Publications by authors named "Anne Boland"

149 Publications

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma.

Cancers (Basel) 2021 May 7;13(9). Epub 2021 May 7.

Section of Genetics, International Agency for Research on Cancer (IARC-WHO), 69372 Lyon, France.

: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association is poorly understood, and hypothetic genetic co-susceptibility remains largely unexplored. We hereby provide a clinical and genetic description of a series of 125 cases affected by both malignant melanoma and RCC. Clinical germline mutation testing identified a pathogenic variant in a melanoma and/or RCC predisposing gene in 17/125 cases (13.6%). This included mutually exclusive variants in (p.E318K locus, N = 9 cases), (N = 3), (N = 2), (N = 2), and (N = 1). A subset of 46 early-onset cases, without underlying germline variation, was whole-exome sequenced. In this series, thirteen genes were significantly enriched in mostly exclusive rare variants predicted to be deleterious, compared to 19,751 controls of similar ancestry. The observed variation mainly consisted of novel or low-frequency variants (<0.01%) within genes displaying strong evolutionary mutational constraints along the PI3K/mTOR pathway, including , , , , and related epigenetic modifier . The screening of independently processed germline exomes from The Cancer Genome Atlas confirmed an association with melanoma and RCC but not with cancers of established differing etiology such as lung cancers. Our study highlights that an exome-wide case-control enrichment approach may better characterize the rare variant-based missing heritability of multiple primary cancers. In our series, the co-occurrence of malignant melanoma and RCC was associated with germline variation in the PI3K/mTOR signaling cascade, with potential relevance for early diagnostic and clinical management.
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http://dx.doi.org/10.3390/cancers13092243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125037PMC
May 2021

Evaluation of saliva as a source of accurate whole-genome and microbiome sequencing data.

Genet Epidemiol 2021 May 16. Epub 2021 May 16.

Univ Brest, EFS, UMR 1078, GGB, Inserm, Brest, France.

This study sets out to establish the suitability of saliva-based whole-genome sequencing (WGS) through a comparison against blood-based WGS. To fully appraise the observed differences, we developed a novel technique of pseudo-replication. We also investigated the potential of characterizing individual salivary microbiomes from non-human DNA fragments found in saliva. We observed that the majority of discordant genotype calls between blood and saliva fell into known regions of the human genome that are typically sequenced with low confidence; and could be identified by quality control measures. Pseudo-replication demonstrated that the levels of discordance between blood- and saliva-derived WGS data were entirely similar to what one would expect between technical replicates if an individual's blood or saliva had been sequenced twice. Finally, we successfully sequenced salivary microbiomes in parallel to human genomes as demonstrated by a comparison against the Human Microbiome Project.
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http://dx.doi.org/10.1002/gepi.22386DOI Listing
May 2021

Genomic insights into population history and biological adaptation in Oceania.

Nature 2021 Apr 14;592(7855):583-589. Epub 2021 Apr 14.

Human Evolutionary Genetics Unit, Institut Pasteur, UMR 2000, CNRS, Paris, France.

The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes. However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago. Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.
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http://dx.doi.org/10.1038/s41586-021-03236-5DOI Listing
April 2021

Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

Genet Med 2021 Apr 8. Epub 2021 Apr 8.

Pediatric and Fetal Imaging Department, Hospices Civils de Lyon, Bron, France.

Purpose: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI.

Methods: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies.

Results: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI.

Conclusion: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.
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http://dx.doi.org/10.1038/s41436-021-01161-6DOI Listing
April 2021

Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case-Control Studies.

Cancer Epidemiol Biomarkers Prev 2021 Jun 7;30(6):1208-1217. Epub 2021 Apr 7.

INSERM, Centre for Research in Epidemiology and Population Health (CESP), 94800 Villejuif, France.

Background: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer.

Methods: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case-control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies.

Results: The OR/mGy was 1.02 (95% confidence interval, 1.00-1.03). We found significant associations between DTC and rs7164173 in CHD2 ( = 5.79 × 10), rs6067822 in NFATc2 ( = 9.26 × 10), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses ( = 3.40 × 10).

Conclusions: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk.

Impact: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1142DOI Listing
June 2021

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.

Brain 2021 Apr 1. Epub 2021 Apr 1.

Guy's and St Thomas' NHS Trust and King's College London, London, UK.

Marinesco-Sjögren syndrome (MSS) is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms that are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between MSS and the INPP5K-phenotype. We applied unbiased proteomic profiling on cells derived from MSS- and INPP5K-patients and identified alterations in D-3-phosphoglycerate dehydrogenase as a common molecular feature. D-3-phosphoglycerate dehydrogenase modulates the production of L-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with MSS and INPP5K-disease. As, L-serine administration represents a promising therapeutic strategy for D-3-phosphoglycerate dehydrogenase patients, we tested the effect of L-serine in generated sil1, phgdh and inpp5k a + b zebrafish models which showed an improvement in their neuronal phenotype. Thus our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.
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http://dx.doi.org/10.1093/brain/awab133DOI Listing
April 2021

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Oncotarget 2021 Mar 2;12(5):493-506. Epub 2021 Mar 2.

University Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Exposome and Heredity Team, Villejuif, France.

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in . This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, = 1.9 x 10). It is also associated with expression of and of the nearby gene in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, = 7.6 x 10) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, = 0.001). These SNPs are linked to the expression of in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.
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http://dx.doi.org/10.18632/oncotarget.27888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939525PMC
March 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 05;42(20):2000-2011

Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139853PMC
May 2021

The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD.

Biomedicines 2021 Feb 20;9(2). Epub 2021 Feb 20.

SU, INSERM UMRS974, AIM, Center of Research in Myology, Pitié-Salpêtrière Hospital, 75013 Paris, France.

In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of gene mutations are represented by deletions, and 63% of patients carrying deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion.
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http://dx.doi.org/10.3390/biomedicines9020219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924625PMC
February 2021

Whole exome sequencing, a hypothesis-free approach to investigate recurrent early miscarriage.

Reprod Biomed Online 2021 Apr 19;42(4):789-798. Epub 2021 Jan 19.

Université de Brest, EA 3878 (GETBO) Brest 29609, France. Electronic address:

Research Question: Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)?

Design: Thirty REM cases and 30 controls were selected with extreme phenotype among women from Eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live births, respectively. Peripheral blood was collected for DNA extraction at initial visit. The burden of low-frequency variants in the coding part of the genes was compared using whole exome sequencing (WES).

Results: Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and no miscarriages. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P = 0.68). The top five most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2 ± 32.1 versus 92.9 ± 34.3 pmol/l, respectively, P = 0.186). Five cases but no controls were below 50 pmol/l (P = 0.052).

Conclusions: This study highlights four new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). The study also confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.
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http://dx.doi.org/10.1016/j.rbmo.2021.01.008DOI Listing
April 2021

Hypersociability associated with developmental delay, macrocephaly and facial dysmorphism points to CHD3 mutations.

Eur J Med Genet 2021 Apr 9;64(4):104166. Epub 2021 Feb 9.

Normandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and reference center for developmental disorders, FHU G4 Génomique, F-76000 Rouen, France. Electronic address:

CHD3-related syndrome, also known as Snijders Blok-Campeau syndrome, is a rare developmental disorder described in 2018, caused by de novo pathogenic variants in the CHD3 gene. This syndrome is characterized by global developmental delay, speech delay, intellectual disability, hypotonia and behavioral disorders including autism spectrum disorder (ASD). Typical dysmorphic features include macrocephaly, hypertelorism, enophthalmia, sparse eyebrows, bulging forehead, midface hypoplasia, prominent nose and pointed chin. To our knowledge, there have been no other clinical descriptions of patients since the initial publication. We report the clinical description of a 21-year-old patient harboring a pathogenic de novo variant in CHD3. We reviewed the clinical features of the 35 previously reported patients. Main features were severe intellectual disability, dysmorphic facies, macrocephaly, cryptorchidism, pectus carinatum, severe ophthalmologic abnormalities and behavioral disorders including ASD, and a frank happy demeanor. Hypersociability, which was a noticeable clinical feature in our case, despite ASD, is an uncommon behavioral feature in syndromic intellectual disabilities. Our report supports hypersociability as a suggestive feature of CHD3-related syndrome along with developmental delay, macrocephaly and a dysmorphic facies.
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http://dx.doi.org/10.1016/j.ejmg.2021.104166DOI Listing
April 2021

Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma.

Hum Mol Genet 2021 Apr;30(5):343-355

Section of Genetics, International Agency for Research on Cancer (IARC-WHO), 69372 Lyon, France.

Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained 2-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.
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http://dx.doi.org/10.1093/hmg/ddab031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098110PMC
April 2021

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation.

Blood 2021 Apr;137(17):2394-2402

Aix Marseille University, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), Centre de Recherche en CardioVasculaire et Nutrition, Marseille, France.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.
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http://dx.doi.org/10.1182/blood.2020008997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085481PMC
April 2021

Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data.

JNCI Cancer Spectr 2020 Oct 11;4(5):pkaa039. Epub 2020 May 11.

Gustave Roussy, INSERM Unit 981, Villejuif, France.

Background: We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data.

Methods: We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic ( < .001) variables, a multivariable preconditioned random-forest regression model was built and validated on a hold-out subset to predict fatigue. Gene set enrichment analysis identified key biological correlates (MetaCore). All statistical tests were 2-sided.

Results: Statistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association ( < .001) with the different fatigue endpoints, although there were no genome-wide statistically significant ( < 5.00 × 10) associations. Only for Cognitive Fatigue, the predictive ability of the genomic multivariable model was statistically significantly better than random (area under the curve = 0.59,  = .01) and marginally improved with clinical variables (area under the curve = 0.60,  = .005). Single nucleotide polymorphisms found to be associated ( < .001) with Cognitive Fatigue belonged to genes linked to inflammation (false discovery rate adjusted  = .03), cognitive disorders ( = 1.51 × 10), and synaptic transmission ( = 6.28 × 10).

Conclusions: Genomic analyses in this large cohort of breast cancer survivors suggest a possible genetic role for severe Cognitive Fatigue that warrants further exploration.
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http://dx.doi.org/10.1093/jncics/pkaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583150PMC
October 2020

Feasibility of high-throughput sequencing in clinical routine cancer care: lessons from the cancer pilot project of the France Genomic Medicine 2025 plan.

ESMO Open 2020 07;5(4)

U1147, Centre universitaire des Saint-Pères, Institut national de la santé et de la recherche médicale, Paris, France.

Background: Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame-that is, compatible with the clinical pathway-is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli).

Methods: Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonié's Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified.

Results: Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days.

Conclusion: Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms.
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http://dx.doi.org/10.1136/esmoopen-2020-000744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383956PMC
July 2020

Exome sequencing in 57 patients with self-limited focal epilepsies of childhood with typical or atypical presentations suggests novel candidate genes.

Eur J Paediatr Neurol 2020 Jul 29;27:104-110. Epub 2020 May 29.

Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon, Lyon, France; Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Lyon, France; Université de Lyon - Université Claude Bernard Lyon 1, Lyon, France. Electronic address:

Objective: Self-limited focal epilepsies of childhood (SFEC) are amongst the best defined and most frequent epilepsy syndromes affecting children with usually normal developmental milestones. They include core syndromes such as Rolandic epilepsy or "Benign" epilepsy with Centro-Temporal Spikes and the benign occipital epilepsies, the early onset Panayiotopoulos syndrome and the late-onset Gastaut type. Atypical forms exist for all of them. Atypical Rolandic epilepsies are conceptualized as belonging to a continuum reaching from the "benign" RE to the severe end of the Landau-Kleffner (LKS) and Continuous Spike-Waves during Sleep syndromes (CSWS). GRIN2A has been shown to cause the epilepsy-aphasia continuum that includes some patients with atypical Rolandic epilepsy with frequent speech disorders, LKS and CSWS. In the present study, we searched novel genes causing SFEC with typical or atypical presentations.

Methods: Exome sequencing was performed in 57 trios. Patients presented with typical or atypical SFEC, negative for GRIN2A pathogenic variant.

Results: We found rare candidate variants in 20 patients. Thirteen had occurred de novo and were mostly associated to atypical Rolandic Epilepsy. Two of them could be considered as disease related: a null variant in GRIN2B and a missense variant in CAMK2A. Others were considered good candidates, including a substitution affecting a splice site in CACNG2 and missense variants in genes encoding enzymes involved in chromatin remodeling.

Significance: Our results further illustrate the fact that atypical SFEC are more likely to have Mendelian inheritance than typical SFEC.
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http://dx.doi.org/10.1016/j.ejpn.2020.05.003DOI Listing
July 2020

Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation.

Eur J Hum Genet 2021 Jan 26;29(1):99-109. Epub 2020 Jun 26.

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

The detection of copy-number variations (CNVs) from NGS data is underexploited as chip-based or targeted techniques are still commonly used. We assessed the performances of a workflow centered on CANOES, a bioinformatics tool based on read depth information. We applied our workflow to gene panel (GP) and whole-exome sequencing (WES) data, and compared CNV calls to quantitative multiplex PCR of short fluorescent fragments (QMSPF) or array comparative genomic hybridization (aCGH) results. From GP data of 3776 samples, we reached an overall positive predictive value (PPV) of 87.8%. This dataset included a complete comprehensive QMPSF comparison of four genes (60 exons) on which we obtained 100% sensitivity and specificity. From WES data, we first compared 137 samples with aCGH and filtered comparable events (exonic CNVs encompassing enough aCGH probes) and obtained an 87.25% sensitivity. The overall PPV was 86.4% following the targeted confirmation of candidate CNVs from 1056 additional WES. In addition, our CANOES-centered workflow on WES data allowed the detection of CNVs with a resolution of single exons, allowing the detection of CNVs that were missed by aCGH. Overall, switching to an NGS-only approach should be cost-effective as it allows a reduction in overall costs together with likely stable diagnostic yields. Our bioinformatics pipeline is available at: https://gitlab.bioinfo-diag.fr/nc4gpm/canoes-centered-workflow .
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http://dx.doi.org/10.1038/s41431-020-0672-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852510PMC
January 2021

Haploinsufficiency of the Primary Familial Brain Calcification Gene SLC20A2 Mediated by Disruption of a Regulatory Element.

Mov Disord 2020 08 7;35(8):1336-1345. Epub 2020 Jun 7.

Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.

Objective: Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Five genes were reported as PFBC causative when carrying pathogenic variants. Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC. However, PFBC remains genetically unexplained in a proportion of patients, suggesting the existence of additional genes or cryptic mutations. We analyzed exome sequencing data of 71 unrelated, genetically unexplained PFBC patients with the aim to detect copy number variations that may disrupt the expression of core PFBC-causing genes.

Methods: After the identification of a deletion upstream of SLC20A2, we assessed its consequences on gene function by reverse transcriptase droplet digital polymerase chain reaction (RT-ddPCR), an ex vivo inorganic phosphate uptake assay, and introduced the deletion of a putative SLC20A2 enhancer mapping to this region in human embryonic kidney 293 (HEK293) cells by clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9).

Results: The 8p11.21 deletion, segregating with PFBC in a family, mapped 35 kb upstream of SLC20A2. The deletion carriers/normal controls ratio of relative SLC20A2 mRNA levels was 60.2% (P < 0.001). This was comparable with that of patients carrying an SLC20A2 premature stop codon (63.4%; P < 0.001). The proband exhibited a 39.3% decrease of inorganic phosphate uptake in blood (P = 0.015). In HEK293 cells, we observed a 39.8% decrease in relative SLC20A2 mRNA levels after normalization on DNA copy number (P < 0.001).

Discussion: We identified a deletion of an enhancer of SLC20A2 expression, with carriers showing haploinsufficiency in similar ranges to loss-of-function alleles, and we observed reduced mRNA levels after deleting this element in a cellular model. We propose a 3-step strategy to identify and easily assess the effect of such events. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28090DOI Listing
August 2020

Circadian genes polymorphisms, night work and prostate cancer risk: Findings from the EPICAP study.

Int J Cancer 2020 12 20;147(11):3119-3129. Epub 2020 Jul 20.

Université Paris-Saclay, UVSQ, Inserm, CESP, Villejuif, France.

Over the past two decades, several studies have attempted to understand the hypothesis that disrupting the circadian rhythm may promote the development of cancer. Some have suggested that night work and some circadian genes polymorphisms are associated with cancer, including prostate cancer. Our study aims to test the hypothesis that prostate cancer risk among night workers may be modulated by genetic polymorphisms in the circadian pathway genes based on data from the EPICAP study, a population-based case-control study including 1511 men (732 cases/779 controls) with genotyped data. We estimated odds ratio (ORs) and P values of the association between prostate cancer and circadian gene variants using logistic regression models. We tested the interaction between circadian genes variants and night work indicators that were significantly associated with prostate cancer at pathway, gene and SNP levels. Analyses were also stratified by each of these night work indicators and by cancer aggressiveness. The circadian pathway was significantly associated with aggressive prostate cancer among night workers (P = .004), particularly for men who worked at night for <20 years (P = .0002) and those who performed long night shift (>10 hours, P = .001). At the gene level, we observed among night workers significant associations between aggressive prostate cancer and ARNTL, NPAS2 and RORA. At the SNP-level, no significant association was observed. Our findings provide some clues of a potential modulating effect of circadian genes in the relationship between night work and prostate cancer. Further investigation is warranted to confirm these findings and to better elucidate the biological pathways involved.
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http://dx.doi.org/10.1002/ijc.33139DOI Listing
December 2020

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress.

EMBO Mol Med 2020 07 5;12(7):e11861. Epub 2020 Jun 5.

Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France.

The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.
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http://dx.doi.org/10.15252/emmm.201911861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338805PMC
July 2020

Papuan mitochondrial genomes and the settlement of Sahul.

J Hum Genet 2020 Oct 1;65(10):875-887. Epub 2020 Jun 1.

Laboratoire Évolution and Diversité Biologique (EDB UMR 5174), Université de Toulouse Midi-Pyrénées, CNRS, IRD, UPS, 118 route de Narbonne, Bat 4R1, 31062, Toulouse, France.

New Guineans represent one of the oldest locally continuous populations outside Africa, harboring among the greatest linguistic and genetic diversity on the planet. Archeological and genetic evidence suggest that their ancestors reached Sahul (present day New Guinea and Australia) by at least 55,000 years ago (kya). However, little is known about this early settlement phase or subsequent dispersal and population structuring over the subsequent period of time. Here we report 379 complete Papuan mitochondrial genomes from across Papua New Guinea, which allow us to reconstruct the phylogenetic and phylogeographic history of northern Sahul. Our results support the arrival of two groups of settlers in Sahul within the same broad time window (50-65 kya), each carrying a different set of maternal lineages and settling Northern and Southern Sahul separately. Strong geographic structure in northern Sahul remains visible today, indicating limited dispersal over time despite major climatic, cultural, and historical changes. However, following a period of isolation lasting nearly 20 ky after initial settlement, environmental changes postdating the Last Glacial Maximum stimulated diversification of mtDNA lineages and greater interactions within and beyond Northern Sahul, to Southern Sahul, Wallacea and beyond. Later, in the Holocene, populations from New Guinea, in contrast to those of Australia, participated in early interactions with incoming Asian populations from Island Southeast Asia and continuing into Oceania.
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http://dx.doi.org/10.1038/s10038-020-0781-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449881PMC
October 2020

Genotyping on blood and buccal cells using loop-mediated isothermal amplification in healthy humans.

Biotechnol Rep (Amst) 2020 Jun 13;26:e00468. Epub 2020 May 13.

Institut de Recherche Biomédicale des Armées (IRBA), Brétigny sur Orge, France.

Genetic variations contribute to phenotypic individual vulnerabilities to sleep debt, particularly for five single nucleotide polymorphisms (SNPs). Loop-mediated isothermal amplification and melting curve analysis (LAMP-MC) is a recently developed method to characterize SNPs. The aim of present study was to evaluate the LAMP-MC method on blood and buccal cells for detection of five SNPs of interest in healthy humans. We first analyzed signals obtained from LAMP-MC method on 42 samples. Then we compared the results with those of referent TaqMan method. The LAMP-MC method produced specific melting curves for the five SNPs. A high concordance of genotyping results was observed between the two methods for rs5751876_ADORA2A, rs1800629_TNF-α, rs73598374_ADA and rs228697_PER3 in blood and saliva (Cohen's kappa coefficient >0.80). A good agreement ( = 0.61) was observed for rs4680_COMT in blood only. LAMP-MC is a simple and reliable method to study genetic influences on health, sleep debt-related performance impairments and countermeasures.
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http://dx.doi.org/10.1016/j.btre.2020.e00468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240324PMC
June 2020

A novel rare c.-39C>T mutation in the PROS1 5'UTR causing PS deficiency by creating a new upstream translation initiation codon.

Clin Sci (Lond) 2020 05;134(10):1181-1190

INSERM UMR 1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.

Autosomal dominant inherited Protein S deficiency (PSD) (MIM 612336) is a rare disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with seven PSD affected members in whom no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via an multiplex ligation-dependent probe amplification (MLPA) approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG→ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated in HeLa cells that the variant generates a novel overlapping upstream open reading frame (uORF) and inhibits the translation of the wild-type PS. This work describes the first example of 5'UTR PROS1 mutation causing PSD through the creation of an uORF, a mutation that is not predicted to be deleterious by standard annotation softwares, and emphasizes the need for better exploration of such type of non-coding variations in clinical genomics.
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http://dx.doi.org/10.1042/CS20200403DOI Listing
May 2020

Family-based genome-wide association study of leprosy in Vietnam.

PLoS Pathog 2020 05 18;16(5):e1008565. Epub 2020 May 18.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.

Leprosy is a chronic infectious disease of the skin and peripheral nerves with a strong genetic predisposition. Recent genome-wide approaches have identified numerous common variants associated with leprosy, almost all in the Chinese population. We conducted the first family-based genome-wide association study of leprosy in 622 affected offspring from Vietnam, followed by replication in an independent sample of 1181 leprosy cases and 668 controls of the same ethnic origin. The most significant results were observed within the HLA region, in which six SNPs displayed genome-wide significant associations, all of which were replicated in the independent case/control sample. We investigated the signal in the HLA region in more detail, by conducting a multivariate analysis on the case/control sample of 319 GWAS-suggestive HLA hits for which evidence for replication was obtained. We identified three independently associated SNPs, two located in the HLA class I region (rs1265048: OR = 0.69 [0.58-0.80], combined p-value = 5.53x10-11; and rs114598080: OR = 1.47 [1.46-1.48], combined p-value = 8.77x10-13), and one located in the HLA class II region (rs3187964 (OR = 1.67 [1.55-1.80], combined p-value = 8.35x10-16). We also validated two previously identified risk factors for leprosy: the missense variant rs3764147 in the LACC1 gene (OR = 1.52 [1.41-1.63], combined p-value = 5.06x10-14), and the intergenic variant rs6871626 located close to the IL12B gene (OR = 0.73 [0.61-0.84], combined p-value = 6.44x10-8). These results shed new light on the genetic control of leprosy, by dissecting the influence of HLA SNPs, and validating the independent role of two additional variants in a large Vietnamese sample.
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http://dx.doi.org/10.1371/journal.ppat.1008565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259797PMC
May 2020

Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.

J Med Genet 2020 07 10;57(7):466-474. Epub 2020 Apr 10.

Centre de Compétence Anomalies du Développement et Syndromes Malformatifs Sud-Est, CHI de Toulon - La Seyne-sur-Mer, France.

Purpose: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects.

Methods: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.

Results: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals ( and ). Using simulation models, we showed that five genes ( and ) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including and , which are known to be mutated in overgrowth syndromes.

Conclusion: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10) and genes regulated by the fragile X mental retardation protein (p=3×10), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
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http://dx.doi.org/10.1136/jmedgenet-2019-106425DOI Listing
July 2020

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

Acta Neuropathol 2020 06 12;139(6):1025-1044. Epub 2020 Mar 12.

Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau, total tau, and Aβ was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.
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http://dx.doi.org/10.1007/s00401-020-02138-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244617PMC
June 2020

Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.

Transl Psychiatry 2020 02 24;10(1):77. Epub 2020 Feb 24.

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component whose knowledge evolves quickly. Next-generation sequencing is the only effective technology to deal with the high genetic heterogeneity of ASD in a clinical setting. However, rigorous criteria to classify rare genetic variants conferring ASD susceptibility are currently lacking. We have performed whole-exome sequencing to identify both nucleotide variants and copy number variants (CNVs) in 253 ASD patients, including 68 patients with intellectual disability (ID) and 90 diagnosed as Asperger syndrome. Using explicit criteria to classify both susceptibility genes and susceptibility variants we prioritized 217 genes belonging to the following categories: syndromic genes, genes with an excess of de novo protein truncating variants and genes targeted by rare CNVs. We obtained a susceptibility variant detection rate of 19.7% (95% CI: [15-25.2%]). The rate for CNVs was 7.1% (95% CI: [4.3-11%]) and 12.6% (95% CI: [8.8-17.4%]) for nucleotide variants. The highest rate (30.1%, 95% CI: [20.2-43.2%]) was obtained in the ASD + ID subgroup. A strong contributor for at risk nucleotide variants was the recently identified set of genes (n = 81) harboring an excess of de novo protein truncating variants. Since there is currently no evidence that the genes targeted here are necessary and sufficient to cause ASD, we recommend to avoid the term "causative of ASD" when delivering the information about a variant to a family and to use instead the term "genetic susceptibility factor contributing to ASD".
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http://dx.doi.org/10.1038/s41398-020-0760-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039996PMC
February 2020

Genome sequencing in cytogenetics: Comparison of short-read and linked-read approaches for germline structural variant detection and characterization.

Mol Genet Genomic Med 2020 03 27;8(3):e1114. Epub 2020 Jan 27.

Centre National de Recherche en Génomique Humaine (CNRGH), CEA, Evry, France.

Background: Structural variants (SVs) include copy number variants (CNVs) and apparently balanced chromosomal rearrangements (ABCRs). Genome sequencing (GS) enables SV detection at base-pair resolution, but the use of short-read sequencing is limited by repetitive sequences, and long-read approaches are not yet validated for diagnosis. Recently, 10X Genomics proposed Chromium, a technology providing linked-reads to reconstruct long DNA fragments and which could represent a good alternative. No study has compared short-read to linked-read technologies to detect SVs in a constitutional diagnostic setting yet. The aim of this work was to determine whether the 10X Genomics technology enables better detection and comprehension of SVs than short-read WGS.

Methods: We included 13 patients carrying various SVs. Whole genome analyses were performed using paired-end HiSeq X sequencing with (linked-read strategy) or without (short-read strategy) Chromium library preparation. Two different bioinformatic pipelines were used: Variants are called using BreakDancer for short-read strategy and LongRanger for long-read strategy. Variant interpretations were first blinded.

Results: The short-read strategy allowed diagnosis of known SV in 10/13 patients. After unblinding, the linked-read strategy identified 10/13 SVs, including one (patient 7) missed by the short-read strategy.

Conclusion: In conclusion, regarding the results of this study, 10X Genomics solution did not improve the detection and characterization of SV.
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http://dx.doi.org/10.1002/mgg3.1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057128PMC
March 2020

High degree of polyclonality hinders somatic mutation calling in lung brush samples of COPD cases and controls.

Sci Rep 2019 12 27;9(1):20158. Epub 2019 Dec 27.

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n = 8), as well as from ex-smokers with variable degrees of COPD (n = 4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data. However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls. High polyclonality in airway brush samples renders medium-depth sequencing insufficient to provide the resolution to detect somatic mutations. Deep sequencing data of airway biopsies are needed to tackle the question.
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http://dx.doi.org/10.1038/s41598-019-56618-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934450PMC
December 2019

The Impact of Genetic Variations in ADORA2A in the Association between Caffeine Consumption and Sleep.

Genes (Basel) 2019 12 6;10(12). Epub 2019 Dec 6.

Unité Fatigue et Vigilance, Institut de recherche biomédicale des armées (IRBA), EA 7330 VIFASOM, Université de Paris, Paris, France.

ADORA2A has been shown to be responsible for the wakefulness-promoting effect of caffeine and the 1976T>C genotype (SNP rs5751876, formerly 1083T>C) to contribute to individual sensitivity to caffeine effects on sleep. We investigate the association between six single nucleotide polymorphisms (SNP) from ADORA2A and self-reported sleep characteristics and caffeine consumption in 1023 active workers of European ancestry aged 18-60 years. Three groups of caffeine consumers were delineated: low (0-50 mg/day, less than one expresso per day), moderate (51-300 mg/day), and high (>300 mg/day). We found that at caffeine levels higher than 300 mg/day, total sleep time (TST) decreased ( = 13.9, < 0.01), with an increase of insomnia (ORa [95%CI] = 1.5 [1.1-1.9]) and sleep complaints (ORa [95%CI] = 1.9 [1.1-3.3]), whatever the ADORA2A polymorphism. Odds ratios were adjusted (ORa) for sex, age, and tobacco. However, in low caffeine consumers, lower TST was observed in the T allele compared to homozygote rs5751876 and rs3761422 C carriers. Conversely, higher TST was observed in rs2298383 T allele compared to C and in rs4822492G allele compared to the homozygote C ( < 0.05). These 4 SNPs are in strong linkage disequilibrium. Haplotype analysis confirmed the influence of multiple ADORA2a SNPs on TST. In addition, the rs2298383 T and rs4822492 G alleles were associated with higher risk of sleep complaints (Ora = 1.9 [1.2-3.1] and Ora = 1.5 [1.1-2.1]) and insomnia (Ora = 1.5 [1.3-2.5] and Ora = 1.9 [1.3-3.2). The rs5751876 T allele was associated with a decreased risk of sleep complaints (Ora = 0.7 [0.3-0.9]) and insomnia (Ora = 0.5 [0.3-0.9]). Our results identified ADORA2A polymorphism influences in the less-than-300-mg-per-day caffeine consumers. This opens perspectives on the diagnosis and pharmacology of sleep complaints and caffeine chronic consumption.
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http://dx.doi.org/10.3390/genes10121021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947650PMC
December 2019