Autosomal-dominant polycystic kidney disease (ADPKD) is a common, progressive, adult-onset disease that is an important cause of end-stage renal disease (ESRD), which requires transplantation or dialysis. Mutations in PKD1 or PKD2 (∼85% and ∼15% of resolved cases, respectively) are the known causes of ADPKD. Extrarenal manifestations include an increased level of intracranial aneurysms and polycystic liver disease (PLD), which can be severe and associated with significant morbidity. Autosomal-dominant PLD (ADPLD) with no or very few renal cysts is a separate disorder caused by PRKCSH, SEC63, or LRP5 mutations. After screening, 7%-10% of ADPKD-affected and ∼50% of ADPLD-affected families were genetically unresolved (GUR), suggesting further genetic heterogeneity of both disorders. Whole-exome sequencing of six GUR ADPKD-affected families identified one with a missense mutation in GANAB, encoding glucosidase II subunit α (GIIα). Because PRKCSH encodes GIIβ, GANAB is a strong ADPKD and ADPLD candidate gene. Sanger screening of 321 additional GUR families identified eight further likely mutations (six truncating), and a total of 20 affected individuals were identified in seven ADPKD- and two ADPLD-affected families. The phenotype was mild PKD and variable, including severe, PLD. Analysis of GANAB-null cells showed an absolute requirement of GIIα for maturation and surface and ciliary localization of the ADPKD proteins (PC1 and PC2), and reduced mature PC1 was seen in GANAB(+/-) cells. PC1 surface localization in GANAB(-/-) cells was rescued by wild-type, but not mutant, GIIα. Overall, we show that GANAB mutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation.

We have conducted a large systematic study of 365 cystic fibrosis (CF) chromosomes in a Celtic population from Brittany, France, in which we have been able to identify more than 98% of the cystic fibrosis gene mutations. We detected 19 different CFTR mutations located in 9 exons. Eleven of these mutations have not been described previously and nine of them are presented in this study. The denaturing gradient gel electrophoresis strategy we have used, can be applied to other populations suggesting that population screening for CF on a large scale might be possible.

Background PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. Study Design Case series, January 2010 to March 2016. Settings & Participants Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease. Outcomes Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate. Results The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54–0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10–3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%–14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%–81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n = 36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD. Limitations Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers. Conclusions Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.

The very good sensitivity, specificity, and positive predictive value obtained suggest that the four-tiered IRT/DNA/IRT/sweat test procedure may provide an effective strategy for newborn screening for cystic fibrosis.

Nowadays, most of the neonatal screening programs for cystic fibrosis (CF) combine the assay of immunoreactive trypsinogen (IRT) with the analysis of the most common mutations of the CFTR gene. The efficiency of this strategy is now well established, but the identification of heterozygotes among neonates with increased IRT is perceived as a drawback. We proposed to assess the heterozygosity frequency among the children with hypertrypsinaemia detected through the CF screening program implemented in Brittany (France) 10 years ago, to describe the CFTR mutations detected in them and to determine the frequency of the IVS8-5T variant. The molecular analysis relies, in our protocol, on the systematic analysis of three exons of the gene (7-10-11). A total of 160,019 babies were screened for CF in western Brittany between 1992 and 1998. Of the 1964 newborns with increased IRT (1.2%), 60 were CF and 213 were carriers. Heterozygosity frequency was 12.8%), i.e. 3 times greater than in the general population (3.9%; p < 10(-6)), Variability of mutations detected in carriers was greater than in CF children (21 mutations versus 10) and a high proportion of mild mutations or variants (A349V, R297Q, R347H, V317A, G544S, R553G, etc) was observed in carriers. The allelic frequency of the 5T (5.6%) was not significantly increased in this cohort. This study is consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinaemia. The strategy of screening used here allows to highlight the variability of mutations detected in heterozygotes and to show that severe mutations, as well as mild mutations, have been observed in neonates with hypertrypsinaemia. If there is no doubt that neonatal hypertrypsinaemia is associated with an elevated frequency of carriers, the underlying mechanisms remain obscure.

Type IV collagen α1 and α2 chains form heterotrimers that constitute an essential component of basement membranes. Mutations in COL4A1, encoding the α1 chain, cause a multisystem disease with prominent cerebrovascular manifestations, including porencephaly, bleeding-prone cerebral small vessel disease, and intracranial aneurysms. Mutations in COL4A2 have only been reported in a few porencephaly families so far. Herein, we report on a young adult patient with recurrent intracerebral hemorrhage, leukoencephalopathy, intracranial aneurysms, nephropathy, and myopathy associated with a novel COL4A2 mutation. We extensively investigated a 29-year-old male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes. Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally. Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase. Genetic testing found a de novo glycine mutation within the COL4A2 triple helical domain. The presented case completes the spectrum of cerebral and systemic manifestations of COL4A2 mutations that appears to be very similar to that in COL4A1 mutations. Therefore, we emphasize the importance of screening both COL4A1 and COL4A2 in patients showing recurrent intracerebral hemorrhage of unknown etiology, particularly if associated with leukoencephalopathy.

Longitudinal quantitative chest radiography provides a new strategy for CF pulmonary phenotype categorization that should be useful for genotype-phenotype delineation in individual patients and in both epidemiologic studies and clinical trials involving groups of children with CF.

Newborn screening (NBS) of cystic fibrosis (CF) was implemented throughout the whole of France in 2002, but it had been established earlier in three western French regions. It can reveal atypical CF with one or two known CFTR mild mutations, with an uncertain evolution. The sweat test can be normal or borderline. In Brittany, from 1989 to 2004, 196 CF cases were diagnosed (1/2885 births). The incidence of atypical CF diagnosed by NBS is 9.7% (19 from 196). The outcome of 17 (2 lost of view) has been studied, with 9 other atypical CF cases diagnosed by NBS in two other regions. The follow-up period extends from 0.25 to 19.8 years (NBS implemented in Normandy in 1980) with mean age 4.6 years. The most frequent mild mutation is R117H ISV8-7T (50%). At the time of the last visit, nutritional status is normal. All these CF patients are pancreatic sufficient. Only one patient exhibits respiratory infections, whereas 7 others have them intermittently. Two of them had intermittent Pseudomonas aeruginosa colonization at 2.8 and 6.5 years. Mean Shwachman score is 96.7, mean Brasfield score is 22.8. Eight children have had lung function tests (mean follow-up of 10 years): mean FVC was 99% of predicted, mean FEV1 101%, but one of them has FEV1 of 48%. Predicting the phenotype of these atypical CF patients remains difficult, thus complicating any genetic counselling. A regular clinical evaluation is necessary, if possible by a CF unit, because CF symptoms may appear later.