Novel mutation in the epithelial sodium channel causing type I pseudohypoaldosteronism in a patient misdiagnosed with cystic fibrosis.

UNLABELLED: Cystic fibrosis (CF) is an inherited disorder with a devastating prognosis. Determination of chloride concentration in sweat has been the gold standard test for diagnosing CF for over 50 years and still remains the primary screening test. However, now that the genetic cause is known and can be studied, genetic confirmation is mandatory in every suspected patient. We present a patient who had been clinically diagnosed and whose genetic testing could not confirm CF, leading us to search for other options that may also give a positive sweat test. The patient turned out to suffer type 1 pseudohypoaldosteronism, a condition that may cause severe dehydration, hyponatremia and hyperkalemia episodes if not diagnosed and treated early with sodium supplementation. We found a genetic variation in the epithelial sodium channel gene which has not been reported previously, and we discuss the possibility of it being the cause of our patient's phenotype. CONCLUSION: this patient clearly illustrates the usefulness of genetic confirmation for CF for the diagnosis and genetic counselling, even when it is clinically oriented, and describes a novel mutation of the amiloride-sensitive epithelial sodium channel possibly causing type 1 pseudohypoaldosteronism.

C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

OBJECTIVE: We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. METHODS: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. RESULTS: We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. CONCLUSIONS: Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

C9orf72 and intracerebral hemorrhage.

The chromosome 9 open reading frame 72 (C9orf72) GGGGCC repeat expansion has been associated with several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. It has also been associated with increased white matter changes in frontotemporal dementia and risk of cognitive impairment in ALS. Dementia is common both before and after intracerebral hemorrhage (ICH). Because the mechanisms of cognitive impairment in patients with ICH are uncertain, we investigated whether C9orf72 could influence dementia risk in this patient group. Therefore, we genotyped 1010 clinically characterized ICH cases and 2147 population controls in comparison with prior data of dementia and ALS cases. We did not find any association between C9orf72 repeat expansion and repeat size with ICH compared with controls or with dementia when assessing ICH patients only. The frequency of C9orf72 expansions in our series of individuals born in 1946 (2/2147) and other U.K. controls was age dependent, decreasing with increasing age, highlighting the high age-dependent penetrance of this expansion.

Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL.

OBJECTIVE: To determine the frequency of distinctive EGFr cysteine altering NOTCH3 mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database. METHODS: ExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype-phenotype correlation predicted by the ExAC data was tested in an independent cohort of Dutch CADASIL patients using quantified MRI lesions. The Dutch CADASIL registry was probed for paucisymptomatic individuals older than 70 years. RESULTS: We identified 206 EGFr cysteine altering NOTCH3 mutations in ExAC, with a total prevalence of 3.4/1000. More than half of the distinct mutations have been previously reported in CADASIL patients. Despite the clear overlap, the mutation distribution in ExAC differs from that in reported CADASIL patients, as mutations in ExAC are predominantly located outside of EGFr domains 1-6. In an independent Dutch CADASIL cohort, we found that patients with a mutation in EGFr domains 7-34 have a significantly lower MRI lesion load than patients with a mutation in EGFr domains 1-6. INTERPRETATION: The frequency of EGFr cysteine altering NOTCH3 mutations is 100-fold higher than expected based on estimates of CADASIL prevalence. This challenges the current CADASIL disease paradigm, and suggests that certain mutations may more frequently cause a much milder phenotype, which may even go clinically unrecognized. Our data suggest that individuals with a mutation located in EGFr domains 1-6 are predisposed to the more severe "classical" CADASIL phenotype, whereas individuals with a mutation outside of EGFr domains 1-6 can remain paucisymptomatic well into their eighth decade.

BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling.

The B cell adaptor protein with ankyrin repeats (BANK1) and the B lymphoid tyrosine kinase (BLK) have been genetically associated with autoimmunity. The proteins of these genes interact physically and work in concert during B-cell signaling. Little is know about their interactions with other B-cell signaling molecules or their role in the process. Using yeast two hybrid (Y2H) we sought for factors that interact with BANK1. We found that the molecular switch PLCg2 interacts with BANK1 and that the interaction is promoted by B-cell receptor (BCR) stimulation. We found further that the kinase activity of BLK enhanced BANK1- PLCg2 binding and that the interaction was suppressed upon BLK depletion. Immunoprecipitation and mutational analysis demonstrated that the interaction between BANK1 and PLCg2 was dependent on specific tyrosine and proline residues on the adaptor protein. Our results provide new information important to understand the role of these two genes in basic B-cell physiology and immune-related diseases.