D2 rDNA regions, the yeast was identified as Trichosporon loubieri. Postsurgically, the patient was treated with amphotericin B and oral itraconazole, followed by maintenance therapy with fluconazole. He remained afebrile and asymptomatic. At the final follow-up, all parameters were found normal and the patient was doing well, with normal renal function reports. This paper presents the first known case of human infection caused by T. loubieri.     

Presymptomatic testing for adult onset polycystic kidney disease in at-risk kidney transplant donors.

Autosomal dominant adult-onset polycystic kidney disease (ADPKD) is estimated to have an incidence of 1/1,000 and accounts for approximately 10% of all end-stage renal disease in the United States. While relatives are attractive as renal donors due to their availability and the improved transplant success associated with living-related donors, they may coincidentally be at risk for ADPKD. Accurate presymptomatic testing for at-risk potential donors is critical for both the donor and the recipient. We report here 2 families in which presymptomatic testing for ADPKD was accomplished by DNA linkage analysis on several potential renal donors prior to transplant. This resulted in the protection of both donors and recipients by preventing the transplantation of a kidney affected by ADPKD. Thorough counseling prior to DNA analysis (including discussion of accuracy and possible testing outcomes of presymptomatic diagnosis of ADPKD, diagnosis of noncarrier status, false paternity, and non-informative study) was essential to provide informed consent and preserve confidentiality within the family. Confidentiality for potential donors found presymptomatically to be affected (with a 94% or greater probability) was especially difficult to maintain.     

The genetic landscape of polycystic kidney disease in Ireland

Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71–83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.Subject terms: Polycystic kidney disease, Disease genetics, Next-generation sequencing, Genetics research, Genetic testing     

一成人型多囊肾家系的遗传检测及产前诊断

目的 对一常染色体显性遗传性多囊肾病(ADPKD)家系进行致病基因突变鉴定,并对先证者妻子首次妊娠进行产前诊断.方法 用聚合酶链式反应,通过微卫星标记进行基因定位、DNA序列测定,确定基因突变;用AS-PCR对家系其他患者成员进行突变点检测和筛查;联合应用突变检测和连锁分析进行产前诊断.结果 该家系中多囊肾疾病的致病基因为PKD2,突变为外显子5中c.1249C>T(p.R417X);胎儿产前诊断结果显示未获得致病突变.结论 该家系的致病突变为c-12A9C>>(p.R417X),成功进行了产前诊断.     

Ultrastructural tubular basement membrane lesions in adult polycystic kidney disease

The pathogenesis of adult polycystic kidney disease (PCKD) remains an enigma. In an attempt to find a defect that might explain the cyst formation, an ultrastructural study was performed on seven fresh bilateral nephrectomies of seven patients suffering from adult PCKD. Marked electron microscopic changes of the tubular basement membranes were detected, including thickening, splitting, fraying, and multilayering of the basement membranes. By contrast, glomerular basement membranes lacked these alterations. The kidneys from two control groups (five donor kidneys harvested for transplantation; 10 patients who suffered from end stage renal disease) showed none of the lesions detected in the polycystic kidneys. The lesions of the tubular basement membrane, the principal support of tubular wall, may be the primary phenotypic expression and cause of the inherited defect.     

Familial orofaciodigital syndrome type I presenting as adult polycystic kidney disease.

A three generation family with orofaciodigital syndrome type I is described. Several family members had been thought to suffer from autosomal dominant polycystic kidney disease but examination of the proband led to establishment of the correct diagnosis. The genetic implications for the offspring of the affected women and other family members were significantly altered.     

Autosomal dominant polycystic kidney disease: new information for genetic counselling.

We evaluated the accuracy of ultrasonographic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) and factors influencing its prognosis in members of 17 Newfoundland families originally described in 1984. In 10 families showing genetic linkage between ADPKD and markers for the PKD1 locus, rates of false negative ultrasonographic diagnosis are estimated as 36% below the age of 10 years and 8% or less thereafter, comparable with findings of genetic linkage studies of a subset of family members. At ages above 30 years, false negative ultrasonographic diagnosis of PKD1 disease is unlikely. In 2 families in which ADPKD is not co-inherited with PKD1 markers, only 11% of members aged less than 30 years had kidney cysts. The mean (SE) age of onset of ESRD is 56.3 (1.8) years for persons with the PKD1 form of ADPKD, and 68.7 (1.7) years for affected members of families in which ADPKD is not co-inherited with PKD1 markers (P = 0.01). In the PKD1 families, age of onset of end stage renal disease (ESRD) was unrelated to the sex of the affected individual but was earlier in persons inheriting the disease from their mothers than from their fathers (50.5 vs. 64.8 years, P = 0.004), consistent with an influence of genetic imprinting on disease progression. In females with a PKD1 mutation, onset of ESRD was not influenced by parity. In PKD1 families, resemblance in age of onset of ESRD was apparent; variation was less within than between families (F = 13.0, P less than 0.0001), and risk of false negative ultrasonographic diagnosis appears largely restricted to families in which ESRD occurs relatively late.     

Presymptomatic testing for adult onset polycystic kidney disease in at-risk kidney transplant donors

Autosomal dominant adult-onset polycystic kidney disease (ADPKD) is estimated to have an incidence of 1/1,000 and accounts for approximately 10% of all end-stage renal disease in the United States. While relatives are attractive as renal donors due to their availability and the improved transplant success associated with living-related donors, they may coincidentally be at risk for ADPKD. Accurate presymptomatic testing for at-risk potential donors is critical for both the donor and the recipient. We report here 2 families in which presymptomatic testing for ADPKD was accomplished by DNA linkage analysis on several potential renal donors prior to transplant. This resulted in the protection of both donors and recipients by preventing the transplantation of a kidney affected by ADPKD. Thorough counseling prior to DNA analysis (including discussion of accuracy and possible testing outcomes of presymptomatic diagnosis of ADPKD, diagnosis of noncarrier status, false paternity, and noninformative study) was essential to provide informed consent and preserve confidentiality within the family. Confidentiality for potential donors found presymptomatically to be affected (with a 94% or greater probability) was especially difficult to maintain.     

Genetic counselling for adult polycystic kidney disease. Ultrasound a useful tool in pre-symptomatic diagnosis?

A study was performed to assess the reliability and sensitivity of ultrasound for the screening of asymptomatic children of patients with known adult polycystic kidney disease (APKD) and to compare this technique with the IVP and conventional laboratory techniques. Ultrasound appears to be at least as sensitive as IVP for identifying carriers of the gene for polycystic kidney disease. The identification of about 50 % of a group of 21 asymptomatic individuals-at-risk in the 21–30-year age group as gene carriers, both with ultrasound and IVP, is promising for the early detection of this disease and therefore for genetic counselling in the future. This is the first step toward the construction of an age-specific detection curve for gene carriers, which is necessary in order to be able to calculate the probability that symptomatic subjects-at-risk carry the APKD gene.     

Utilization and evaluation of living-related donors for patients with adult polycystic kidney disease.

Adult onset polycystic kidney disease (ADPKD) causes 10% of all end-stage renal disease in the United States. Use of living-related donors for renal transplants provides significant advantages over cadaver donors. Presymptomatic testing to determine ADPKD status of potential donors by DNA linkage analysis is potentially more accurate than renal ultrasonography for related donors < 30 years old. To determine the utilization of living donor transplants and linkage studies, a survey was mailed to 202 transplant centers in the United Network of Organ Sharing. The 111 respondents reported 5,026 renal transplants done in 1988 of which 390 (7.8%) involved an ADPKD recipient. Only 7% of these 390 transplants utilized a living-related donor compared to the 20% rate reported for all renal transplants. DNA linkage studies were not used by any of the centers performing related donor transplants in 1988 and only 29% reported provision of risk counseling. We conclude that living-related transplants are underutilized for ADPKD recipients due to conservative transplant policies, concern about the inaccuracy of presymptomatic diagnosis, or decreased availability of asymptomatic donors in these families. DNA linkage analysis is also underutilized due to lack of knowledge of its availability and accuracy, concerns about its cost and misconceptions about the accuracy of ultrasonography.(ABSTRACT TRUNCATED AT 250 WORDS)     

5例成人型多囊肾家系调查

目的 了解5例成人型多囊肾先证者家族中的患病情况及患病规律。方法 对76例家族成员进行B型超声波检查．在肾脏中发现多个囊肿为主要诊断依据。结果 家族中患病率43．6％，男42．8％，女44．1％，男女患病率无明显差异，符合常染色体显性遗传患病规律。结论 家系调查对开展遗传咨询、优生指导有重要意义。