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Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures.

ABSTRACT: BACKGROUND: Benign familial neonatal seizures are most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. More than 60 mutations have been described in BFNS families, approximately half of which lead to protein truncation. The hypothesis of this study was that deletion or duplication of >or=1 exons of KCNQ2 could cause BFNS in cases without coding or splicing mutations. METHODS: Multiplex ligation-dependent probe amplification (MLPA) was used to test a group of 21 unrelated patients with clinical features consistent with either BFNS, benign familial neonatal-infantile seizures or sporadic neonatal seizures, for exonic deletions and duplications. RESULTS: Three deletions and one duplication mutation were identified in four familial cases and cascade testing of their available family members showed that the mutations segregated with the phenotype in each family. The junction fragment for one of the deletions was amplified by PCR and sequenced to characterise the breakpoint and verify that a deletion had occurred. CONCLUSIONS: Submicroscopic deletions or duplications of KCNQ2 are seen in a significant proportion of BFNS families: four of nine (44%) cases previously testing negative for coding or splice site mutation by sequencing KCNQ2 and KCNQ3. MLPA is an efficient second-tier testing strategy for KCNQ2 to identify pathogenic intragenic mutations not detectable by conventional DNA sequencing methods.

SUBMITTER: Heron SE

PROVIDER: S-EPMC2652819 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures.

Heron S E SE Cox K K Grinton B E BE Zuberi S M SM Kivity S S Afawi Z Z Straussberg R R Berkovic S F SF Scheffer I E IE Mulley J C JC

Journal of medical genetics 20070803 12

<h4>Background</h4>Benign familial neonatal seizures are most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. More than 60 mutations have been described in BFNS families, approximately half of which lead to protein truncation. The hypothesis of this study was that deletion or duplication of >or=1 exons of KCNQ2 could cause BFNS in cases without coding or splicing mutations.<h4>Methods</h4>Multiplex ligation-dependent probe amplification (MLPA) was used to tes ...[more]

PMID: 17675531

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Project description:BackgroundPrior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline.MethodsPatients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings.FindingsDetailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits.InterpretationPatients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment.FundingSupported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.

Project description:BackgroundGenomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM.MethodsTo understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children's Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3.ResultsWe found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb-1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age.ConclusionThe distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3.

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Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures.

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Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures.

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