Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers.

Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.

A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.

A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a(N641Y/N641Y) knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na(v)1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na(v)1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.

Electroconvulsive seizure thresholds and kindling acquisition rates are altered in mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions.

PURPOSE: Benign familial neonatal convulsions (BFNC) is caused by mutations in the KCNQ2 and KCNQ3 genes, which encode subunits of the M-type potassium channel. The purpose of this study was to examine the effects of orthologous BFNC-causing mutations on seizure thresholds and the acquisition of corneal kindling in mice with heterozygous expression of the mutations. METHODS: The effects of the Kcnq2 gene A306T mutation and the Kcnq3 gene G311V mutation were determined for minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures. The rate of corneal kindling acquisition was also determined for Kcnq2 A306T and Kcnq3 G311V mice. RESULTS: Seizure thresholds were significantly altered relative to wild-type animals in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Differences in seizure threshold were found to be dependent on the mutation expressed, the seizure testing paradigm, the genetic background strain, and the gender of the animal. Mutations in Kcnq2 and Kcnq3 were associated with an increased rate of corneal kindling. In the Kcnq2 A306T mice, an increased incidence of death occurred during and immediately following the conclusion of the kindling acquisition period. CONCLUSIONS: These results suggest that genetic alterations in the subunits that underlie the M-current and cause BFNC alter seizure susceptibility in a sex-, mouse strain-, and seizure-test dependent manner. Although the heterozygous mice do not appear to have spontaneous seizures, the increased seizure susceptibility and incidence of death during and after kindling suggests that these mutations lead to altered excitability in these animals.

A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction.

People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began daily nicotine exposure during adolescence. We compared nicotine addiction-measured by the Fagerstrom Test of Nicotine Dependence-in three cohorts of long-term smokers recruited in Utah, Wisconsin, and by the NHLBI Lung Health Study, using a candidate-gene approach with the neuronal nAChR subunit genes. This SNP panel included common coding variants and haplotypes detected in eight alpha and three beta nAChR subunit genes found in European American populations. In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity (p = 2.0x10(-5); odds ratio = 1.82; 95% confidence interval 1.39-2.39) in subjects who began daily smoking at or before the age of 16, an exposure period that results in a more severe form of adult nicotine dependence. A substantial shift in susceptibility versus protective diplotype frequency (AA versus BC = 17%, AA versus CC = 27%) was observed in the group that began smoking by age 16. This genetic effect was not observed in subjects who began daily nicotine use after the age of 16. These results establish a strong mechanistic link among early nicotine exposure, common CHRNA5-A3-B4 haplotypes, and adult nicotine addiction in three independent populations of European origins. The identification of an age-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies.

Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization.

The childhood epilepsy syndrome of benign familial neonatal convulsions (BFNC) exhibits the remarkable feature of clinical remission within a few weeks of onset and a favourable prognosis, sparing cognitive abilities despite persistent expression of the mutant KCNQ2 or KCNQ3 potassium channels throughout adulthood. To better understand such dynamic neuroprotective plasticity within the developing brain, we introduced missense mutations that underlie human BFNC into the orthologous murine Kcnq2 (Kv7.2) and Kcnq3 (Kv7.3) genes. Mutant mice were examined for altered thresholds to induced seizures, spontaneous seizure characteristics, hippocampal histology, and M-current properties of CA1 hippocampal pyramidal neurons. Adult Kcnq2(A306T/+) and Kcnq3(G311V/+) heterozygous knock-in mice exhibited reduced thresholds to electrically induced seizures compared to wild-type littermate mice. Both Kcnq2(A306T/A306T) and Kcnq3(G311V/G311V) homozygous mutant mice exhibited early onset spontaneous generalized tonic-clonic seizures concurrent with a significant reduction in amplitude and increased deactivation kinetics of the neuronal M-current. Mice had recurrent seizures into adulthood that triggered molecular plasticity including ectopic neuropeptide Y (NPY) expression in granule cells, but without hippocampal mossy fibre sprouting or neuronal loss. These novel knocking mice recapitulate proconvulsant features of the human disorder yet show that inherited M-current defects spare granule cells from reactive changes in adult hippocampal networks. The absence of seizure-induced pathology found in these epileptic mouse models parallels the benign neurodevelopmental cognitive profile exhibited by the majority of BFNC patients.

KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum.

Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant generalized epilepsy of the newborn infant. Seizures occur repeatedly in the first days of life and remit by approximately 4 months of age. Previously our laboratory cloned two novel potassium channel genes, KCNQ2 and KCNQ3, and showed that they are mutated in patients with BFNC. In this report, we characterize the breakpoints of a previously reported interstitial deletion in the KCNQ2 gene and show that only KCNQ2 is deleted. We identify 11 novel mutations in KCNQ2 and one novel mutation in the KCNQ3 potassium channel genes. In one family, the phenotype extends beyond neonatal seizures and includes rolandic seizures, and a subset of families has onset of seizures in infancy. In the Xenopus oocyte expression system, we characterize five KCNQ2 and one KCNQ3 disease-causing mutations. These mutations cause a variable loss of function, and selective effects on the biophysical properties of KCNQ2/KCNQ3 heteromultimeric channels. We report here the first dominant negative mutation in KCNQ2 that has a phenotype of neonatal seizures without permanent clinical CNS impairment.

Nonsyndromic seizure disorders: epilepsy and the use of the internet to advance research.

The progress in understanding the genetics of nonsyndromic epilepsy is the direct result of dramatic advances made by the Human Genome Project. The development of thousands of precisely mapped genetic markers and the nearly complete sequencing of the entire human genome in 2001 allowed genetic researchers in epilepsy to identify many loci and genes as causal in inherited idiopathic epilepsy. This substantial increase in information has required the development of accurate and online bioinformatic databases. Only the Internet can enable such large amounts of precise DNA sequence information to be transferred to researchers. Along with the construction of these databases has been the development of efficient search algorithms for specific DNA sequences and genetic information. This article summarizes the effect that this burst of new genomic information has had on research aimed at discovering the underlying genetic factors for nonsyndromic epilepsy. Many of the web sites important to epilepsy gene discovery are listed and discussed in this article, including sites with extensive information on genetic markers, genetic analysis, gene sequence, gene expression, gene mutations, and DNA sequence variation. Continued acquisition of information on naturally occurring DNA sequence variants will greatly help research directed towards understanding the genetic susceptibility of the common, nonsyndromic epilepsies and will lead to the promise of personalized medicine.