Publications by authors named "Jean-François Deleuze"

248 Publications

Gene network and biological pathways associated with susceptibility to differentiated thyroid carcinoma.

Sci Rep 2021 Apr 26;11(1):8932. Epub 2021 Apr 26.

Inserm, U900, Institut Curie, PSL University, Mines ParisTech, 75248, Paris, France.

Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.
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http://dx.doi.org/10.1038/s41598-021-88253-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076215PMC
April 2021

Integrated genomic analysis identifies driver genes and cisplatin-resistant progenitor phenotype in pediatric liver cancer.

Cancer Discov 2021 Apr 23. Epub 2021 Apr 23.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris

Pediatric liver cancers (PLCs) comprise diverse diseases affecting infants, children and adolescents. Despite overall good prognosis, PLCs display heterogeneous response to chemotherapy. Integrated genomic analysis of 126 pediatric liver tumors showed a continuum of driver mechanisms associated with patient age, including new targetable oncogenes. In 10% of hepatoblastoma patients, all before 3 years old, we identified a mosaic premalignant clonal expansion of cells altered at the 11p15.5 locus. Analysis of spatial and longitudinal heterogeneity revealed an important plasticity between 'Hepatocytic', 'Liver Progenitor' and 'Mesenchymal' molecular subgroups of hepatoblastoma. We showed that during chemotherapy, 'Liver Progenitor' cells accumulated massive loads of cisplatin-induced mutations with a specific mutational signature, leading to the development of heavily mutated relapses and metastases. Drug screening in PLC cell lines identified promising targets for cisplatin-resistant progenitor cells, validated in mouse xenograft experiments. These data provide new insights into cisplatin resistance mechanisms in PLC and suggest alternative therapies.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1809DOI Listing
April 2021

Region-specific expression of young small-scale duplications in the human central nervous system.

BMC Ecol Evol 2021 04 21;21(1):59. Epub 2021 Apr 21.

Centre National de Recherche en Génomique Humaine (CNRGH), Institut François Jacob, CEA, Université Paris-Saclay, Evry, France.

Background: The duplication of genes is one of the main genetic mechanisms that led to the gain in complexity of biological tissue. Although the implication of duplicated gene expression in brain evolution was extensively studied through comparisons between organs, their role in the regional specialization of the adult human central nervous system has not yet been well described.

Results: Our work explored intra-organ expression properties of paralogs through multiple territories of the human central nervous system (CNS) using transcriptome data generated by the Genotype-Tissue Expression (GTEx) consortium. Interestingly, we found that paralogs were associated with region-specific expression in CNS, suggesting their involvement in the differentiation of these territories. Beside the influence of gene expression level on region-specificity, we observed the contribution of both duplication age and duplication type to the CNS region-specificity of paralogs. Indeed, we found that small scale duplicated genes (SSDs) and in particular ySSDs (SSDs younger than the 2 rounds of whole genome duplications) were more CNS region-specific than other paralogs. Next, by studying the two paralogs of ySSD pairs, we observed that when they were region-specific, they tend to be specific to the same region more often than for other paralogs, showing the high co-expression of ySSD pairs. The extension of this analysis to families of paralogs showed that the families with co-expressed gene members (i.e. homogeneous families) were enriched in ySSDs. Furthermore, these homogeneous families tended to be region-specific families, where the majority of their gene members were specifically expressed in the same region.

Conclusions: Overall, our study suggests the involvement of ySSDs in the differentiation of human central nervous system territories. Therefore, we show the relevance of exploring region-specific expression of paralogs at the intra-organ level.
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http://dx.doi.org/10.1186/s12862-021-01794-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059171PMC
April 2021

A form of muscular dystrophy associated with pathogenic variants in JAG2.

Am J Hum Genet 2021 May 15;108(5):840-856. Epub 2021 Apr 15.

Centre de Référence Neuromusculaire and Paediatric Neurology Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1020 Brussels, Belgium.

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.020DOI 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 Apr 7. 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
April 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

Impact of pre- and post-variant filtration strategies on imputation.

Sci Rep 2021 Mar 18;11(1):6214. Epub 2021 Mar 18.

CEA Paris-Saclay, Institut François Jacob, Centre National de Recherche en Génomique Humaine, 2 rue Gaston Crémieux, Evry, 91057, France.

Quality control (QC) methods for genome-wide association studies and fine mapping are commonly used for imputation, however they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1089 NCBI recorded individuals for additional validation. Without QC-based variant pre-filtration, we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E-04-1E-03) and rare variants (1E-03-5E-03) (p < 1E-04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs) < 0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E-04). Thus, to maintain confidence and enough SNVs, we propose here a two-step filtering procedure which allows less stringent filtering prior to imputation and post-imputation in order to increase the number of very rare and rare variants compared to conservative filtration methods.
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http://dx.doi.org/10.1038/s41598-021-85333-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973508PMC
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 Mar 3. Epub 2021 Mar 3.

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 27% 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
March 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

Genome-wide haplotype association study in imaging genetics using whole-brain sulcal openings of 16,304 UK Biobank subjects.

Eur J Hum Genet 2021 Mar 4. Epub 2021 Mar 4.

Université Paris-Saclay, CEA, Neurospin, Gif-sur-Yvette, France.

Neuroimaging-genetics cohorts gather two types of data: brain imaging and genetic data. They allow the discovery of associations between genetic variants and brain imaging features. They are invaluable resources to study the influence of genetics and environment in the brain features variance observed in normal and pathological populations. This study presents a genome-wide haplotype analysis for 123 brain sulcus opening value (a measure of sulcal width) across the whole brain that include 16,304 subjects from UK Biobank. Using genetic maps, we defined 119,548 blocks of low recombination rate distributed along the 22 autosomal chromosomes and analyzed 1,051,316 haplotypes. To test associations between haplotypes and complex traits, we designed three statistical approaches. Two of them use a model that includes all the haplotypes for a single block, while the last approach considers each haplotype independently. All the statistics produced were assessed as rigorously as possible. Thanks to the rich imaging dataset at hand, we used resampling techniques to assess False Positive Rate for each statistical approach in a genome-wide and brain-wide context. The results on real data show that genome-wide haplotype analyses are more sensitive than single-SNP approach and account for local complex Linkage Disequilibrium (LD) structure, which makes genome-wide haplotype analysis an interesting and statistically sound alternative to the single-SNP counterpart.
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http://dx.doi.org/10.1038/s41431-021-00827-8DOI Listing
March 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

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Int J Cancer 2021 Jun 24;148(12):2935-2946. Epub 2021 Feb 24.

Inserm, U1078, GGB, Université de Bretagne Occidentale, EFS, Brest, France.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.
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http://dx.doi.org/10.1002/ijc.33488DOI Listing
June 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

Exome-Wide Association Study Identifies FN3KRP and PGP as New Candidate Longevity Genes.

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):786-795

Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Germany.

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).
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http://dx.doi.org/10.1093/gerona/glab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087267PMC
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

DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes.

Eur J Endocrinol 2021 Mar;184(3):455-468

ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.

Objective: DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome.

Methods: Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined.

Results: The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA.

Conclusions: This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.
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http://dx.doi.org/10.1530/EJE-20-0636DOI Listing
March 2021

Identification of biological pathways specific to phases preceding rheumatoid arthritis development through gene expression profiling.

Int J Immunogenet 2021 Jun 22;48(3):239-249. Epub 2021 Jan 22.

Laboratoire Européen de Recherche pour la Polyarthrite rhumatoïde - Genhotel, Université Paris-Saclay, Univ Evry, Evry, France.

The etiopathogenesis of rheumatoid arthritis is partially understood; however, it is believed to result from a multi-step process. The immune onset followed by pre-clinical phases will eventually lead to the development of symptomatic disease. We aim at identifying differentially expressed genes in order to highlight pathways involved in the pre-clinical stages of rheumatoid arthritis development. The study population consisted of first-degree relatives of patients with rheumatoid arthritis, known to have an increased risk of developing disease as compared to the general population. Whole transcriptome analysis was performed in four groups: asymptomatic without autoantibodies or symptoms associated with possible rheumatoid arthritis (controls); having either clinically suspect arthralgias, undifferentiated arthritis or autoimmunity associated with RA (pre-clinical stages of RA: Pcs-RA); having subsequently developed classifiable RA (pre-RA); and early untreated rheumatoid arthritis patients (RA). Differentially expressed genes were determined, and enrichment analysis was performed. Functional enrichment analysis revealed 31 pathways significantly enriched in differentially expressed genes for Pcs-RA, pre-RA and RA compared to the controls. Osteoclast pathway is among the seven pathways specific for RA. In Pcs-RA and in pre-RA, several enriched pathways include TP53 gene connections, such as P53 and Wnt signalling pathways. Analysis of whole transcriptome for phenotypes related to rheumatoid arthritis allows highlighting which pathways are requested in the pre-clinical stages of disease development. After validation in replication studies, molecules belonging to some of these pathways could be used to identify new specific biomarkers for individuals with impending rheumatoid arthritis.
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http://dx.doi.org/10.1111/iji.12528DOI Listing
June 2021

Analysis and annotation of DNA methylation in two nonhuman primate species using the Infinium Human Methylation 450K and EPIC BeadChips.

Epigenomics 2021 Feb 20;13(3):169-186. Epub 2021 Jan 20.

Laboratory for Epigenetics & Environment, Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie François Jacob, Evry, France.

Nonhuman primates are essential for research on many human diseases. The Infinium Human Methylation450/EPIC BeadChips are popular tools for the study of the methylation state across the human genome at affordable cost. We performed a precise evaluation and re-annotation of the BeadChip probes for the analysis of genome-wide DNA methylation patterns in rhesus macaques and African green monkeys through analyses combined with functional validation by pyrosequencing. Up to 165,847 of the 450K and 261,545 probes of the EPIC BeadChip can be reliably used. The annotation files are provided in a format compatible with a variety of standard bioinformatic pipelines. Our study will facilitate high-throughput DNA methylation analyses in and .
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http://dx.doi.org/10.2217/epi-2020-0200DOI Listing
February 2021

Heterogeneous Hunter-Gatherer and Steppe-Related Ancestries in Late Neolithic and Bell Beaker Genomes from Present-Day France.

Curr Biol 2021 Mar;31(5):1072-1083.e10

Centre d'Anthropobiologie et de Génomique de Toulouse CAGT, CNRS UMR 5288, Université Toulouse III Paul Sabatier, Faculté de Médecine Purpan, Bâtiment A, 37 allées Jules Guesde, 31000 Toulouse, France. Electronic address:

The transition from the Late Neolithic to the Bronze Age has witnessed important population and societal changes in western Europe. These include massive genomic contributions of pastoralist herders originating from the Pontic-Caspian steppes into local populations, resulting from complex interactions between collapsing hunter-gatherers and expanding farmers of Anatolian ancestry. This transition is documented through extensive ancient genomic data from present-day Britain, Ireland, Iberia, Mediterranean islands, and Germany. It remains, however, largely overlooked in France, where most focus has been on the Middle Neolithic (n = 63), with the exception of one Late Neolithic genome sequenced at 0.05× coverage. This leaves the key transitional period covering ∼3,400-2,700 cal. years (calibrated years) BCE genetically unsampled and thus the exact time frame of hunter-gatherer persistence and arrival of steppe migrations unknown. To remediate this, we sequenced 24 ancient human genomes from France spanning ∼3,400-1,600 cal. years BCE. This reveals Late Neolithic populations that are genetically diverse and include individuals with dark skin, hair, and eyes. We detect heterogeneous hunter-gatherer ancestries within Late Neolithic communities, reaching up to ∼63.3% in some individuals, and variable genetic contributions of steppe herders in Bell Beaker populations. We provide an estimate as late as ∼3,800 years BCE for the admixture between Neolithic and Mesolithic populations and as early as ∼2,650 years BCE for the arrival of steppe-related ancestry. The genomic heterogeneity characterized underlines the complex history of human interactions even at the local scale.
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http://dx.doi.org/10.1016/j.cub.2020.12.015DOI Listing
March 2021

Selective loss of a LAP1 isoform causes a muscle-specific nuclear envelopathy.

Neurogenetics 2021 03 6;22(1):33-41. Epub 2021 Jan 6.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Strasbourg University, Illkirch, France.

The nuclear envelope (NE) separates the nucleus from the cytoplasm in all eukaryotic cells. A disruption of the NE structure compromises normal gene regulation and leads to severe human disorders collectively classified as nuclear envelopathies and affecting skeletal muscle, heart, brain, skin, and bones. The ubiquitous NE component LAP1B is encoded by TOR1AIP1, and the use of an alternative start codon gives rise to the shorter LAP1C isoform. TOR1AIP1 mutations have been identified in patients with diverging clinical presentations such as muscular dystrophy, progressive dystonia with cerebellar atrophy, and a severe multi-systemic disorder, but the correlation between the mutational effect and the clinical spectrum remains to be determined. Here, we describe a novel TOR1AIP1 patient manifesting childhood-onset muscle weakness and contractures, and we provide clinical, histological, ultrastructural, and genetic data. We demonstrate that the identified TOR1AIP1 frameshift mutation leads to the selective loss of the LAP1B isoform, while the expression of LAP1C was preserved. Through comparative review of all previously reported TOR1AIP1 cases, we delineate a genotype/phenotype correlation and conclude that LAP1B-specific mutations cause a progressive skeletal muscle phenotype, while mutations involving a loss of both LAP1B and LAP1C isoforms induce a syndromic disorder affecting skeletal muscle, brain, eyes, ear, skin, and bones.
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http://dx.doi.org/10.1007/s10048-020-00632-3DOI Listing
March 2021

Exploring the Link Between Additive Heritability and Prediction Accuracy From a Ridge Regression Perspective.

Front Genet 2020 4;11:581594. Epub 2020 Nov 4.

CNRGH, Institut Jacob, CEA - Université Paris-Saclay, Évry, France.

Genome-Wide Association Studies (GWAS) explain only a small fraction of heritability for most complex human phenotypes. Genomic heritability estimates the variance explained by the SNPs on the whole genome using mixed models and accounts for the many small contributions of SNPs in the explanation of a phenotype. This paper approaches heritability from a machine learning perspective, and examines the close link between mixed models and ridge regression. Our contribution is two-fold. First, we propose estimating genomic heritability using a predictive approach via ridge regression and Generalized Cross Validation (GCV). We show that this is consistent with classical mixed model based estimation. Second, we derive simple formulae that express prediction accuracy as a function of the ratio , where is the population size and the total number of SNPs. These formulae clearly show that a high heritability does not imply an accurate prediction when > . Both the estimation of heritability via GCV and the prediction accuracy formulae are validated using simulated data and real data from UK Biobank.
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http://dx.doi.org/10.3389/fgene.2020.581594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672157PMC
November 2020

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.

Nat Genet 2020 12 23;52(12):1364-1372. Epub 2020 Nov 23.

Genomic and Post-Genomic Center, Istituto di Ricovero e Cura a Carattere Scientifico, Mondino Foundation, Pavia, Italy.

Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
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http://dx.doi.org/10.1038/s41588-020-00737-3DOI Listing
December 2020

Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia.

Arterioscler Thromb Vasc Biol 2021 01 19;41(1):e63-e71. Epub 2020 Nov 19.

Hospices Civils de Lyon, UF Dyslipidémies Service de Biochimie et de Biologie Moléculaire Grand Est, Bron, France (X.V., D.C., O.M., E.D., M.D.F.).

Objective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the (apolipoprotein B) and genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, <0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia.

Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.
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http://dx.doi.org/10.1161/ATVBAHA.120.315491DOI Listing
January 2021

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome.

Clin Genet 2021 Feb 14;99(2):318-324. Epub 2020 Nov 14.

Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France.

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
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http://dx.doi.org/10.1111/cge.13878DOI Listing
February 2021