Publications by authors named "Stéphane Bézieau"

146 Publications

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.

Am J Hum Genet 2021 Mar 31. Epub 2021 Mar 31.

Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France. Electronic address:

Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.017DOI Listing
March 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 Mar 19. Epub 2021 Mar 19.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
March 2021

First French study relative to preconception genetic testing: 1500 general population participants' opinion.

Orphanet J Rare Dis 2021 Mar 12;16(1):130. Epub 2021 Mar 12.

Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093, Nantes Cedex 1, France.

Background: Until very recently, preconception genetic testing was only conducted in particular communities, ethnic groups or families for which an increased risk of genetic disease was identified. To detect in general population a risk for a couple to have a child affected by a rare, recessive or X-linked, genetic disease, carrier screening is proposed in several countries. We aimed to determine the current public opinion relative to this approach in France, using either a printed or web-based questionnaire.

Results: Among the 1568 participants, 91% are favorable to preconception genetic tests and 57% declare to be willing to have the screening if the latter is available. A medical prescription by a family doctor or a gynecologist would be the best way to propose the test for 73%, with a reimbursement from the social security insurance. However, 19% declare not to be willing to use the test because of their ethic or moral convictions, and the fear that the outcome would question the pregnancy. Otherwise, most participants consider that the test is a medical progress despite the risk of an increased medicalization of the pregnancy.

Conclusion: This first study in France highlights a global favorable opinion for the preconception genetic carrier testing under a medical prescription and a reimbursement by social security insurance. Our results emphasize as well the complex concerns underpinned by the use of this screening strategy. Therefore, the ethical issues related to these tests include the risk of eugenic drift mentioned by more than half of the participants.
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http://dx.doi.org/10.1186/s13023-021-01754-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955630PMC
March 2021

Response to Li and Hopper.

Authors:
Minta Thomas Lori C Sakoda Michael Hoffmeister Elisabeth A Rosenthal Jeffrey K Lee Franzel J B van Duijnhoven Elizabeth A Platz Anna H Wu Christopher H Dampier Albert de la Chapelle Alicja Wolk Amit D Joshi Andrea Burnett-Hartman Andrea Gsur Annika Lindblom Antoni Castells Aung Ko Win Bahram Namjou Bethany Van Guelpen Catherine M Tangen Qianchuan He Christopher I Li Clemens Schafmayer Corinne E Joshu Cornelia M Ulrich D Timothy Bishop Daniel D Buchanan Daniel Schaid David A Drew David C Muller David Duggan David R Crosslin Demetrius Albanes Edward L Giovannucci Eric Larson Flora Qu Frank Mentch Graham G Giles Hakon Hakonarson Heather Hampel Ian B Stanaway Jane C Figueiredo Jeroen R Huyghe Jessica Minnier Jenny Chang-Claude Jochen Hampe John B Harley Kala Visvanathan Keith R Curtis Kenneth Offit Li Li Loic Le Marchand Ludmila Vodickova Marc J Gunter Mark A Jenkins Martha L Slattery Mathieu Lemire Michael O Woods Mingyang Song Neil Murphy Noralane M Lindor Ozan Dikilitas Paul D P Pharoah Peter T Campbell Polly A Newcomb Roger L Milne Robert J MacInnis Sergi Castellví-Bel Shuji Ogino Sonja I Berndt Stéphane Bézieau Stephen N Thibodeau Steven J Gallinger Syed H Zaidi Tabitha A Harrison Temitope O Keku Thomas J Hudson Veronika Vymetalkova Victor Moreno Vicente Martín Volker Arndt Wei-Qi Wei Wendy Chung Yu-Ru Su Richard B Hayes Emily White Pavel Vodicka Graham Casey Stephen B Gruber Robert E Schoen Andrew T Chan John D Potter Hermann Brenner Gail P Jarvik Douglas A Corley Ulrike Peters Li Hsu

Am J Hum Genet 2021 03;108(3):527-529

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008475PMC
March 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Authors:
Jeroen R Huyghe Tabitha A Harrison Stephanie A Bien Heather Hampel Jane C Figueiredo Stephanie L Schmit David V Conti Sai Chen Conghui Qu Yi Lin Richard Barfield John A Baron Amanda J Cross Brenda Diergaarde David Duggan Sophia Harlid Liher Imaz Hyun Min Kang David M Levine Vittorio Perduca Aurora Perez-Cornago Lori C Sakoda Fredrick R Schumacher Martha L Slattery Amanda E Toland Fränzel J B van Duijnhoven Bethany Van Guelpen Antonio Agudo Demetrius Albanes M Henar Alonso Kristin Anderson Coral Arnau-Collell Volker Arndt Barbara L Banbury Michael C Bassik Sonja I Berndt Stéphane Bézieau D Timothy Bishop Juergen Boehm Heiner Boeing Marie-Christine Boutron-Ruault Hermann Brenner Stefanie Brezina Stephan Buch Daniel D Buchanan Andrea Burnett-Hartman Bette J Caan Peter T Campbell Prudence R Carr Antoni Castells Sergi Castellví-Bel Andrew T Chan Jenny Chang-Claude Stephen J Chanock Keith R Curtis Albert de la Chapelle Douglas F Easton Dallas R English Edith J M Feskens Manish Gala Steven J Gallinger W James Gauderman Graham G Giles Phyllis J Goodman William M Grady John S Grove Andrea Gsur Marc J Gunter Robert W Haile Jochen Hampe Michael Hoffmeister John L Hopper Wan-Ling Hsu Wen-Yi Huang Thomas J Hudson Mazda Jenab Mark A Jenkins Amit D Joshi Temitope O Keku Charles Kooperberg Tilman Kühn Sébastien Küry Loic Le Marchand Flavio Lejbkowicz Christopher I Li Li Li Wolfgang Lieb Annika Lindblom Noralane M Lindor Satu Männistö Sanford D Markowitz Roger L Milne Lorena Moreno Neil Murphy Rami Nassir Kenneth Offit Shuji Ogino Salvatore Panico Patrick S Parfrey Rachel Pearlman Paul D P Pharoah Amanda I Phipps Elizabeth A Platz John D Potter Ross L Prentice Lihong Qi Leon Raskin Gad Rennert Hedy S Rennert Elio Riboli Clemens Schafmayer Robert E Schoen Daniela Seminara Mingyang Song Yu-Ru Su Catherine M Tangen Stephen N Thibodeau Duncan C Thomas Antonia Trichopoulou Cornelia M Ulrich Kala Visvanathan Pavel Vodicka Ludmila Vodickova Veronika Vymetalkova Korbinian Weigl Stephanie J Weinstein Emily White Alicja Wolk Michael O Woods Anna H Wu Goncalo R Abecasis Deborah A Nickerson Peter C Scacheri Anshul Kundaje Graham Casey Stephen B Gruber Li Hsu Victor Moreno Richard B Hayes Polly A Newcomb Ulrike Peters

Gut 2021 Feb 25. Epub 2021 Feb 25.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
February 2021

Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder.

Hum Mutat 2021 Feb 18. Epub 2021 Feb 18.

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.

ARHGEF9 defects lead to an X-linked intellectual disability disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males, with a few affected females reported. Up to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. We report three novel loss-of-function (LoF) variants in ARHGEF9: A de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)), that is, also present as a somatically mosaic variant in her father, and a de novo nonsense variant in a boy (c.899G>A; p.(Trp300*)). Both females showed a random XCI. Thus, we suggest that missense variants are responsible for an XLR disorder affecting males and that LoF variants, mainly occurring de novo, may be responsible for an X-linked dominant disorder affecting males and females.
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http://dx.doi.org/10.1002/humu.24188DOI Listing
February 2021

Mapping of colorectal carcinoma diseases with activation of Wnt/beta-catenin signalling pathway using hierarchical clustering approach.

J Clin Pathol 2021 Jan 13. Epub 2021 Jan 13.

Department of Biochemistry and Oncogenomics, Centre Hospitalier Universitaire, Nantes, France.

Aims: To map the colorectal carcinoma (CRC) diseases with significant Wnt signalling pathway activation for delineating their clinicopathological and molecular profiles.

Methods: Mapping is based on hierarchical clustering analyses of a series of 283 CRCs. Data tabulated were histopathological patterns, immunophenotypic differentiation, , , mutations and microsatellite instability status, tumour-infiltrating lymphocytes (TILs) and genetic setting. Beta-catenin expression in more than 10% of cell nuclei in the centre of tumour serves as a surrogate marker of significant activation of Wnt signalling pathway.

Results: Nuclei beta-catenin expression was present in 95% of CRCs; 56% of them met the criteria of high level of nuclei beta-catenin expression (≥10%). Proportion of beta-catenin positive nuclei was significantly higher in younger patients, rectal and left-sided colonic carcinomas. CRCs with high level of nuclei beta-catenin expression were regrouped into three clusters: (1) microsatellite stability (MSS) CRCs with no constitutive MAPK pathway activation including 90% of low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs; (2) -mutated MSS CRCs including low-grade adenocarcinoma, NOS, with intestinal differentiation and mucinous adenocarcinoma without TILs; (3) MSI-H CRCs including both -mutated CRCs evolving from serrated pathway and -mutated CRCs associated with Lynch syndrome.

Conclusions: MSS low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs ('crypt-like adenocarcinoma') might be the morphological pending of canonical molecular subtype of CRC defined as displayed molecular epithelial differentiation and upregulation of WNT in consensus molecular classification of CRC.
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http://dx.doi.org/10.1136/jclinpath-2020-207144DOI Listing
January 2021

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

BMC Med 2020 12 17;18(1):396. Epub 2020 Dec 17.

Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

Results: In sex-specific MR analyses, higher BMI (per 4.2 kg/m) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

Conclusions: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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http://dx.doi.org/10.1186/s12916-020-01855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745469PMC
December 2020

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Authors:
Laura Bryant Dong Li Samuel G Cox Dylan Marchione Evan F Joiner Khadija Wilson Kevin Janssen Pearl Lee Michael E March Divya Nair Elliott Sherr Brieana Fregeau Klaas J Wierenga Alexandrea Wadley Grazia M S Mancini Nina Powell-Hamilton Jiddeke van de Kamp Theresa Grebe John Dean Alison Ross Heather P Crawford Zoe Powis Megan T Cho Marcia C Willing Linda Manwaring Rachel Schot Caroline Nava Alexandra Afenjar Davor Lessel Matias Wagner Thomas Klopstock Juliane Winkelmann Claudia B Catarino Kyle Retterer Jane L Schuette Jeffrey W Innis Amy Pizzino Sabine Lüttgen Jonas Denecke Tim M Strom Kristin G Monaghan Zuo-Fei Yuan Holly Dubbs Renee Bend Jennifer A Lee Michael J Lyons Julia Hoefele Roman Günthner Heiko Reutter Boris Keren Kelly Radtke Omar Sherbini Cameron Mrokse Katherine L Helbig Sylvie Odent Benjamin Cogne Sandra Mercier Stephane Bezieau Thomas Besnard Sebastien Kury Richard Redon Karit Reinson Monica H Wojcik Katrin Õunap Pilvi Ilves A Micheil Innes Kristin D Kernohan Gregory Costain M Stephen Meyn David Chitayat Elaine Zackai Anna Lehman Hilary Kitson Martin G Martin Julian A Martinez-Agosto Stan F Nelson Christina G S Palmer Jeanette C Papp Neil H Parker Janet S Sinsheimer Eric Vilain Jijun Wan Amanda J Yoon Allison Zheng Elise Brimble Giovanni Battista Ferrero Francesca Clementina Radio Diana Carli Sabina Barresi Alfredo Brusco Marco Tartaglia Jennifer Muncy Thomas Luis Umana Marjan M Weiss Garrett Gotway K E Stuurman Michelle L Thompson Kirsty McWalter Constance T R M Stumpel Servi J C Stevens Alexander P A Stegmann Kristian Tveten Arve Vøllo Trine Prescott Christina Fagerberg Lone Walentin Laulund Martin J Larsen Melissa Byler Robert Roger Lebel Anna C Hurst Joy Dean Samantha A Schrier Vergano Jennifer Norman Saadet Mercimek-Andrews Juanita Neira Margot I Van Allen Nicola Longo Elizabeth Sellars Raymond J Louie Sara S Cathey Elly Brokamp Delphine Heron Molly Snyder Adeline Vanderver Celeste Simon Xavier de la Cruz Natália Padilla J Gage Crump Wendy Chung Benjamin Garcia Hakon H Hakonarson Elizabeth J Bhoj

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Structural abnormalities of chromosome 8 and fetoplacental discrepancy: A second case report and review of fetal phenotype of 8p inverted duplication deletion syndrome.

Eur J Med Genet 2021 Jan 26;64(1):104118. Epub 2020 Nov 26.

Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000, Nantes, France.

We described a new second case of fetoplacental discrepancy involving first trimester prenatal detection of mosaic isochromosome i (8) (q10). A 32-year-old woman underwent chorionic villous sampling because of increased fetal nuchal translucency. Analysis of direct chromosome preparations was performed by R-banding and FISH using subtelomeric, centromeric and whole chromosome painting probes for chromosome 8 showing the presence of an isochromosome 8q with a complex, female mosaic karyotype: mos 46,XX,i (8) (q10)[13]/46,XX,del (8) (p23)[10]. Cytogenetic analysis of cultured CVS showed an interstitial duplication with concomitant terminal deletion of the short arm of chromosome 8: 46,XX,der (8)del (8) (p23)dup (8) (p?)[18]. Array-CGH analysis from cultured trophoblasts and fetal tissues revealed a 6.69 Mb terminal deletion in 8p23.3p23.1 associated with a 31.49 Mb duplication in 8p23.1p11.1. FISH analysis confirmed the 8p inverted duplication deletion syndrome. Moreover, polymorphic DNA marker analysis demonstrated that the derivative chromosome 8 was of maternal origin. FISH analysis of cultured peripheral blood lymphocytes showed that the mother also carried a cryptic paracentric inversion inv (8) (p23). Our report contributes to expand the fetal phenotype of 8p inverted duplication deletion syndrome and also provides further insight into the underlying mechanism of this rare genomic disorder.
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http://dx.doi.org/10.1016/j.ejmg.2020.104118DOI Listing
January 2021

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Gastroenterology 2021 Mar 12;160(4):1164-1178.e6. Epub 2020 Oct 12.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Background And Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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http://dx.doi.org/10.1053/j.gastro.2020.08.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956223PMC
March 2021

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Authors:
Roddy Walsh Najim Lahrouchi Rafik Tadros Florence Kyndt Charlotte Glinge Pieter G Postema Ahmad S Amin Eline A Nannenberg James S Ware Nicola Whiffin Francesco Mazzarotto Doris Škorić-Milosavljević Christian Krijger Elena Arbelo Dominique Babuty Hector Barajas-Martinez Britt M Beckmann Stéphane Bézieau J Martijn Bos Jeroen Breckpot Oscar Campuzano Silvia Castelletti Candan Celen Sebastian Clauss Anniek Corveleyn Lia Crotti Federica Dagradi Carlo de Asmundis Isabelle Denjoy Sven Dittmann Patrick T Ellinor Cristina Gil Ortuño Carla Giustetto Jean-Baptiste Gourraud Daisuke Hazeki Minoru Horie Taisuke Ishikawa Hideki Itoh Yoshiaki Kaneko Jørgen K Kanters Hiroki Kimoto Maria-Christina Kotta Ingrid P C Krapels Masahiko Kurabayashi Julieta Lazarte Antoine Leenhardt Bart L Loeys Catarina Lundin Takeru Makiyama Jacques Mansourati Raphaël P Martins Andrea Mazzanti Stellan Mörner Carlo Napolitano Kimie Ohkubo Michael Papadakis Boris Rudic Maria Sabater Molina Frédéric Sacher Hatice Sahin Georgia Sarquella-Brugada Regina Sebastiano Sanjay Sharma Mary N Sheppard Keiko Shimamoto M Benjamin Shoemaker Birgit Stallmeyer Johannes Steinfurt Yuji Tanaka David J Tester Keisuke Usuda Paul A van der Zwaag Sonia Van Dooren Lut Van Laer Annika Winbo Bo G Winkel Kenichiro Yamagata Sven Zumhagen Paul G A Volders Steven A Lubitz Charles Antzelevitch Pyotr G Platonov Katja E Odening Dan M Roden Jason D Roberts Jonathan R Skinner Jacob Tfelt-Hansen Maarten P van den Berg Morten S Olesen Pier D Lambiase Martin Borggrefe Kenshi Hayashi Annika Rydberg Tadashi Nakajima Masao Yoshinaga Johan B Saenen Stefan Kääb Pedro Brugada Tomas Robyns Daniela F Giachino Michael J Ackerman Ramon Brugada Josep Brugada Juan R Gimeno Can Hasdemir Pascale Guicheney Silvia G Priori Eric Schulze-Bahr Naomasa Makita Peter J Schwartz Wataru Shimizu Takeshi Aiba Jean-Jacques Schott Richard Redon Seiko Ohno Vincent Probst Elijah R Behr Julien Barc Connie R Bezzina

Genet Med 2021 Jan 7;23(1):47-58. Epub 2020 Sep 7.

Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.

Authors:
Nazlisadat Seyed Khoei Mazda Jenab Neil Murphy Barbara L Banbury Robert Carreras-Torres Vivian Viallon Tilman Kühn Bas Bueno-de-Mesquita Krasimira Aleksandrova Amanda J Cross Elisabete Weiderpass Magdalena Stepien Andrew Bulmer Anne Tjønneland Marie-Christine Boutron-Ruault Gianluca Severi Franck Carbonnel Verena Katzke Heiner Boeing Manuela M Bergmann Antonia Trichopoulou Anna Karakatsani Georgia Martimianaki Domenico Palli Giovanna Tagliabue Salvatore Panico Rosario Tumino Carlotta Sacerdote Guri Skeie Susana Merino Catalina Bonet Miguel Rodríguez-Barranco Leire Gil Maria-Dolores Chirlaque Eva Ardanaz Robin Myte Johan Hultdin Aurora Perez-Cornago Dagfinn Aune Konstantinos K Tsilidis Demetrius Albanes John A Baron Sonja I Berndt Stéphane Bézieau Hermann Brenner Peter T Campbell Graham Casey Andrew T Chan Jenny Chang-Claude Stephen J Chanock Michelle Cotterchio Steven Gallinger Stephen B Gruber Robert W Haile Jochen Hampe Michael Hoffmeister John L Hopper Li Hsu Jeroen R Huyghe Mark A Jenkins Amit D Joshi Ellen Kampman Susanna C Larsson Loic Le Marchand Christopher I Li Li Li Annika Lindblom Noralane M Lindor Vicente Martín Victor Moreno Polly A Newcomb Kenneth Offit Shuji Ogino Patrick S Parfrey Paul D P Pharoah Gad Rennert Lori C Sakoda Clemens Schafmayer Stephanie L Schmit Robert E Schoen Martha L Slattery Stephen N Thibodeau Cornelia M Ulrich Franzel J B van Duijnhoven Korbinian Weigl Stephanie J Weinstein Emily White Alicja Wolk Michael O Woods Anna H Wu Xuehong Zhang Pietro Ferrari Gabriele Anton Annette Peters Ulrike Peters Marc J Gunter Karl-Heinz Wagner Heinz Freisling

BMC Med 2020 09 3;18(1):229. Epub 2020 Sep 3.

Nutritional Methodology and Biostatistics Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69372, Lyon CEDEX 08, France.

Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.

Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.

Results: The associations between circulating UCB levels and CRC risk differed by sex (P = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P ≥ 0.2).

Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
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http://dx.doi.org/10.1186/s12916-020-01703-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469292PMC
September 2020

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Authors:
Minta Thomas Lori C Sakoda Michael Hoffmeister Elisabeth A Rosenthal Jeffrey K Lee Franzel J B van Duijnhoven Elizabeth A Platz Anna H Wu Christopher H Dampier Albert de la Chapelle Alicja Wolk Amit D Joshi Andrea Burnett-Hartman Andrea Gsur Annika Lindblom Antoni Castells Aung Ko Win Bahram Namjou Bethany Van Guelpen Catherine M Tangen Qianchuan He Christopher I Li Clemens Schafmayer Corinne E Joshu Cornelia M Ulrich D Timothy Bishop Daniel D Buchanan Daniel Schaid David A Drew David C Muller David Duggan David R Crosslin Demetrius Albanes Edward L Giovannucci Eric Larson Flora Qu Frank Mentch Graham G Giles Hakon Hakonarson Heather Hampel Ian B Stanaway Jane C Figueiredo Jeroen R Huyghe Jessica Minnier Jenny Chang-Claude Jochen Hampe John B Harley Kala Visvanathan Keith R Curtis Kenneth Offit Li Li Loic Le Marchand Ludmila Vodickova Marc J Gunter Mark A Jenkins Martha L Slattery Mathieu Lemire Michael O Woods Mingyang Song Neil Murphy Noralane M Lindor Ozan Dikilitas Paul D P Pharoah Peter T Campbell Polly A Newcomb Roger L Milne Robert J MacInnis Sergi Castellví-Bel Shuji Ogino Sonja I Berndt Stéphane Bézieau Stephen N Thibodeau Steven J Gallinger Syed H Zaidi Tabitha A Harrison Temitope O Keku Thomas J Hudson Veronika Vymetalkova Victor Moreno Vicente Martín Volker Arndt Wei-Qi Wei Wendy Chung Yu-Ru Su Richard B Hayes Emily White Pavel Vodicka Graham Casey Stephen B Gruber Robert E Schoen Andrew T Chan John D Potter Hermann Brenner Gail P Jarvik Douglas A Corley Ulrike Peters Li Hsu

Am J Hum Genet 2020 09 5;107(3):432-444. Epub 2020 Aug 5.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Electronic address:

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477007PMC
September 2020

Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND).

Eur J Med Genet 2020 Oct 17;63(10):104004. Epub 2020 Jul 17.

Normandie Univ, UNIROUEN, Inserm U1245, Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France. Electronic address:

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management.
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http://dx.doi.org/10.1016/j.ejmg.2020.104004DOI Listing
October 2020

Diagnosis of exon 12-positive polycythemia vera rescued by NGS.

Clin Case Rep 2020 May 21;8(5):790-792. Epub 2020 Mar 21.

Service d'Hématologie Biologique Pôle Biologie CHU de Dijon Dijon France.

A V617F-negative polycythemia associated with low serum epo needs to be tested for an exon 12 mutation. When negative, due to potential serious complications in PV, a next generation sequencing is necessary to rule out false negative results.
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http://dx.doi.org/10.1002/ccr3.2720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250982PMC
May 2020

Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Am J Hum Genet 2020 06 7;106(6):893-904. Epub 2020 May 7.

CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France. Electronic address:

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273529PMC
June 2020

Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.

Cancer Med 2020 05 24;9(10):3563-3573. Epub 2020 Mar 24.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Background: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.

Methods: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.

Results: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10 ), PSMC5 (P = 4.51 × 10 ) and CD33 (P = 2.71 × 10 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10 ) and SCN1B (P = 2.76 × 10 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10 ).

Conclusions: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.
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http://dx.doi.org/10.1002/cam4.2971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221445PMC
May 2020

Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development.

Neuron 2020 05 4;106(3):404-420.e8. Epub 2020 Mar 4.

Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.
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http://dx.doi.org/10.1016/j.neuron.2020.01.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331285PMC
May 2020

A dominant vimentin variant causes a rare syndrome with premature aging.

Eur J Hum Genet 2020 09 17;28(9):1218-1230. Epub 2020 Feb 17.

Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes, France.

Progeroid syndromes are a group of rare genetic disorders, which mimic natural aging. Unraveling the molecular defects in such conditions could impact our understanding of age-related syndromes such as Alzheimer's or cardiovascular diseases. Here we report a de novo heterozygous missense variant in the intermediate filament vimentin (c.1160 T > C; p.(Leu387Pro)) causing a multisystem disorder associated with frontonasal dysostosis and premature aging in a 39-year-old individual. Human vimentin p.(Leu387Pro) expression in zebrafish perturbed body fat distribution, and craniofacial and peripheral nervous system development. In addition, studies in patient-derived and transfected cells revealed that the variant affects vimentin turnover and its ability to form filaments in the absence of wild-type vimentin. Vimentin p.(Leu387Pro) expression diminished the amount of peripilin and reduced lipid accumulation in differentiating adipocytes, recapitulating key patient's features in vivo and in vitro. Our data highlight the function of vimentin during development and suggest its contribution to natural aging.
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http://dx.doi.org/10.1038/s41431-020-0583-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609319PMC
September 2020

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 04 12;29(4):860-870. Epub 2020 Feb 12.

Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.

Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.

Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [OR = 0.96; 95% confidence interval (CI) = 0.93-0.98; = 5.2 × 10] and α-linolenic acid (OR = 0.95; 95% CI = 0.92-0.97; = 5.4 × 10), whereas modest increased risks were observed for arachidonic (OR = 1.06; 95% CI = 1.03-1.08; = 3.3 × 10), eicosapentaenoic (OR = 1.04; 95% CI = 1.01-1.07; = 2.5 × 10), and docosapentaenoic acids (OR = 1.03; 95% CI = 1.01-1.06; = 1.2 × 10). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.

Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.

Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125012PMC
April 2020

Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.

Gastroenterology 2020 04 27;158(5):1300-1312.e20. Epub 2019 Dec 27.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.

Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.

Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
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http://dx.doi.org/10.1053/j.gastro.2019.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152801PMC
April 2020

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Authors:
Alexi N Archambault Yu-Ru Su Jihyoun Jeon Minta Thomas Yi Lin David V Conti Aung Ko Win Lori C Sakoda Iris Lansdorp-Vogelaar Elisabeth F P Peterse Ann G Zauber David Duggan Andreana N Holowatyj Jeroen R Huyghe Hermann Brenner Michelle Cotterchio Stéphane Bézieau Stephanie L Schmit Christopher K Edlund Melissa C Southey Robert J MacInnis Peter T Campbell Jenny Chang-Claude Martha L Slattery Andrew T Chan Amit D Joshi Mingyang Song Yin Cao Michael O Woods Emily White Stephanie J Weinstein Cornelia M Ulrich Michael Hoffmeister Stephanie A Bien Tabitha A Harrison Jochen Hampe Christopher I Li Clemens Schafmayer Kenneth Offit Paul D Pharoah Victor Moreno Annika Lindblom Alicja Wolk Anna H Wu Li Li Marc J Gunter Andrea Gsur Temitope O Keku Rachel Pearlman D Timothy Bishop Sergi Castellví-Bel Leticia Moreira Pavel Vodicka Ellen Kampman Graham G Giles Demetrius Albanes John A Baron Sonja I Berndt Stefanie Brezina Stephan Buch Daniel D Buchanan Antonia Trichopoulou Gianluca Severi María-Dolores Chirlaque Maria-José Sánchez Domenico Palli Tilman Kühn Neil Murphy Amanda J Cross Andrea N Burnett-Hartman Stephen J Chanock Albert de la Chapelle Douglas F Easton Faye Elliott Dallas R English Edith J M Feskens Liesel M FitzGerald Phyllis J Goodman John L Hopper Thomas J Hudson David J Hunter Eric J Jacobs Corinne E Joshu Sébastien Küry Sanford D Markowitz Roger L Milne Elizabeth A Platz Gad Rennert Hedy S Rennert Fredrick R Schumacher Robert S Sandler Daniela Seminara Catherine M Tangen Stephen N Thibodeau Amanda E Toland Franzel J B van Duijnhoven Kala Visvanathan Ludmila Vodickova John D Potter Satu Männistö Korbinian Weigl Jane Figueiredo Vicente Martín Susanna C Larsson Patrick S Parfrey Wen-Yi Huang Heinz-Josef Lenz Jose E Castelao Manuela Gago-Dominguez Victor Muñoz-Garzón Christoph Mancao Christopher A Haiman Lynne R Wilkens Erin Siegel Elizabeth Barry Ban Younghusband Bethany Van Guelpen Sophia Harlid Anne Zeleniuch-Jacquotte Peter S Liang Mengmeng Du Graham Casey Noralane M Lindor Loic Le Marchand Steven J Gallinger Mark A Jenkins Polly A Newcomb Stephen B Gruber Robert E Schoen Heather Hampel Douglas A Corley Li Hsu Ulrike Peters Richard B Hayes

Gastroenterology 2020 04 19;158(5):1274-1286.e12. Epub 2019 Dec 19.

Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York. Electronic address:

Background & Aims: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

Methods: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.

Results: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.

Conclusions: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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http://dx.doi.org/10.1053/j.gastro.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103489PMC
April 2020

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

Am J Hum Genet 2019 11 17;105(5):1040-1047. Epub 2019 Oct 17.

CHU Nantes, Service de génétique médicale, F-44000 Nantes, France. Electronic address:

Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849359PMC
November 2019

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Authors:
Brett V Johnson Raman Kumar Sabrina Oishi Suzy Alexander Maria Kasherman Michelle Sanchez Vega Atma Ivancevic Alison Gardner Deepti Domingo Mark Corbett Euan Parnell Sehyoun Yoon Tracey Oh Matthew Lines Henrietta Lefroy Usha Kini Margot Van Allen Sabine Grønborg Sandra Mercier Sébastien Küry Stéphane Bézieau Laurent Pasquier Martine Raynaud Alexandra Afenjar Thierry Billette de Villemeur Boris Keren Julie Désir Lionel Van Maldergem Martina Marangoni Nicola Dikow David A Koolen Peter M VanHasselt Marjan Weiss Petra Zwijnenburg Joaquim Sa Claudia Falcao Reis Carlos López-Otín Olaya Santiago-Fernández Alberto Fernández-Jaén Anita Rauch Katharina Steindl Pascal Joset Amy Goldstein Suneeta Madan-Khetarpal Elena Infante Elaine Zackai Carey Mcdougall Vinodh Narayanan Keri Ramsey Saadet Mercimek-Andrews Loren Pena Vandana Shashi Kelly Schoch Jennifer A Sullivan Filippo Pinto E Vairo Pavel N Pichurin Sarah A Ewing Sarah S Barnett Eric W Klee M Scott Perry Mary Kay Koenig Catherine E Keegan Jane L Schuette Stephanie Asher Yezmin Perilla-Young Laurie D Smith Jill A Rosenfeld Elizabeth Bhoj Paige Kaplan Dong Li Renske Oegema Ellen van Binsbergen Bert van der Zwaag Marie Falkenberg Smeland Ioana Cutcutache Matthew Page Martin Armstrong Angela E Lin Marcie A Steeves Nicolette den Hollander Mariëtte J V Hoffer Margot R F Reijnders Serwet Demirdas Daniel C Koboldt Dennis Bartholomew Theresa Mihalic Mosher Scott E Hickey Christine Shieh Pedro A Sanchez-Lara John M Graham Kamer Tezcan G B Schaefer Noelle R Danylchuk Alexander Asamoah Kelly E Jackson Naomi Yachelevich Margaret Au Luis A Pérez-Jurado Tjitske Kleefstra Peter Penzes Stephen A Wood Thomas Burne Tyler Mark Pierson Michael Piper Jozef Gécz Lachlan A Jolly

Biol Psychiatry 2020 01 29;87(2):100-112. Epub 2019 Jun 29.

University of Adelaide and Robinson Research Institute, Adelaide, Australia. Electronic address:

Background: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.

Methods: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.

Results: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.

Conclusions: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.
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http://dx.doi.org/10.1016/j.biopsych.2019.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925349PMC
January 2020

The inhibitory receptor CD94/NKG2A on CD8 tumor-infiltrating lymphocytes in colorectal cancer: a promising new druggable immune checkpoint in the context of HLAE/β2m overexpression.

Mod Pathol 2020 03 13;33(3):468-482. Epub 2019 Aug 13.

Service d'Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France.

We previously demonstrated that HLA-E/β2m overexpression by tumor cells in colorectal cancers is associated with an unfavorable prognosis. However, the expression of its specific receptor CD94/NKG2 by intraepithelial tumor-infiltrating lymphocytes, their exact phenotype and function, as well as the relation with the molecular status of colorectal cancer and prognosis remain unknown. Based on a retrospective cohort of 234 colorectal cancer patients, we assessed the expression of HLA-E, β2m, CD94, CD8, and NKp46 by immunohistochemistry on tissue microarray. The expression profile of HLA-E/β2m on tumor cells and the density of tumor-infiltrating lymphocytes were correlated to the clinicopathological and molecular features (Microsatellite status, BRAF and RAS mutations). Then, from the primary tumors of 27 prospective colorectal cancers, we characterized by multiparameter flow cytometry the nature (T and/or NK cells) and the co-expression of the inhibitory NKG2A or activating NKG2C chain of ex vivo isolated CD94 tumor-infiltrating lymphocytes. Their biological function was determined using an in vitro redirected cytolytic activity assay. Our results showed that HLA-E/β2m was preferentially overexpressed in microsatellite instable tumors compared with microsatellite stable ones (45% vs. 19%, respectively, p = 0.0001), irrespective of the RAS or BRAF mutational status. However, HLA-E/β2m colorectal cancers were significantly enriched in CD94 intraepithelial tumor-infiltrating lymphocytes in microsatellite instable as well as in microsatellite stable tumors. Those CD94 tumor-infiltrating lymphocytes mostly corresponded to CD8 αβ T cells, and  to a lesser extent to NK cells, and mainly co-expressed a functional inhibitory NKG2A chain. Finally, a high number of CD94 intraepithelial tumor-infiltrating lymphocytes in close contact with tumor cells was independently associated with a worse overall survival. In conclusion, these findings strongly suggest that HLA-E/β2m-CD94/NKG2A represents a new druggable inhibitory immune checkpoint, preferentially expressed in microsatellite instable tumors, but also in a subgroup of microsatellite stable tumors, leading to a new opportunity in colorectal cancer immunotherapies.
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http://dx.doi.org/10.1038/s41379-019-0322-9DOI Listing
March 2020

Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.

Ann Clin Transl Neurol 2019 07 1;6(7):1263-1272. Epub 2019 Jul 1.

Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Melbourne, Australia.

Objective: To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations.

Methods: Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole-exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the K 3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two-electrode voltage clamping were used.

Results: Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole-cell current, but no dominant-negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole-cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance.

Interpretation: These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.
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http://dx.doi.org/10.1002/acn3.50822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649578PMC
July 2019

Correction: Variants in MED12L, encoding a subunit of the Mediator kinase module, are responsible for intellectual disability associated with transcriptional defect.

Genet Med 2019 11;21(11):2663

CHU Nantes, Service de Génétique Médicale, Nantes, France.

In the Acknowledgements section of the paper the authors neglected to mention that the study was supported by a grant from the National Human Genome Research Institute (NHGRI) UM1HG007301 (S.H., M.L.T.). In addition, the award of MD was associated with the authors Michelle L. Thompson and Susan Hiatt instead of PhD. The PDF and HTML versions of the Article have been modified accordingly.
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http://dx.doi.org/10.1038/s41436-019-0590-2DOI Listing
November 2019

Correction to: Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.

Hum Genet 2019 Jul;138(7):789-791

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.

Every author has erroneously been assigned to the affiliation "62". The affiliation 62 belongs to the author Graham Casey.
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http://dx.doi.org/10.1007/s00439-019-02030-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828521PMC
July 2019