Publications by authors named "Alexandra Afenjar"

98 Publications

Using deep-neural-network-driven facial recognition to identify distinct Kabuki syndrome 1 and 2 gestalt.

Eur J Hum Genet 2021 Nov 22. Epub 2021 Nov 22.

Montpellier University, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Génétique clinique, CHU Montpellier, Centre de référence anomalies du développement SOOR, INSERM U1183, Montpellier, France.

Kabuki syndrome (KS) is a rare genetic disorder caused by mutations in two major genes, KMT2D and KDM6A, that are responsible for Kabuki syndrome 1 (KS1, OMIM147920) and Kabuki syndrome 2 (KS2, OMIM300867), respectively. We lack a description of clinical signs to distinguish KS1 and KS2. We used facial morphology analysis to detect any facial morphological differences between the two KS types. We used a facial-recognition algorithm to explore any facial morphologic differences between the two types of KS. We compared several image series of KS1 and KS2 individuals, then compared images of those of Caucasian origin only (12 individuals for each gene) because this was the main ethnicity in this series. We also collected 32 images from the literature to amass a large series. We externally validated results obtained by the algorithm with evaluations by trained clinical geneticists using the same set of pictures. Use of the algorithm revealed a statistically significant difference between each group for our series of images, demonstrating a different facial morphotype between KS1 and KS2 individuals (mean area under the receiver operating characteristic curve = 0.85 [p = 0.027] between KS1 and KS2). The algorithm was better at discriminating between the two types of KS with images from our series than those from the literature (p = 0.0007). Clinical geneticists trained to distinguished KS1 and KS2 significantly recognised a unique facial morphotype, which validated algorithm findings (p = 1.6e-11). Our deep-neural-network-driven facial-recognition algorithm can reveal specific composite gestalt images for KS1 and KS2 individuals.
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http://dx.doi.org/10.1038/s41431-021-00994-8DOI 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

MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects.

Hum Genet 2021 Nov 8. Epub 2021 Nov 8.

Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, Paris, France.

Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.
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http://dx.doi.org/10.1007/s00439-021-02383-zDOI Listing
November 2021

Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders.

Clin Genet 2021 11 31;100(5):628-633. Epub 2021 Aug 31.

Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.

Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase-3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA). Here we present the clinical and genetic features of 21 individuals with biallelic PUS3 variants: seven new and 14 previously reported individuals, where clinical features of two were updated. The clinical and genetic information were collected through collaborations or by literature search. All individuals were characterized by the local clinicians and the gene variants were identified by next generation sequencing (NGS) based methodologies. The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly. Gray sclera, which has previously been suggested to be a characteristic feature of PUS3-associated phenotypes, was reported in only seven individuals. The patients had some dysmorphic facial features, but a recognizable gestalt was not observed. In conclusion, homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder. Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development.
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http://dx.doi.org/10.1111/cge.14051DOI Listing
November 2021

Delineating the genotypic and phenotypic spectrum of -related neurodevelopmental disorders.

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

GeneDx, Gaithersburg, Maryland, USA.

Background: Variants in have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.

Methods: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a related neurodevelopmental disorder.

Results: We identified 13 novel missense variants in in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.

Conclusion: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of disorders, aiding future molecular and clinical diagnosis and management.
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http://dx.doi.org/10.1136/jmedgenet-2021-107871DOI Listing
July 2021

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Genome Med 2021 04 19;13(1):63. Epub 2021 Apr 19.

The Atwal Clinic: Genomic & Personalized Medicine, Jacksonville, FL, USA.

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
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http://dx.doi.org/10.1186/s13073-021-00870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056596PMC
April 2021

Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy.

Am J Med Genet A 2021 06 23;185(6):1803-1815. Epub 2021 Mar 23.

Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, Strasbourg, France.

High-throughput sequencing (HTS) improved the molecular diagnosis in individuals with intellectual deficiency (ID) and helped to broaden the phenotype of previously known disease-causing genes. We report herein four unrelated patients with isolated ID, carriers of a likely pathogenic variant in KCNQ2, a gene usually implicated in benign familial neonatal seizures (BFNS) or early onset epileptic encephalopathy (EOEE). Patients were diagnosed by targeted HTS or exome sequencing. Pathogenicity of the variants was assessed by multiple in silico tools. Patients' ID ranged from mild to severe with predominance of speech disturbance and autistic features. Three of the four variants disrupted the same amino acid. Compiling all the pathogenic variants previously reported, we observed a strong overlap between variants causing EOEE, isolated ID, and BFNS and an important intra-familial phenotypic variability, although missense variants in the voltage-sensing domain and the pore are significantly associated to EOEE (p < 0.01, Fisher test). Thus, pathogenic variants in KCNQ2 can be associated with isolated ID. We did not highlight strong related genotype-phenotype correlations in KCNQ2-related disorders. A second genetic hit, a burden of rare variants, or other extrinsic factors may explain such a phenotypic variability. However, it is of interest to study encephalopathy genes in non-epileptic ID patients.
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http://dx.doi.org/10.1002/ajmg.a.62181DOI Listing
June 2021

Biallelic variants in cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration.

J Med Genet 2021 Jan 4. Epub 2021 Jan 4.

Medical Genetics Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Next-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.

Methods: Here, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).

Results: We identified five patients from four unrelated families with homozygous variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from -4 SD to -8 SD), profound psychomotor delay, hypertonic-dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.

Conclusion: Our findings support the role of biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.
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http://dx.doi.org/10.1136/jmedgenet-2020-107430DOI Listing
January 2021

Neuropsychological study in 19 French patients with White-Sutton syndrome and POGZ mutations.

Clin Genet 2021 03 15;99(3):407-417. Epub 2020 Dec 15.

Service de génétique médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France.

White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.
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http://dx.doi.org/10.1111/cge.13894DOI Listing
March 2021

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

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

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

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

Congenital immobility and stiffness related to biallelic variants.

Neurol Genet 2020 Dec 24;6(6):e520. Epub 2020 Sep 24.

Département de Génétique (R.B., S.W., B.K., S.C.-B., M.-C.V., L.B., D.H., J.B., A.A., C.M.), Hôpital Armand Trousseau & Groupe Hospitalier Pitié-Salpêtrière, and Unité de Neuropédiatrie et Pathologie du Développement (D.D., M.M., D.R., A.I., T.B.V.), Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris; Centre de Référence des Maladies Neurogénétiques (D.D., D.R.); Centre de Référence Anomalies du Développement et Syndromes Malformatifs (S.W., C.M.); Hôpital de Pédiatrie et de Rééducation (K.M.), Bullion; INSERM UMR 1141 (D.R.), Paris; Réanimation Néonatale et Pédiatrique (P.-L.L.), and Service de Néonatologie (F.K., I.M.), Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris; Centre de Référence Déficience Intellectuelles de Causes Rares (D.H., A.A., T.B.V., C.M.); and INSERM (C.M.), U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France.

Objective: To delineate the phenotype associated with biallelic variants.

Methods: We describe 2 new patients with -related disorder diagnosed by whole-exome sequencing and compare their phenotype to 6 previous patients.

Results: Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. Both had absent brainstem evoked auditory responses (BEARs). Patient 1 carried the homozygous p.(His357Argfs*15) variant in . In the light of the finding in patient 1, a second reading of exome data for patient 2 revealed the novel homozygous p.(Gly128Val) variant.

Conclusions: Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia.
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http://dx.doi.org/10.1212/NXG.0000000000000520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577533PMC
December 2020

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

Epilepsia 2020 11 21;61(11):2461-2473. Epub 2020 Sep 21.

Reference Center for Rare Developmental Abnormalities CLAD-Ouest, Rennes University Hospital Center, Rennes, France.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.

Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature.

Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants.

Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
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http://dx.doi.org/10.1111/epi.16679DOI Listing
November 2020

Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect.

J Inherit Metab Dis 2021 03 28;44(2):415-425. Epub 2020 Sep 28.

Cardiology Unit, Necker-Enfants-Malades University Hospital, APHP, Paris, France.

TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15/17), neurological symptoms (14/17), and cardiac features (12/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly l-carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF-21, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life-threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.
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http://dx.doi.org/10.1002/jimd.12314DOI Listing
March 2021

Serum bikunin isoforms in congenital disorders of glycosylation and linkeropathies.

J Inherit Metab Dis 2020 11 7;43(6):1349-1359. Epub 2020 Aug 7.

INSERM UMR1193, Université Paris-Saclay, Châtenay-Malabry, France.

Bikunin (Bkn) isoforms are serum chondroitin sulfate (CS) proteoglycans synthesized by the liver. They include two light forms, that is, the Bkn core protein and the Bkn linked to the CS chain (urinary trypsin inhibitor [UTI]), and two heavy forms, that is, pro-α-trypsin inhibitor and inter-α-trypsin inhibitor, corresponding to UTI esterified by one or two heavy chains glycoproteins, respectively. We previously showed that the Western-blot analysis of the light forms could allow the fast and easy detection of patients with linkeropathy, deficient in enzymes involved in the synthesis of the initial common tetrasaccharide linker of glycosaminoglycans. Here, we analyzed all serum Bkn isoforms in a context of congenital disorders of glycosylation (CDG) and showed very specific abnormal patterns suggesting potential interests for their screening and diagnosis. In particular, genetic deficiencies in V-ATPase (ATP6V0A2-CDG, CCDC115-CDG, ATP6AP1-CDG), in Golgi manganese homeostasis (TMEM165-CDG) and in the N-acetyl-glucosamine Golgi transport (SLC35A3-CDG) all share specific abnormal Bkn patterns. Furthermore, for each studied linkeropathy, we show that the light abnormal Bkn could be further in-depth characterized by two-dimensional electrophoresis. Moreover, besides being interesting as a specific biomarker of both CDG and linkeropathies, Bkn isoforms' analyses can provide new insights into the pathophysiology of the aforementioned diseases.
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http://dx.doi.org/10.1002/jimd.12291DOI Listing
November 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

Lessons learned from 40 novel PIGA patients and a review of the literature.

Epilepsia 2020 06 26;61(6):1142-1155. Epub 2020 May 26.

Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations.

Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches.

Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein.

Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
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http://dx.doi.org/10.1111/epi.16545DOI Listing
June 2020

Loss of the KH1 domain of FMR1 in humans due to a synonymous variant causes global developmental retardation.

Gene 2020 Aug 21;753:144793. Epub 2020 May 21.

Assistance Publique - Hôpitaux de Paris, APHP. Centre Universitaire Paris, Hôpital Cochin, Laboratoire de Génétique et Biologie Moléculaires, Paris, France; Institut de Psychiatrie et de Neurosciences de Paris (IPNP), INSERM U1266, Team « Vulnérabilité aux troubles psychiatriques et addictifs », Université de Paris, Paris, France. Electronic address:

Background: Fragile X syndrome (FXS) is a monogenic disorder and a common cause of intellectual disability (ID). Up to now, very few pathological variants other than the typical CGG-repeat expansion have been reported in the FMR1 gene.

Methods: A panel of 56 intellectual disability (ID) genes including the FMR1 gene was sequenced in a cohort of 300 patients with unexplained ID. To determine the effect of a new FMR1 variant, total RNA from peripheral blood cells was reverse transcribed, amplified by polymerase chain reaction and sequenced.

Results: We report a novel G to A point variant (c.801G > A) located at the last nucleotide of exon 8 in the FMR1 gene in one patient with ID. Direct sequencing of the RT-PCR products revealed that the transcript from the allele with G to A variant skips exon 8 entirely, resulting in a joining of exons 7 and 9. Skipping of exon 8 may result in an abnormal FMR1 protein (FMRP), which removes the highly conserved region that encoding the KH1 domain of FMRP.

Conclusions: This report describes for the first time that a synonymous variant in the FMR1 gene is associated with an error in mRNA processing, leading preferentially to the production of an aberrant transcript without exon 8. This splice variant was associated with an unspecific clinical presentation, suggesting the need for more detailed investigation of silent variants in ID patients with a large spectrum of phenotypes.
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http://dx.doi.org/10.1016/j.gene.2020.144793DOI Listing
August 2020

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

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

APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France.

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

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):356-370. Epub 2020 Feb 27.

Université de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058829PMC
March 2020

primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

J Med Genet 2020 06 3;57(6):389-399. Epub 2020 Feb 3.

Département de Génétique, APHP, Hopital Robert Debré, 75019 Paris, France

Background: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level.

Methods: 7 patients with newly identified mutations in (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions.

Results: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases.

Conclusion: This is the first report indicating that not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential.

Trial Registration Number: NCT01565005.
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http://dx.doi.org/10.1136/jmedgenet-2019-106474DOI Listing
June 2020

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction.

Am J Hum Genet 2019 12 27;105(6):1237-1253. Epub 2019 Nov 27.

Centre Hospitalier Universitaire Saint-Justine Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada. Electronic address:

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904826PMC
December 2019

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.

Am J Hum Genet 2019 12 14;105(6):1126-1147. Epub 2019 Nov 14.

Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904804PMC
December 2019

Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.

Nat Commun 2019 10 15;10(1):4679. Epub 2019 Oct 15.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
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http://dx.doi.org/10.1038/s41467-019-12435-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794285PMC
October 2019

A 14q distal chromoanagenesis elucidated by whole genome sequencing.

Eur J Med Genet 2020 Apr 25;63(4):103776. Epub 2019 Sep 25.

Service de Génétique, Laboratoire de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, Bron, France; GENDEV Team, Neurosciences Research Center of Lyon, INSERM U1028, CNRS UMR5292, UCBL1, 69677, Bron, France.

Chromoanagenesis represents an extreme form of genomic rearrangements involving multiple breaks occurring on a single or multiple chromosomes. It has been recently described in both acquired and rare constitutional genetic disorders. Constitutional chromoanagenesis events could lead to abnormal phenotypes including developmental delay and congenital anomalies, and have also been implicated in some specific syndromic disorders. We report the case of a girl presenting with growth retardation, hypotonia, microcephaly, dysmorphic features, coloboma, and hypoplastic corpus callosum. Karyotype showed a de novo structurally abnormal chromosome 14q31qter region. Molecular characterization using SNP-array revealed a complex unbalanced rearrangement in 14q31.1-q32.2, on the paternal chromosome 14, including thirteen interstitial deletions ranging from 33 kb to 1.56 Mb in size, with a total of 4.1 Mb in size, thus suggesting that a single event like chromoanagenesis occurred. To our knowledge, this is one of the first case of 14q distal deletion due to a germline chromoanagenesis. Genome sequencing allowed the characterization of 50 breakpoints, leading to interruption of 10 genes including YY1 which fit with the patient's phenotype. This precise genotyping of breaking junction allowed better definition of genotype-phenotype correlations.
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http://dx.doi.org/10.1016/j.ejmg.2019.103776DOI Listing
April 2020

Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature.

Hum Mutat 2020 01 4;41(1):69-80. Epub 2019 Oct 4.

Departments of Neurology and Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of K 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.
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http://dx.doi.org/10.1002/humu.23915DOI Listing
January 2020

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

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

Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.

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

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

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

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

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

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

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

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

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

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

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