Tabular data of analysed data presented in figures of the manuscript "Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele" by Soutar et al., 2022.
Inflammatory linear verrucous epidermal nevus should be genotyped to direct treatment and genetic counselingTo the Editor: Inflammatory linear verrucous epidermal nevus (ILVEN) is a clinical diagnosis based on persistent Blaschko-linear erythematous scaly and usually pruritic lesions.Sixteen patients with a clinical diagnosis of ILVEN as defined by published diagnostic criteria were recruited and consented under Research Ethics Committee approval for phenotypic, histological, and genotypic analysis.At the time of initiating this study in 2014 no genetic causes of ILVEN were known.Causative genetic variants since described are in GJA1, 1 ABCA12 2 , CARD14, 3 PMVK 4 , NSDHL, 4 HRAS 4 and KRT10. 4Disease mechanisms thus far include germline X-linked variants, mosaic variants, and germline first hit with mosaic second hit.Paired blood and affected skin DNA underwent deep whole exome sequencing (WES, mean 250X), n ¼ 14, and if negative, skin DNA underwent targeted sequencing panel R327 (mosaic disorders, UK National Genomic Test Directory), n ¼ 8. Two patients had a negative WES and did not go forward to next generation sequencing panel due to sample limitations.Two patients recruited late in the study had next generation sequencing panel first and did not proceed to WES.We confirm here that ILVEN has multiple monogenic causes, with mutations in NSDHL (n ¼ 2, germline, NSDHL c.613G [ T, p.[G205T ], c.603_604delTG, p.[H201fs*69], both picked up on WES), PMVK (n ¼ 1, mosaic in blood and skin, no second variant detected in the same gene in skin, PMVK c.126delG, p.R42fs, picked up on WES), HRAS (n ¼ 1, mosaic, HRAS c.37G [ C, p.(G13R), picked up on panel, and CARD14 (n ¼ 2, mosaic, these 2 only previously published, 1 both picked up on WES).Ten patients had no pathogenic variants identified and we specifically excluded any variants in all previously described genes.No patients who were negative on WES had genes identified on a subsequent panel, suggesting that variants still unidentified are not in known mosaic genes, or if they are they are unlikely to be
Pathological tau protein inclusions have long been recognized to define the diverse range of neurodegenerative disorders called the tauopathies, which include Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration. Mutations in the tau gene, MAPT, cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and common variation in MAPT is strongly associated with the risk of PSP, corticobasal degeneration and, to a lesser extent, AD and Parkinson's disease (PD), implicating the involvement of tau in common neurodegenerative pathway(s). This review will discuss recent work towards the unravelling of the functional basis of this MAPT gene association. The region of chromosome 17q21 containing MAPT locus is characterized by the complex genomic architecture, including a large inversion that leads to a bipartite haplotype architecture, an inversion-mediated deletion and multiplications resulting from non-allelic homologous recombination between the MAPT family of low-copy repeats.
The -93G > A (rs1800734) polymorphism within the core promoter region of the MutL homolog 1 ( MLH1 ) gene has recently been proposed as a low penetrance variant for colorectal cancer (CRC). We evaluated the significance of rs1800734 on CRC risk by genotyping 10 409 CRC cases and 6965 controls. The per allele odds ratio (OR) for all CRC-associated MLH1 -93G > A was 1.06 ( P = 0.037). Using a subset of 3132 cases with known microsatellite instability (MSI) status, the risk was shown to be confined to microsatellite instability-high (MSI-H) CRC; OR = 1.39 ( P = 1.45 × 10 −4 ). A meta-analysis of our study and four smaller published studies (totalling 801 cases, 10 890 controls) provided for increased evidence of relationship between MLH1 -93G > A and MSI-H CRC risk ( P = 3.43 × 10 −12 ). The impact of MLH1 -93G > A on CRC risk was shown to be independent of the 14 low penetrance loci for CRC identified by recent genome-wide association studies. These data provide further evidence that MLH1 -93G > A is a low-penetrance variant for CRC and support the proposition that MLH1 -93G > A acts as marker for a somatic event defining a specific CRC subtype.
Abstract Lipoedema is a chronic adipose tissue disorder mainly affecting women, causing excess subcutaneous fat deposition on the lower limbs with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is currently unclear. A tightly phenotyped cohort of 200 lipoedema patients was recruited from two UK specialist clinics. Objective clinical characteristics and measures of quality of life data were obtained. In an attempt to understand the genetic architecture of the disease better, genome-wide single nucleotide polymorphism (SNP) genotype data were obtained, and a genome wide association study (GWAS) performed on 130 of the recruits. The analysis revealed genetic loci suggestively associated with the lipoedema phenotype, with further support provided by an independent cohort taken from the 100,000 Genomes Project. Top SNPs included loci associated with lipoma formation, biosynthesis of hormones and lipid hydroxylation. Exactly how these SNPs relate to a lipoedema disease mechanism is not yet understood but the findings are consistent with existing fat and hormone hypotheses. This first GWAS of a UK lipoedema cohort has identified genetic regions of suggestive association with the disease. Further replication of these findings in different populations is warranted.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.
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