New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The bulk hydraulic conductivity of mangrove soil perforated with animal burrows

Flow of groundwater from mangrove swamp sediment to mangrove creeks is likely to be an important pathway in mangrove swamps, particularly for the removal of salt excluded at the mangrove root. The swamps are generally saturated with water, and are perforated with animal burrows, allowing significant groundwater flow to mangrove creeks to occur. The hydraulic conductivity of the sediment is thus an important physical parameter but is very difficult to measure in-situ. In this work, we describe a simple method for determining the hydraulic conductivity of mangrove sediment, including the effect of macropores\ud such as crab burrows, which uses the existing animal burrows as piezometers. Experiments to measure the hydraulic conductivity of the sediment were carried out in a variety of mangrove forests. It was found that hydraulic conductivity varied from around 1 to 10 m per day, which is at least 10 times greater than would be expected if there were no burrows. In order to check the validity of the method, conventional piezometers were used to determine the free water table level in an area of mangroves fringing a creek. From these measurements, hydraulic conductivity was determined independently and found to be consistent with\ud the new methodology

Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy

We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies

Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants

First published: 03 June 2021PCDH19 is a non-clustered protocadherin molecule involved in axon bundling, synapse function and transcriptional co-regulation. Pathogenic variants in PCDH19 cause an infantile onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance, or VUS. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. Application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification. This article is protected by copyright. All rights reserved.Duyen H. Pham, Melissa R. Pitman, Raman Kumar, Lachlan A. Jolly, Renee Schulz, Alison E. Gardner ... et al

Association of SLC32A1 missense variants with genetic epilepsy with febrile seizures plus

Objective To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. Methods We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. Results Eight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). Conclusion Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype–phenotype spectrum associated with SLC32A1 variants.Sarah E. Heron, Brigid M. Regan, Rebekah V. Harris, Alison E. Gardner, Matthew J. Coleman, Mark F. Bennett ... et al

Callosal agenesis and congenital mirror movements: outcomes associated with DCC mutations

Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability