Publications by authors named "Delphine Heron"

156 Publications

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

Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in .

Neurol Genet 2021 Dec 21;7(6):e631. Epub 2021 Oct 21.

Department of Genetics (A.M.R.C., D.A.D.), Children's Hospital of Eastern Ontario, Ottawa; CHU Sainte Justine Research Centre (S.S., T.T.M.N., P.M.C.), Université de Montréal, Quebec, Canada; Pediatric Neurology & Development Center (H.B.), Shamir (Assaf Harofeh) Medical Center, Zerifin, Tel Aviv University; Pediatric Genetics Clinic (E.S.-D.), Schneider Children's Medical Centre, Petach Tikya, Tel Aviv University, Israel; Unit of Neurophysiology, Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy; Section of Medical Genomics (K.C.H.), Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, Sacramento; APHP (B.K.), Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France; APHP Sorbonne-Université (D.H.), UF Génétique Médicale, Hôpitaux Pitié-Salpêtrière et Trousseau, Centre de Référence "déficiences intellectuelles de causes rares", Paris, France; Children's Hospital of Eastern Ontario Research Institute (D.L.J., W. M., D.A.D.), Ottawa, Canada; Department of Human Genetics (S.M., H.W.), Hannover Medical School, Germany; Biochemical Diseases (R.R.), BC Children's Hospital, Vancouver, British Columbia, Canada; Greenwood Genetic Center (E.S., J.R., W.B.B., J.R.J.), SC; Department of Molecular Medicine (V.S.), University of Pavia; Neurogenetics Research Center (V.S.), IRCCS Mondino Foundation, Pavia; Unit of Neuromuscular and Neurodegenerative Disorders (G.Z.), Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy; and Medical Genetics Division (P.M.C.), Department of Pediatrics, Sainte-Justine University Hospital Centre, Montreal, Quebec, Canada.

Background And Objectives: To expand the clinical knowledge of 1-related glycosylphosphatidylinositol (GPI) deficiency.

Methods: An international case series of 7 patients with biallelic variants were identified. Clinical, biochemical, and neuroimaging data were collected for comparison. Where possible, GPI-anchored proteins were assessed using flow cytometry.

Results: Ten novel variants were identified in 7 patients. Flow cytometry samples of 3 available patients confirmed deficiency of several GPI-anchored proteins on leukocytes. Extensive phenotypic information was available for each patient. The majority experienced developmental delay, seizures, and hypotonia. Neuroimaging revealed cerebellar anomalies in the majority of the patients. Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects. We notably describe individuals either less affected or older than the ones published previously.

Discussion: Clinical features of the cases reported broaden the spectrum of the known phenotype of -related GPI deficiency, while outlining the importance of using functional studies such as flow cytometry to aid in variant classification.
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http://dx.doi.org/10.1212/NXG.0000000000000631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532669PMC
December 2021

Tremor-like subcortical myoclonus in STXBP1 encephalopathy.

Eur J Paediatr Neurol 2021 Sep 3;34:62-66. Epub 2021 Jul 3.

APHP-Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière and Hôpital Armand Trousseau, Paris, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.

The phenotypic spectrum of STXBP1-related encephalopathy ranges from infantile epileptic encephalopathy to intellectual disability with nonsyndromic or absent epilepsy. Although being frequently reported, the tremor associated with STXBP1 has not been fully characterized to date. The aim of our study was to describe it. We recruited patients with intellectual disability due to STXBP1 variants, regardless of their epileptic phenotype, who had tremor at examination and who underwent neurophysiological testing including polymyographic registration of upper limbs muscles activity at rest, during posture maintenance and action. Six patients met the inclusion criteria over four years. Clinically, all had a postural and action distal tremor increased by emotions. Neurophysiological recordings showed a specific myoclonus pattern and were highly suggestive of a subcortical generator. The tremor-like observed in STXBP1 encephalopathy is due to a subcortical pseudo-rhythmic myoclonus.
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http://dx.doi.org/10.1016/j.ejpn.2021.06.005DOI Listing
September 2021

Care management in a French cohort with Down syndrome from the AnDDI-Rares/CNSA study.

Eur J Med Genet 2021 Oct 15;64(10):104290. Epub 2021 Jul 15.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs Ile de France, APHP Robert Debré, Paris, France.

Down syndrome (DS) is a genetic neurodevelopmental disorder. In individuals with DS, a multidisciplinary approach to care is required to prevent multiple medical complications. The aim of this study was to describe the rehabilitation, medical care, and educational and social support provided to school-aged French DS patients with varying neuropsychological profiles. A mixed study was conducted. Quantitative data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Qualitative data were collected by semi-structured face-to-face interviews and focus groups. Ninety-five DS subjects with a mean age of 10.9 years were included. Sixty-six per cent had a moderate intellectual disability (ID) and 18.9% had a severe ID. Medical supervision was generally multidisciplinary but access to medical specialists was often difficult. In terms of education, 94% of children under the age of six were in typical classes. After the age of 15, 75% were in medico-social institutions. Analysis of multidisciplinary rehabilitation conducted in the public and private sectors revealed failure to access physiotherapy, psychomotor therapy and occupational therapy, but not speech therapy. The main barrier encountered by patients was the difficulty accessing appropriate facilities due to a lack of space and long waiting lists. In conclusion, children and adolescents with DS generally received appropriate care. Though the management of children with DS has been improved considerably, access to health facilities remains inadequate.
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http://dx.doi.org/10.1016/j.ejmg.2021.104290DOI Listing
October 2021

Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay.

Cells 2021 05 22;10(6). Epub 2021 May 22.

Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97210, USA.

PARP6, a member of a family of enzymes (17 in humans) known as poly-ADP-ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that Parp6 is a regulator of dendrite morphogenesis in rat hippocampal neurons, its function in the nervous system in vivo is poorly understood. Here, we describe the generation of a loss-of-function mouse model for examining the function of Parp6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, we generated a mouse line that expressed a Parp6 truncated variant (Parp6) in place of Parp6. Unlike Parp6, Parp6 is devoid of catalytic activity. Homozygous Parp6 do not exhibit obvious neuromorphological defects during development, but nevertheless die perinatally. This suggests that Parp6 catalytic activity is important for postnatal survival. We also report PARP6 mutations in six patients with several neurodevelopmental disorders, including microencephaly, intellectual disabilities, and epilepsy. The most severe mutation in (C563R) results in the loss of catalytic activity. Expression of Parp6 in hippocampal neurons decreases dendrite morphogenesis. To gain further insight into function in neurons we also performed a BioID proximity labeling experiment in hippocampal neurons and identified several microtubule-binding proteins (e.g., MAP-2) using proteomics. Taken together, our results suggest that PARP6 is an essential microtubule-regulatory gene in mice, and that the loss of PARP6 catalytic activity has detrimental effects on neuronal function in humans.
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http://dx.doi.org/10.3390/cells10061289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224619PMC
May 2021

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

Genet Med 2021 09 30;23(9):1715-1725. Epub 2021 May 30.

Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.

Purpose: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development.

Methods: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b.

Results: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye.

Conclusion: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
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http://dx.doi.org/10.1038/s41436-021-01196-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460429PMC
September 2021

Syndromic neurodevelopmental disorder associated with de novo variants in DDX23.

Am J Med Genet A 2021 10 29;185(10):2863-2872. Epub 2021 May 29.

Greenwood Genetic Center, Greenwood, South Carolina, USA.

The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23). The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA. Our cohort of patients, gathered through GeneMatcher, exhibited features including tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The individuals presented in this article provide evidence of a syndrome related to alterations in DDX23 characterized predominantly by atypical neurodevelopment.
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http://dx.doi.org/10.1002/ajmg.a.62359DOI Listing
October 2021

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

Am J Hum Genet 2021 05;108(5):857-873

GeneDx, Gaithersburg, MD 20877, USA.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206167PMC
May 2021

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

J Med Genet 2021 Apr 5. Epub 2021 Apr 5.

Department of Pediatric Neurology, APHP-Bicêtre Hospital, Le Kremlin-Bicêtre, France.

Background: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.

Methods: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.

Results: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (, , , , , , , and ). Moreover, we identified pathogenic variants in and expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).

Conclusion: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
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http://dx.doi.org/10.1136/jmedgenet-2020-107595DOI Listing
April 2021

Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants.

Eur J Hum Genet 2021 Sep 18;29(9):1405-1417. Epub 2021 Feb 18.

Biochemistry & Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.
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http://dx.doi.org/10.1038/s41431-021-00821-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440520PMC
September 2021

Smith-Magenis syndrome: Clinical and behavioral characteristics in a large retrospective cohort.

Clin Genet 2021 04 5;99(4):519-528. Epub 2021 Jan 5.

Department of Genetics, APHP Nord-Université de Paris Robert Debré University Hospital and INSERM U1141 NeuroDiderot, Paris, France.

Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.
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http://dx.doi.org/10.1111/cge.13906DOI Listing
April 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

Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.

Eur J Med Genet 2020 Dec 28;63(12):104064. Epub 2020 Sep 28.

Clinical Investigation Centre, INSERM 1432 - Clinical Epidemiology, Faculty of Medicine, Dijon University Hospital, France.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.
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http://dx.doi.org/10.1016/j.ejmg.2020.104064DOI Listing
December 2020

Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation.

Genet Med 2020 11 22;22(11):1887-1891. Epub 2020 Jun 22.

Service de Génétique Clinique, CHU de Dijon, Dijon, France.

Purpose: Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC).

Methods: CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered.

Results: pES results were available within a median of 21.5 days (9-53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy.

Conclusion: Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.
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http://dx.doi.org/10.1038/s41436-020-0872-8DOI Listing
November 2020

De novo variants in encoding an E3 ubiquitin ligase, are associated with developmental delay, hypotonia and dysmorphic features.

J Med Genet 2021 03 19;58(3):205-212. Epub 2020 May 19.

Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Background: Ubiquitination has a central role in numerous biological processes, including cell development, stress responses and ageing. Perturbed ubiquitination has been implicated in human diseases ranging from cancer to neurodegenerative diseases. encodes a RING-type E3 ubiquitin ligase involved in protein ubiquitination. Among numerous other roles, SIAH1 regulates metabotropic glutamate receptor signalling and affects neural cell fate. Moreover, SIAH1 positively regulates Wnt signalling through ubiquitin-mediated degradation of Axin and accumulation of β-catenin.

Methods: Trio exome sequencing followed by Sanger validation was undertaken in five individuals with syndromic developmental delay. Three-dimensional structural modelling was used to predict pathogenicity of affected residues. Wnt stimulatory activity was measured by luciferase reporter assays and Axin degradation assays in HEK293 cells transfected with wild-type and mutant SIAH1 expression plasmids.

Results: We report five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia, in whom exome sequencing identified de novo monoallelic variants in . In silico protein modelling suggested alteration of conserved functional sites. In vitro experiments demonstrated loss of Wnt stimulatory activity with the SIAH1 mutants, suggesting variant pathogenicity.

Conclusion: Our results lend support to as a candidate Mendelian disease gene for a recognisable syndrome, further strengthening the connection between and neurodevelopmental disorders. Furthermore, the results suggest that dysregulation of the Wnt/β-catenin pathway may be involved in the pathogenesis.
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http://dx.doi.org/10.1136/jmedgenet-2019-106335DOI Listing
March 2021

Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity.

Nat Commun 2020 05 15;11(1):2441. Epub 2020 May 15.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.
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http://dx.doi.org/10.1038/s41467-020-16294-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229210PMC
May 2020

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

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

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

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

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

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

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

Two Novel Cases of Resistance to Thyroid Hormone Due to Mutation.

Thyroid 2020 08 23;30(8):1217-1221. Epub 2020 Apr 23.

Institut de Génomique Fonctionnelle de Lyon, INRA USC 1370, Université de Lyon, Université Lyon 1, CNRS UMR 5242, Ecole Normale Supérieure de Lyon, Lyon, France.

Resistance to thyroid hormone alpha (RTHα) is a rare and under-recognized genetic disease caused by mutations of , the gene encoding thyroid hormone receptor α1 (TRα1). We report here two novel missense mutations (M259T, T273A) in patients with RTHα. We combined biochemical and cellular assays with modeling to assess the capacity of mutant TRα1 to bind triiodothyronine (T3), to heterodimerize with RXR, to interact with transcriptional coregulators, and to transduce a T3 transcriptional response. M259T, and to a lower extent T273A, reduces the affinity of TRα1 for T3. Their negative influence is only reverted by large excess of T3. The severity of the two novel RTHα cases originates from a reduction in the binding affinity of TRα1 mutants to T3 and thus correlates with the incapacity of corepressors to dissociate from TRα1 mutants in the presence of T3.
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http://dx.doi.org/10.1089/thy.2019.0602DOI 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

Callosal agenesis and congenital mirror movements: outcomes associated with DCC mutations.

Dev Med Child Neurol 2020 06 14;62(6):758-762. Epub 2020 Feb 14.

School of Psychology, The University of Queensland, St Lucia, Brisbane, Australia.

Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability. WHAT THIS PAPER ADDS: Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum. A DCC pathogenic variant in isolation is associated with the best prognosis.
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http://dx.doi.org/10.1111/dmcn.14486DOI Listing
June 2020

De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype.

Am J Med Genet A 2020 05 7;182(5):962-973. Epub 2020 Feb 7.

Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.

CDC42BPB encodes MRCKβ (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.
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http://dx.doi.org/10.1002/ajmg.a.61505DOI Listing
May 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

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

Hum Mutat 2020 04 14;41(4):837-849. Epub 2020 Jan 14.

Department of Allergy/Immunology, Spectrum Health Helen Devos Children's Hospital, Michigan State University College of Human Medicine, East Lansing, Michigan.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
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http://dx.doi.org/10.1002/humu.23975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457149PMC
April 2020

Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene.

Clin Genet 2020 03 15;97(3):477-482. Epub 2020 Jan 15.

APHP, Département de Génétique, GH Pitié-Salpêtrière, Paris, France.

Biallelic mutations in the PLCB1 gene, encoding for a phospholipase C beta isoform strongly expressed in the brain, have been reported to cause infantile epileptic encephalopathy in only four children to date. We report here three additional patients to delineate the phenotypic and genotypic characteristics of the disease. Our three patients were one sporadic case with an intragenic homozygous deletion and two cousins with the homozygous p.(Arg222*) nonsense variant in PLCB1. These patients had severe to profound intellectual disability, epileptic spasms at age 3-5 months concomitant with developmental arrest or regression, other seizure types and drug-resistant epilepsy. With this report, we expand the clinical, radiologic and electroencephalographic knowledge about the extremely rare PLCB1-related encephalopathy. Since the first report in 2010, the overall number of reported patients with our additional patients is currently limited to seven. All seven patients had epileptic encephalopathy, mainly infantile spasms and 6/7 had profound intellectual disability, with one only being able to walk. Truncal hypotonia was the most frequent neurological sign, sometimes associated with pyramidal and/or extrapyramidal hypertonia of limbs. Microcephaly was inconstant. In conclusion, the phenotypical spectrum of PLCB1-related encephalopathy is relatively narrow, comprises infantile spasms and severe to profound intellectual disability, and does not seem to define a recognizable clinical entity.
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http://dx.doi.org/10.1111/cge.13696DOI Listing
March 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

PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration.

Neurobiol Dis 2020 03 14;136:104709. Epub 2019 Dec 14.

Department of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, Orsay, France. Electronic address:

Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "severe" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.
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http://dx.doi.org/10.1016/j.nbd.2019.104709DOI Listing
March 2020
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