Publications by authors named "Marjolaine Willems"

54 Publications

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature.

Genet Med 2022 Jan 18. Epub 2022 Jan 18.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, Dijon, France.

Purpose: Rare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation.

Methods: We obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine-based classifier distinguishing CDK13-RD and non-CDK13-RD samples.

Results: We reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance.

Conclusion: We describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder.
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http://dx.doi.org/10.1016/j.gim.2021.12.016DOI Listing
January 2022

The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes and .

Int J Mol Sci 2021 Dec 10;22(24). Epub 2021 Dec 10.

Molecular Genetics Laboratory, University of Montpellier, CHU Montpellier, F-34000 Montpellier, France.

Usher syndrome is an autosomal recessive disorder characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia. Three clinical subtypes are distinguished, and and represent the two major causal genes involved in Usher type I, the most severe form, and type II, the most frequent form, respectively. Massively parallel sequencing was performed on a cohort of patients in the context of a molecular diagnosis to confirm clinical suspicion of Usher syndrome. We report here 231 pathogenic and genotypes identified in 73 Usher type I and 158 Usher type II patients. Furthermore, we present the ACMG classification of the variants, which comprise all types. Among them, 68 have not been previously reported in the literature, including 12 missense and 16 splice variants. We also report a new deep intronic variant in . Despite the important number of molecular studies published on these two genes, we show that during the course of routine genetic diagnosis, undescribed variants continue to be identified at a high rate. This is particularly pertinent in the current era, where therapeutic strategies based on DNA or RNA technologies are being developed.
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http://dx.doi.org/10.3390/ijms222413294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703989PMC
December 2021

Cochleovestibular involvement in patients with Fabry disease: data from the multicenter cohort FFABRY.

Eur Arch Otorhinolaryngol 2021 Nov 26. Epub 2021 Nov 26.

Internal Medicine Department, Hotel-Dieu University Hospital, Nantes, France.

Purpose: Fabry disease (FD) is a lysosomal storage disease responsible for cochleovestibular involvement. Exact prevalence and pathophysiological mechanisms behind ENT affections are still poorly known. Treating FD with enzyme replacement therapy (ERT) does not seem to significantly improve the ENT symptoms, while the impact of migalastat has yet to be determined.

Methods: We carried out a retrospective multi-centre study on 47 patients from the FFABRY cohort who had an ENT consultation in the context of their FD. The information collected were as follows: clinical examination, videonystagmoscopy, pure-tone speech audiometry, videonystagmography or VHIT (Video Head Impulse Test). Severe hearing loss was defined as greater than 70 dB.

Results: The median age of our cohort was 52 years with a non-negligible proportion of non-classic variants and female carriers. 72.3% of the patients complained of at least one of the following symptoms: hearing loss, tinnitus or vertigo. Pure-tone audiometry was abnormal in 61.7% of the patients (29/47), while speech audiometry was abnormal for 41.7% of the patients. The age of the patients and hypertrophic cardiomyopathy were significantly associated with the existence of an anomaly in pure-tone audiometry results. Severe hearing loss (> 70 dB) was significantly more common in male patients.

Discussion: Hearing loss is particularly frequent in FD and is not limited to classic phenotypes. Close ENT follow-up is essential for Fabry patients to detect those who might benefit from hearing aid. Further studies are needed to define the impact of migalastat on cochleovestibular symptoms.
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http://dx.doi.org/10.1007/s00405-021-07173-xDOI Listing
November 2021

Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.

Neurol Genet 2021 Dec 15;7(6):e613. Epub 2021 Nov 15.

Department of Epilepsy Genetics and Personalized Treatment (K.M.J., E.G., C.E.G., A.B., R.S.M., G.R.), The Danish Epilepsy Centre Filadelfia, member of ERN EpiCARE, Dianalund; Institute for Regional Health Research (K.M.J., E.G., A.B., R.S.M), University of Southern Denmark, Odense; Department of Neurology (R.P.W.R.), Maastricht University Medical Centre (MUMC+); Academic Centre for Epileptology Kempenhaeghe/MUMC+ (R.P.W.R.), Maastricht; School for Mental Health and Neuroscience (R.P.W.R.), Maastricht University; Department of Clinical Genetics (M.R.), Maastricht University Medical Center, the Netherlands; APHP, Sorbonne Université (S.W.), Hôpital Armand Trousseau, UF de Génétique Clinique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Paris, France; Department of Genetics (B.K., J.B., T.C., C.N.), Pitié-Salpêtrière hospital, APHP, Sorbonne Université, Paris, France; Department of Clinical Genomics (K.J.W.), Mayo Clinic Florida, Jacksonville; Service de Génétique Médicale (B.I., A.P., A.-S.D.-P.), CHU de Nantes; Centre de Référence Anomalies du Développement et Syndromes Malformatifs (L.F., A.G., S.M.), FHU TRANSLAD, CHU Dijon; INSERM UMR1231 (L.F., A.G., S.M., F.T.M.-T., A.V.), GAD team, Université de Bourgogne-Franche Comté, Dijon; Unité Fonctionnelle dInnovation diagnostique des maladies rares (F.T.-M.-T., A.V.), Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne; Department of Medical Genetics (C.C., M.W.), Rare Diseases and Personalized Medicine, CHU Montpellier, France; Childrens Hospital Colorado (A.L.), Anschutz Medical Campus, Aurora, CO; Division of Clinical Neuroscience (M.J.E., J.P.A.), Department of Pediatrics, Alberta, Canada; Alberta Childrens Hospital (J.P.A., F.B.), Cumming School of Medicine, University of Calgary, Alberta, Canada; Department of Pediatrics (W.A.-H.), Division of Genetics and Genomics, Boston Childrens Hospital and Harvard Medical School, MA; Instituto de Neurología Infanto Juvenil (B.G.), Neuroinfan; Instituto de Genetica-Hospital Universitario (A.M.), Universidad Nacional de Cuyo; Instituto de Histología y Embriología de Mendoza (IHEM) (L.M.), Universidad Nacional de Cuyo, Mendoza, Argentina; Azienda Ospedaliera Universitaria Pisana (A.O.); Neuropaediatric Section (A.B.), Pediatric Department, Santa Chiara University Hospital, Pisa; Department of Medical Sciences- Pediatric Section (A.S.), University of Ferrara, Italy; CHU Bordeaux (J.V.-G.), Bordeaux, France; West Midlands Regional Genetics Service (J.V.), Birmingham Women's and Children's Hospital, Birmingham, UK; Child Neuropsychiatric Division (S.D., L.G.), Spedali Civili, Brescia, Italy; Institut de Pathologie et de Génétique (IPG) (S.M.), Gosselies, Belgium; Divisions of Child and Adolescent Neurology and Epilepsy (E.W.), Department of Neurology, Mayo Clinic, Rochester, MN; Oxford Centre for Genomic Medicine (S.H., H.S.); Oxford University Hospitals NHS Trust (U.K.), United Kingdom; Blank Children's Developmental Center (N.N.), Unity Point Health, West Des Moines, IA; Sutter Medical Centre (S.A.), Sacramento, CA; Kennedy Krieger Institute (J.S.C.); Johns Hopkins University (S.R.N.), Baltimore, MD; Provincial Medical Genetics Program (A.C.), St. Johns Medical Center, NL, Canada; University Medical Center Utrecht (E.H.B.), Utrecht, the Netherlands; Rush University Medical Center (M.H.L., C.B.), Chicago, IL; Medical Genetic Unit (S.B., D.O.), Maternal and Child Department, Ferrara University Hospital; Medical Science Department (D.O.), Ferrara University; Neonatal Intensive Care Unit (E.B.), Pediatric Section, Department of Medical Sciences, Ferrara University, Italy; Department of Clinical Genetics (C.R.), LUMC, Leiden, the Netherlands; Pediatric Unit, Maternal and Child Department (R.F.), Ferrara University Hospital, Italy; APHP Trousseau (A.A., C.M., D.H.); Service de Neuropédiatrie (D.R., A.I.), Hopital Trousseau, Sorbonne Université, APHP.SU, Paris, France; HudsonAlpha Institute for Biotechnology (D.B.), Huntsville, AL; Department of Pediatrics (D.S., S.K.), Weill Cornell Medicine, New York; Queensland Children's Hospital (D.C.), Brisbane, QL, Australia; Department of Neurology (B.G.), Stichting Epilepsie Instellingen Nederland, Zwolle, the Netherlands; Department of Neurology (O.D.), NYU School of Medicine; Atrium Healths Levine Childrens Hospital (L.A.D.), Charlotte, NC; Phoenix Childrens Hospital (T.G.), the University of Arizona College of Medicine; Division of Child Neurology and Psychiatry (D.P.), Azienda Ospedaliero Universitaria; Neurology and Epileptology Unit (I.C.), Pediatric Department, Brotzu Hospital Trust, Cagliari, Italy; Liverpool Centre for Genomic Medicine (L.G., G.R.), Liverpool Womens NHS Foundation Trust, Liverpool, United Kingdom; U.O. Genetica Medica (C.G.), Policlinico S. Orsola-Malpighi, Bologna, Italy; Department of Children's neurosciences (R.R.S.), Guys and ST. Thomas' NHS foundation trust, London United Kingdom; Department of Child Neuropsychiatry (G.C.), University of Verona, Italy; Christian Medical College (S.Y.), Vellore, India; Neurology Pediatric Unit (F.G.), Pediatric Department, Fernandes Figueira Institute, Fiocruz, Brazil; Royal Childrens Hospital (F.J.L.), Melbourne, Australia; Research & Innovation S.r.l. (D.C.), Padova; Pediatric Neurology Unit (S.O., B.S., F.V.), V. Buzzi Childrens Hospital, Milan, Italy; Department of Paediatrics (A.V.A.), London Health Science Centre/Schulich School of Medicine and Dentisty, University of Western Ontario, London, ON, Canada; Ambry Genetics (K.R.), Aliso Viejo, CA; Advocate Lutheran General Hospital (F.T.), Park Ridge, IL; PPG Pediatric Neurology (A.S.K.), Parkview Health, Fort Wayne, IN; Department of Medical Genetics (C.O.), AP-HP, Necker-Enfants Malades Hospital, Paris, France; Department of Neurology (W.B.), UC Davis, Sacramento, CA; Department of Pediatrics (K.K.), Texas A&M University Medical School, Austin; Leeds General Infirmary (S.H,), United Kingdom; Thompson River Pediatrics (A.F.), Johnstown, CO; Department of Neuropediatrics (S.G.), University Hospital Copenhagen, Denmark; Division of Neurology (F.B., R.W.), Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada; Hunter Genetics Unit, Waratah, Australia (A.R.); Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom (N.F., D.H.); KBO-Kinderzentrum München, Munich, Germany (M.S.); Division of Neurology, Epilepsy Neurogenetics Initiative, Childrens Hospital of Philadelphia (J.B., K.L.H., I.H., X.R.O-G, H.D.); Perelman School of Medicine, Philadelphia, PA (J.B.); PURA Syndrome Foundation, Greensborough, Australia (I.H., M.A., D.S.); PURA Syndrome Foundation, Kansas City, MO (I.H., D.S.).

Background And Objectives: Purine-rich element-binding protein A () gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of syndrome by collecting data, including EEG, from a large cohort of affected patients.

Methods: Data on unpublished and published cases were collected through the Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.

Results: A cohort of 142 patients was included. Characteristics of the syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in without any clear genotype-phenotype associations.

Discussion: The syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.
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http://dx.doi.org/10.1212/NXG.0000000000000613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592566PMC
December 2021

A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder.

NPJ Genom Med 2021 Nov 4;6(1):91. Epub 2021 Nov 4.

Service de Génétique clinique, CH de Chambéry, Chambéry, France.

Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.
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http://dx.doi.org/10.1038/s41525-021-00254-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568906PMC
November 2021

The diagnostic rate of inherited metabolic disorders by exome sequencing in a cohort of 547 individuals with developmental disorders.

Mol Genet Metab Rep 2021 Dec 18;29:100812. Epub 2021 Oct 18.

Centre de Compétence Maladies Héréditaires du Métabolisme, CHU Dijon Bourgogne, France.

Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable.

Synopsis: Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528787PMC
December 2021

When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report.

Diagnostics (Basel) 2021 Sep 7;11(9). Epub 2021 Sep 7.

Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU Montpellier, Université de Montpellier, 34090 Montpellier, France.

We describe a family with both hearing loss (HL) and thrombocytopenia, caused by pathogenic variants in three genes. The proband was a child with neonatal thrombocytopenia, childhood-onset HL, hyper-laxity and severe myopia. The child's mother (and some of her relatives) presented with moderate thrombocytopenia and adulthood-onset HL. The child's father (and some of his relatives) presented with adult-onset HL. An HL panel analysis, completed by whole exome sequencing, was performed in this complex family. We identified three pathogenic variants in three different genes: , and . The thrombocytopenia in the child and her mother is explained by the variant. The post-lingual HL in the paternal branch is explained by the variant, absent in the proband, while the congenital HL of the child is explained by a de novo variant. This family, in which HL segregates, illustrates that multiple genetic conditions coexist in individuals and make patient care more complex than expected.
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http://dx.doi.org/10.3390/diagnostics11091636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465614PMC
September 2021

10 years of CEMARA database in the AnDDI-Rares network: a unique resource facilitating research and epidemiology in developmental disorders in France.

Orphanet J Rare Dis 2021 08 4;16(1):345. Epub 2021 Aug 4.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Dijon, Dijon, France.

Background: In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation.

Methods: Since 2007, clinicians and researchers have reported the "minimum dataset (MDS)" for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses.

Results: Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient's home was 25.1 km (IQR = 6.3 km-64.2 km).

Conclusions: CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.
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http://dx.doi.org/10.1186/s13023-021-01957-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335940PMC
August 2021

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder.

Genet Med 2021 11 3;23(11):2150-2159. Epub 2021 Aug 3.

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.

Purpose: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics.

Methods: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature.

Results: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice.

Conclusion: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene.
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http://dx.doi.org/10.1038/s41436-021-01263-1DOI Listing
November 2021

O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum.

J Med Genet 2021 Jul 28. Epub 2021 Jul 28.

Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

Background: O'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in . It was first described by O'Donnell-Luria in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.

Methods: Affected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.

Results: We report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of . We confirm and refine the phenotypic spectrum of the -related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.

Conclusion: Our study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.
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http://dx.doi.org/10.1136/jmedgenet-2020-107470DOI Listing
July 2021

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.

Hum Genomics 2021 07 13;15(1):44. Epub 2021 Jul 13.

Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.

Background: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737.

Results: We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10), and combined dataset (p = 1.1 × 10). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10, loss-of-function p = 2.26 × 10) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia.

Conclusions: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.
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http://dx.doi.org/10.1186/s40246-021-00342-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278787PMC
July 2021

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Brain 2021 Dec;144(12):3635-3650

Pediatric Neurology Department, Lyon University Hospital, 69500 Bron, France.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.
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http://dx.doi.org/10.1093/brain/awab219DOI Listing
December 2021

Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity.

Genet Med 2021 10 10;23(10):1901-1911. Epub 2021 Jun 10.

Inserm UMR1231 team GAD, University of Burgundy and Franche-Comté, Dijon, France.

Purpose: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.

Methods: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.

Results: We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity.

Conclusion: We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.
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http://dx.doi.org/10.1038/s41436-021-01218-6DOI Listing
October 2021

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Clin Genet 2021 05 20;99(5):650-661. Epub 2021 Jan 20.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.
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http://dx.doi.org/10.1111/cge.13918DOI Listing
May 2021

New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.

Genet Med 2021 03 5;23(3):543-554. Epub 2020 Nov 5.

Department of Medical Genetics, Lyon University Hospital, Lyon, France.

Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.

Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.

Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.

Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
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http://dx.doi.org/10.1038/s41436-020-01011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935717PMC
March 2021

Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations.

J Med Genet 2021 06 30;58(6):400-413. Epub 2020 Jul 30.

Service d'Imagerie médicale, CHU de Besançon, Besançon, France.

Purpose: Molecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.

Methods: We performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.

Results: sES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).

Conclusions: This method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.
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http://dx.doi.org/10.1136/jmedgenet-2020-106867DOI Listing
June 2021

SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect.

Brain 2020 08;143(8):2380-2387

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.

The SLC12 gene family consists of SLC12A1-SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16-18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16-18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.
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http://dx.doi.org/10.1093/brain/awaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447514PMC
August 2020

Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience.

Pediatr Blood Cancer 2020 09 13;67(9):e28486. Epub 2020 Jul 13.

Gustave Roussy Cancer Center, Department of Children and Adolescents Oncology, Paris-Saclay University, Villejuif, France.

Objective: To describe the clinical characteristics and outcome of patients with Li-Fraumeni-associated rhabdomyosarcoma (RMS).

Method: Retrospective analysis of data from 31 French patients with RMS diagnosed before the age of 20 years associated with a TP53 pathogenic germline variant. Cases were identified through the French Li-Fraumeni database. Central histologic review was performed in 16 cases.

Results: The median age at diagnosis was 2.3 years, and the median follow-up was 9.1 years (0.3-34.8). The main tumor sites were head and neck (n = 13), extremities (n = 8), and trunk (n = 8). The local pathology report classified the 31 tumors in embryonal (n = 26), alveolar (n = 1), pleomorphic (n = 1), and spindle-cell (n = 1) RMS (missing = 2). After histological review, anaplasia (diffuse or focal) was reported in 12/16 patients. Twenty-five patients had localized disease, three had lymph node involvement, and three distant metastases. First-line therapy combined surgery (n = 27), chemotherapy (n = 30), and radiotherapy (n = 14) and led to RMS control in all, but one patient. Eleven patients relapsed, and 18 patients had second malignancies. The 10-year event-free, progression-free, and overall survival rates were 36% (95% CI: 20-56), 62% (95% CI: 43-77) and 76% (95% CI: 56-88), respectively. The 10-year cumulative risk of second malignancies was 40% (95% CI: 22-60).

Conclusion: The high incidence of multiple primary tumors strongly influences the long-term prognosis of RMS associated with TP53 pathogenic germline variants. Anaplastic RMS in childhood, independently of the familial history, should lead to TP53 analysis at treatment initiation to reduce, whenever possible, the burden of genotoxic drugs and radiotherapy in carriers and to ensure the early detection of second malignancies.
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http://dx.doi.org/10.1002/pbc.28486DOI Listing
September 2020

Single Circulating Fetal Trophoblastic Cells Eligible for Non Invasive Prenatal Diagnosis: the Exception Rather than the Rule.

Sci Rep 2020 06 17;10(1):9861. Epub 2020 Jun 17.

Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, EA7402 Université de Montpellier, CHU Montpellier, Montpellier, France.

Non-Invasive Prenatal Diagnosis (NIPD), based on the analysis of circulating cell-free fetal DNA (cff-DNA), is successfully implemented for an increasing number of monogenic diseases. However, technical issues related to cff-DNA characteristics remain, and not all mutations can be screened with this method, particularly triplet expansion mutations that frequently concern prenatal diagnosis requests. The objective of this study was to develop an approach to isolate and analyze Circulating Trophoblastic Fetal Cells (CFTCs) for NIPD of monogenic diseases caused by triplet repeat expansion or point mutations. We developed a method for CFTC isolation based on DEPArray sorting and used Huntington's disease as the clinical model for CFTC-based NIPD. Then, we investigated whether CFTC isolation and Whole Genome Amplification (WGA) could be used for NIPD in couples at risk of transmitting different monogenic diseases. Our data show that the allele drop-out rate was 3-fold higher in CFTCs than in maternal cells processed in the same way. Moreover, we give new insights into CFTCs by compiling data obtained by extensive molecular testing by microsatellite multiplex PCR genotyping and by WGA followed by mini-exome sequencing. CFTCs appear to be often characterized by a random state of genomic degradation.
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http://dx.doi.org/10.1038/s41598-020-66923-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300110PMC
June 2020

De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Am J Hum Genet 2020 07 17;107(1):164-172. Epub 2020 Jun 17.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.
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http://dx.doi.org/10.1016/j.ajhg.2020.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332645PMC
July 2020

Clinical and Molecular Spectrum of Nonsyndromic Early-Onset Osteoarthritis.

Arthritis Rheumatol 2020 10 25;72(10):1689-1693. Epub 2020 Aug 25.

Université de Montpellier, Centre Hospitalier Universitaire Montpellier, CLAD Sud Languedoc-Roussillon, Montpellier, France.

Objective: Osteoarthritis (OA) is the most common joint disease worldwide. The etiology of OA is varied, ranging from multifactorial to environmental to monogenic. In a condition called early-onset OA, OA occurs at an earlier age than is typical in the general population. To our knowledge, there have been no large-scale genetic studies of individuals with early-onset OA. The present study was undertaken to investigate causes of monogenic OA in individuals with nonsyndromic early-onset OA.

Methods: The study probands were 45 patients with nonsyndromic early-onset OA who were referred to our skeletal disease center by skeletal dysplasia experts between 2013 and 2019. Criteria for early-onset OA included radiographic evidence, body mass index ≤30 kg/m , age at onset ≤50 years, and involvement of ≥1 joint site. Molecular analysis was performed with a next-generation sequencing panel.

Results: We identified a genetic variant in 13 probands (29%); the affected gene was COL2A1 in 11, ACAN in 1, and SLC26A2 in 1. After familial segregation analysis, 20 additional individuals were identified. The mean ± SD age at onset of joint pain was 19.5 ± 3.9 years (95% confidence interval 3-47). Eighteen of 33 subjects (55%) with nonsyndromic early-onset OA and a genetic variant had had at least 1 joint replacement (mean ± SD age at first joint replacement 41 ± 4.2 years; mean number of joint replacements 2.6 per individual), and 21 (45%) of the joint replacement surgeries were performed when the patient was <45 years old. Of the 20 patients age >40 years, 17 (85%) had had at least 1 joint replacement.

Conclusion: We confirmed that COL2A1 is the main monogenic cause of nonsyndromic early-onset OA. However, on the basis of genetic heterogeneity of early-onset OA, we recommend next-generation sequencing for all individuals who undergo joint replacement prior to the age of 45 years. Lifestyle recommendations for prevention should be implemented.
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http://dx.doi.org/10.1002/art.41387DOI Listing
October 2020

NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients.

EMBO J 2020 07 2;39(13):e104163. Epub 2020 Jun 2.

Université Côte d'Azur, CNRS, Inserm, iBV, Paris, France.

The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra-Bosch-Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss-of-function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria-like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification.
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http://dx.doi.org/10.15252/embj.2019104163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327499PMC
July 2020

Cornea verticillata and acroparesthesia efficiently discriminate clusters of severity in Fabry disease.

PLoS One 2020 22;15(5):e0233460. Epub 2020 May 22.

Internal Medicine Department, Reference Center for Lysosomal Storage Disorders, Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France.

Backgroud: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity.

Methods: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients.

Results: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI.

Conclusion: Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244174PMC
August 2020

Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders.

Hum Genet 2020 Nov 12;139(11):1381-1390. Epub 2020 May 12.

UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Bâtiment B3, 15 avenue du maréchal Delattre de Tassigny, 21000, Dijon, France.

Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate variant selection thanks to rapid parental segregation. We performed a second step trio-ES (not only focusing on genes involved in human disorders) analysis in 70 patients with negative results after solo-cES. All candidate variants were shared with a MatchMaking exchange system to identify additional patients carrying variants in the same genes and with similar phenotype. In 18/70 patients (26%), we confirmed causal implication of nine OMIM-morbid genes and identified nine new strong candidate genes (eight de novo and one compound heterozygous variants). These nine new candidate genes were validated through the identification of patients with similar phenotype and genotype thanks to data sharing. Moreover, 11 genes harbored variants of unknown significance in 10/70 patients (14%). In DD, a second step trio-based ES analysis appears an efficient strategy in diagnostic and translational research to identify highly candidate genes and improve diagnostic yield.
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http://dx.doi.org/10.1007/s00439-020-02178-8DOI Listing
November 2020

Growth charts in Kabuki syndrome 1.

Am J Med Genet A 2020 03 26;182(3):446-453. Epub 2019 Dec 26.

Service de Génétique, Hôpital Saint Pierre, GH Sud Réunion, Ile de la Réunion, Saint Pierre, France.

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.
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http://dx.doi.org/10.1002/ajmg.a.61462DOI Listing
March 2020

Reverse Phenotyping in Patients with Skin Capillary Malformations and Mosaic GNAQ or GNA11 Mutations Defines a Clinical Spectrum with Genotype-Phenotype Correlation.

J Invest Dermatol 2020 05 11;140(5):1106-1110.e2. Epub 2019 Nov 11.

Dermatology Department, Dijon Burgundy University Hospital, Dijon, France; INSERM UMR1231, Team Genetics of Development Anomalies, Bourgogne-Franche-Comté University, Dijon, France; Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC)-Mosaic, Burgundy University Hospital, Dijon, France.

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http://dx.doi.org/10.1016/j.jid.2019.08.455DOI Listing
May 2020

Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

Genet Med 2020 03 8;22(3):598-609. Epub 2019 Nov 8.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Purpose: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.

Methods: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGU) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants.

Results: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease.

Conclusion: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
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http://dx.doi.org/10.1038/s41436-019-0685-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056646PMC
March 2020

Increasing knowledge in defects: lessons from 35 new patients.

J Med Genet 2020 03 5;57(3):160-168. Epub 2019 Oct 5.

Sorbonne Université, UFR Médecine, Paris, France.

Background: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.

Methods: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.

Results: We detected 21 defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of . Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.

Conclusion: We report eight new pathogenic variants of and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.
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http://dx.doi.org/10.1136/jmedgenet-2019-106328DOI Listing
March 2020

Autism and developmental disability caused by KCNQ3 gain-of-function variants.

Ann Neurol 2019 08 26;86(2):181-192. Epub 2019 Jun 26.

Division of Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA.

Objective: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms.

Methods: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording.

Results: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects.

Interpretation: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.
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http://dx.doi.org/10.1002/ana.25522DOI Listing
August 2019

Biallelic variants in and cause deafness and (ovario)leukodystrophy.

Neurology 2019 03 8;92(11):e1225-e1237. Epub 2019 Feb 8.

From the Departments of Child Neurology (M.S.v.d.K., M. Breur) and Neuropathology (M. Bugiani, M. Breur), and Metabolic Unit, Department of Clinical Chemistry (M.I.M., D.E.C.S., G.S.S.), Amsterdam University Medical Centers and Amsterdam Neuroscience; Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands; Genetic Metabolic Disorders Research Unit (L.G.R., J. Christodoulou), The Children's Hospital at Westmead, and Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, NSW, Australia; Architecture et Réactivité de l'ARN (J.R.-T., M.F.), UPR 9002, Université de Strasbourg, CNRS, Strasbourg, France; Institute for Molecular Bioscience (J. Crawford, C.S.), University of Queensland, St. Lucia, Queensland, Australia; Department of Neurology (J.v.G.), Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen; Department of Clinical Genetics (M.S.), Radboud University Medical Center, Nijmegen, the Netherlands; Departement Génétique Médicale (M.W.), Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, France; Department of Clinical Genetics (Q.W.), Amsterdam University Medical Centers, the Netherlands; UF Innovation en Diagnostic Génomique des Maladies Rares (F.T.M.-T.), Centre Hospitalier Universitaire de Dijon, France; Radboud Center for Mitochondrial Medicine (R.J.R.), Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands; Illumina Inc. (R.J.T.), San Diego, CA; AP-HP (B.K., F.M.), La Pitié-Salpêtrière University Hospital, Department of Genetics, Paris; INSERM U 1127 (B.K., C.D., F.M.), CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Murdoch Children's Research Institute (J. Christodoulou, C.S.), Parkville, Victoria, Australia; Department of Paediatrics (J. Christodoulou), University of Melbourne, Australia; Institute of Human Genetics (C.D.), University Hospital Essen, University Duisburg-Essen, Germany; and Sorbonne Universités (F.M.), Neurometabolic Clinical Research Group, Paris, France.

Objective: To describe the leukodystrophy caused by pathogenic variants in and , encoding mitochondrial leucyl transfer RNA (tRNA) synthase and mitochondrial and cytoplasmic lysyl tRNA synthase, respectively.

Methods: We composed a group of 5 patients with leukodystrophy, in whom whole-genome or whole-exome sequencing revealed pathogenic variants in or . Clinical information, brain MRIs, and postmortem brain autopsy data were collected. We assessed aminoacylation activities of purified mutant recombinant mitochondrial leucyl tRNA synthase and performed aminoacylation assays on patients' lymphoblasts and fibroblasts.

Results: Patients had a combination of early-onset deafness and later-onset neurologic deterioration caused by progressive brain white matter abnormalities on MRI. Female patients with pathogenic variants had premature ovarian failure. In 2 patients, MRI showed additional signs of early-onset vascular abnormalities. In 2 other patients with and pathogenic variants, magnetic resonance spectroscopy revealed elevated white matter lactate, suggesting mitochondrial disease. Pathology in one patient with pathogenic variants displayed evidence of primary disease of oligodendrocytes and astrocytes with lack of myelin and deficient astrogliosis. Aminoacylation activities of purified recombinant mutant leucyl tRNA synthase showed a 3-fold loss of catalytic efficiency. Aminoacylation assays on patients' lymphoblasts and fibroblasts showed about 50% reduction of enzyme activity.

Conclusion: This study adds and pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. We discuss the specific MRI characteristics shared by leukodystrophies caused by mitochondrial tRNA synthase defects. We propose to add aminoacylation assays as biochemical diagnostic tools for leukodystrophies.
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http://dx.doi.org/10.1212/WNL.0000000000007098DOI Listing
March 2019
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