Yannis Duffourd

Université de Bourgogne

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Laurence Faivre

Université de Bourgogne

Antonio Vitobello

Université de Bourgogne

Christophe Philippe

Université de Bourgogne

Christel Thauvin‐Robinet

Centre Hospitalier Universitaire Dijon Bourgogne

Frédéric Tran Mau‐Them

Université de Bourgogne

Julien Thévenon

Université Grenoble Alpes

Ange‐Line Bruel

Inserm

Sophie Nambot

Inserm

Arthur Sorlin

Laboratoire National de Santé

Martin Chevarin

Université de Bourgogne

Cooperative Institutions

Inserm

458

Université de Bourgogne

204

Centre Hospitalier Universitaire Dijon Bourgogne

201

Centre National de la Recherche Scientifique

182

Assistance Publique – Hôpitaux de Paris

148

Université Paris Cité

129

National Center on Birth Defects and Developmental Disabilities

124

Maison des Sciences de l’Homme de Dijon

112

Université Bourgogne Franche-Comté

110

Hôpital d'Enfants

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SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

The American Journal of Human Genetics (2023)

Elke Bogaert Aurore Garde Thierry Gautier Kathleen Rooney Yannis Duffourd

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.

Haploinsufficiency

Exonic splicing enhancer

Loss function

10.1016/j.ajhg.2023.03.016

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Citations (17)

Interest of exome sequencing trio‐like strategy based on pooled parental DNA for diagnosis and translational research in rare diseases

Molecular Genetics & Genomic Medicine (2021)

Frédéric Tran Mau‐Them Yannis Duffourd Antonio Vitobello Ange‐Line Bruel Anne‐Sophie Denommé‐Pichon

Exome sequencing (ES) has become the most powerful and cost-effective molecular tool for deciphering rare diseases with a diagnostic yield approaching 30%-40% in solo-ES and 50% in trio-ES. We applied an innovative parental DNA pooling method to reduce the parental sequencing cost while maintaining the diagnostic yield of trio-ES.We pooled six (Agilent-CRE-v2-100X) or five parental DNA (TWIST-HCE-70X) aiming to detect allelic balance around 8-10% for heterozygous status. The strategies were applied as second-tier (74 individuals after negative solo-ES) and first-tier approaches (324 individuals without previous ES).The allelic balance of parental-pool variants was around 8.97%. Sanger sequencing uncovered false positives in 1.5% of sporadic variants. In the second-tier approach, we evaluated than two thirds of the Sanger validations performed after solo-ES (41/59-69%) would have been saved if the parental-pool segregations had been available from the start. The parental-pool strategy identified a causative diagnosis in 18/74 individuals (24%) in the second-tier and in 116/324 individuals (36%) in the first-tier approaches, including 19 genes newly associated with human disorders.Parental-pooling is an efficient alternative to trio-ES. It provides rapid segregation and extension to translational research while reducing the cost of parental and Sanger sequencing.

Exome

Translational Research

10.1002/mgg3.1836

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Combining globally search for a regular expression and print matching lines with bibliographic monitoring of genomic database improves diagnosis

Frontiers in Genetics (2023)

Frédéric Tran Mau‐Them Alexis Overs Ange‐Line Bruel Romain Duquet Mylene Thareau

Introduction: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Retrospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories. Patients and methods: We applied a reanalysis strategy based on intensive prospective bibliographic monitoring along with direct application of the GREP command-line tool (to “globally search for a regular expression and print matching lines”) in a large ES database. For 18 months, we submitted the same five keywords of interest [( intellectual disability , ( neuro ) developmental delay , and ( neuro ) developmental disorder )] to PubMed on a daily basis to identify recently published novel disease–gene associations or new phenotypes in genes already implicated in human pathology. We used the Linux GREP tool and an in-house script to collect all variants of these genes from our 5,459 exome database. Results: After GREP queries and variant filtration, we identified 128 genes of interest and collected 56 candidate variants from 53 individuals. We confirmed causal diagnosis for 19/128 genes (15%) in 21 individuals and identified variants of unknown significance for 19/128 genes (15%) in 23 individuals. Altogether, GREP queries for only 128 genes over a period of 18 months permitted a causal diagnosis to be established in 21/2875 undiagnosed affected probands (0.7%). Conclusion: The GREP query strategy is efficient and less tedious than complete periodic reanalysis. It is an interesting reanalysis strategy to improve diagnosis.

Exome

10.3389/fgene.2023.1122985

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Citations (1)

Epileptic encephalopathy as a new feature of the sudden infant death with dysgenesis of the testes syndrome caused by TSPYL1 variants

American Journal of Medical Genetics Part A (2022)

Benoît Mazel Delphine Mallet Florence Roucher‐Boulez Candace Ben Signor Marie Bournez

Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is a rare autosomal recessive disorder associating developmental sex disorder (DSD) in patients with 46,XY karyotype and visceroautonomic dysfunction responsible for sudden infant death. First described in 2004, very few patients have since been reported. We describe here a new patient with SIDDT and epileptic encephalopathy (EE). We provide the phenotypic description and genetic results of a boy carrying biallelic TSPYL1 deleterious variants. We also reviewed the data of the 26 previously described patients with SIDDT. Our patient presented gonadal dysgenesis, cardio-respiratory dysfunction, and repeated seizures, leading in 1 month to severe intractable EE. He died at age 10 months of cardiorespiratory arrest. Four other reported patients from two families presented with progressive epilepsy, including one with severe EE. No similar phenotype was described in the 22 other patients and the recurrent variant p.Val242Glufs*52 appears to be more frequently associated with seizures. To note, our patient is the first case with compound heterozygous TSPYL1 variants. These findings expand the phenotypic spectrum of SIDDT by reporting progressive epilepsy and severe EE as a possible outcome. This information may help in managing patients with SIDDT.

Dysgenesis

Feature (linguistics)

10.1002/ajmg.a.62966

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Citations (2)

First prenatal PI3K-AKT-mTOR pathway related overgrowth spectrum cohort: Phenotypic and molecular characterization

European Journal of Obstetrics & Gynecology and Reproductive Biology (2019)

Nicolas Bourgon Paul Kuentz Virginie Carmignac Arthur Sorlin Yannis Duffourd

10.1016/j.ejogrb.2018.08.529

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Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations

American Journal of Medical Genetics Part A (2018)

Mirna Assoum Matthew A. Lines Orly Elpeleg Véronique Darmency Sharon Whiting

De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C-terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data-sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.

10.1002/ajmg.a.40357

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Citations (23)

Exome sequencing in the etiologic assessment of the stroke of the young

Journal of the Neurological Sciences (2023)

Loraine Mania-Pâris Quentin Thomas Antonio Vitobello Frédéric Tran Mau‐Them Yannis Duffourd

Stroke

Exome

10.1016/j.jns.2023.121942

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The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance

American Journal of Medical Genetics Part A (2018)

Daphné Lehalle Umut Altunoğlu Ange‐Line Bruel Mirna Assoum Yannis Duffourd

Abstract The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo‐auriculo‐vertebral spectrum (OAVS)‐associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next‐generation sequencing strategy performed on blood‐derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.

Etiology

10.1002/ajmg.a.40662

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Citations (7)

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

Journal of Medical Genetics (2020)

Martin Chevarin Yannis Duffourd Rebecca Barnard Sébastien Moutton François Lecoquierre

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 ( ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2 ). Using simulation models, we showed that five genes ( DLG4, NFIX, EHMT1, ZEB2 and ATP1A1 ) 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 NSD1 and NFIX , which are known to be mutated in overgrowth syndromes. Conclusion We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10 −4 ) and genes regulated by the fragile X mental retardation protein (p=3×10 −8 ), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

Proband

10.1136/jmedgenet-2019-106425

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Citations (12)

A New Presenilin-1 Missense Variant Associated With a Progressive Supranuclear Palsy-like Phenotype

Alzheimer Disease & Associated Disorders (2022)

Quentin Thomas Sophie Nambot Yannick Béjot Christophe Philippe Laurence Faivre

Early-onset forms of Alzheimer disease (AD) have been associated with pathogenic variants in the APP , PSEN1 , and PSEN2 genes. Mutations in presenilin-1 ( PSEN1 ) account for the majority of cases of autosomal dominant AD. Numerous phenotypes have been associated with PSEN1 -pathogenic variants, including cerebellar ataxia and spastic paraplegia. Here, we describe a patient with early-onset AD presenting with extrapyramidal symptoms and supranuclear gaze palsy, mimicking progressive supranuclear palsy.

PSEN1

Hereditary Spastic Paraplegia

10.1097/wad.0000000000000503

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