Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated LDL cholesterol levels and premature coronary artery disease. FH underdiagnosis and undertreatment require novel detection methods. This study evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients.
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.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.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.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.
The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.
Vitrectomy in phakic patients is a procedure intrinsically complicated by vitreous incarceration, because complete removal of vitreous near the sclerotomies without touching the lens is difficult to perform. Vitreous incarcerated in sclerotomies may give rise to complications such as recurrent haemorrhage due to anterior hyaloid fibrovascular proliferation in diabetic patients and recurrent retinal detachment due to anterior loop contraction. This may be one of the explanations why, in retinal detachment surgery, buckling surgery resulted in better outcome than vitrectomy (Heimann et al. 2007). Thorough cleaning of the vitreous base is an important step to prevent vitrectomy-related complications. In phakic patients, this is difficult to achieve without touching the lens and consequent rapid cataract formation. Therefore, vitrectomy is often combined with phacoemulsification. In paediatric and young adult patients, however, it may be desirable to at least temporarily preserve their accommodating lens; also, with a preserved lens, the contour of a silicone oil tamponade has a larger arc of contact with the retina and is thereby more effective (Williams & Wong 1999). We describe a method to shallow the anterior chamber and deepen the vitreous space during surgery: intentional continuous shallowing of the anterior chamber (ICSAC). We insert a wedge (cut out with scissors from a silicone tube) in a paracentesis after injecting some curls of a dispersive viscoelastic to protect the endothelium. Although easily observable through the microscope, we documented the shallowing of the anterior chamber by axial immersion ultrasonography in four patients. The anterior chamber shallowed by a mean of 1.84 mm and the vitreous cavity axis was elongated by a mean of 1.79 mm. With the shallowed anterior chamber, we can easily remove incarcerated vitreous from a contralateral pars plana cannula (Fig. 1) without touching the lens. Other methods have been suggested for shaving the vitreous base in a phakic patient. By deep indentation with the light fibre and shaving (Veckeneer & Wong 2009) or by working from the ipsilateral side, instruments do not cross the posterior pole of the lens and thus can avoid lens touch. However, a crossing instrument has a more effective angle of approach to the contralateral vitreous base, particularly for opening up an anterior loop traction trough. Another method is to place the sclerotomies as far posterior as possible onto the ora serrata and then use deep indentation. This manoeuvre is most acceptable in patients with a giant retinal tear when cleaning the contralateral vitreous base. The latter approach would certainly not be possible in paediatric retinopathy of prematurity vitrectomy, where the pars plana is not yet formed. Shallowing of the anterior chamber during vitrectomy, however, may be potentially harmful to endothelial cells due to iris apposition. After shallowing of the anterior chamber in trabeculectomy, no endothelial damage has been reported (Fiore et al. 1989). We started a prospective trial in which we evaluated pre- and postoperative endothelial cell counts at 1, 3 and 6 months of patients undergoing vitrectomy randomized to ICSAC or no ICSAC (NTR 3046). We restricted the inclusion to phakic patients undergoing vitrectomy for vitreous floaters, macular pucker and macular hole. Unfortunately, inclusion of patients proved to be much slower than anticipated and we had to abort the study after inclusion of only 11 patients. In these patients, endothelial cell loss was limited and not noticeably different between patients with or without ICSAC. Therefore, with the caveats associated with conclusions drawn from small data sets, but with our own experience over 10 years (J. van Meurs, unpublished data, presented at the Euretina Barcelona 2004) of having no corneal decompensation after ICSAC, we conclude that when clinical circumstances warrant the preservation of the patients' lens, intentional shallowing of the anterior chamber is a feasible option.
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are closely related disorders, linked pathologically and genetically by the TAR DNA-binding protein-43 (TDP-43). Pathogenic variants in TARDBP encoding for TDP-43 have been described less frequently in FTD than in ALS, and clinicopathological studies are scarce.1 We previously observed a high frequency of the I383V variant in TARDBP in a Dutch cohort of FTD patients.2 Here, we provide further evidence for the pathogenicity of this variant and present its clinicopathological characteristics.
We ascertained all FTD (n=13) and ALS patients (n=4) with the I383V variant (NM_007375.3: c.1147A>G, p.Ile383Val) in TARDBP from three university medical centres in the Netherlands (Amsterdam, Rotterdam and Utrecht), as identified by whole-exome or whole-genome sequencing in either clinical or research setting. Concurrent pathogenic variants in 20 other genes associated with ALS, FTD or other forms of dementia were excluded in all patients.
Brain imaging (CT or MRI) was available for all FTD patients. Quantitative assessment of volume loss across lobar brain regions was performed in those patients with T1-weighted MRI images of sufficient quality (n=5), and compared with a gender-matched/age-matched reference population.
Family histories were classified into adjusted Goldman categories, which were described previously.2 Additionally, we performed extensive genealogical research to investigate possible relatedness between the index patients.
Brain autopsy and routine immunohistochemistry was performed for two FTD patients by the Netherlands Brain Bank. One patient (4M) was reported previously as M008015-001.1 Detailed information on the genetic, neuroimaging, genealogical and pathological analyses can be found in the1.
### Supplementary data
[jnnp-2020-325150supp001.pdf]
### The variable clinical phenotype and reduced penetrance of the I383V variant
All 13 FTD patients with the I383V variant in TARDBP presented with a combination of behavioural changes and semantic deficits. The diagnoses of semantic variant of primary progressive aphasia (svPPA) are intriguing since this is usually considered a sporadic disorder. One patient (4M) showed additional motor …
Carotid intima-media thickness (cIMT) is an established heritable marker for subclinical atherosclerosis. In this study, we aim to identify rare variants with large effects driving differences in cIMT by performing genome-wide linkage analysis of individuals in the extremes of cIMT trait distribution (>90th percentile) in a large family-based study from a genetically isolated population in the Netherlands. Linked regions were subsequently explored by fine-mapping using exome sequencing. We observed significant evidence of linkage on chromosomes 2p16.3 [rs1017418, heterogeneity LOD (HLOD) = 3.35], 19q13.43 (rs3499, HLOD = 9.09), 20p13 (rs1434789, HLOD = 4.10), and 21q22.12 (rs2834949, HLOD = 3.59). Fine-mapping using exome sequencing data identified a non-coding variant (rs62165235) in PNPT1 gene under the linkage peak at chromosome 2 that is likely to have a regulatory function. The variant was associated with quantitative cIMT in the family-based study population (effect = 0.27, p-value = 0.013). Furthermore, we identified several genes under the linkage peak at chromosome 21 highly expressed in tissues relevant for atherosclerosis. To conclude, our linkage analysis identified four genomic regions significantly linked to cIMT. Further analyses are needed to demonstrate involvement of identified candidate genes in development of atherosclerosis.
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