Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome.

Autor: Steele JL; University of Connecticut School of Medicine, Farmington, Connecticut., Morrow MM; GeneDx, Inc., Gaithersburg, Maryland., Sarnat HB; Departments of Paediatrics, Pathology (Neuropathology), and Clinical Neurosciences, University of Calgary Cumming School of Medicine and Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada., Alkhunaizi E; Department of Obstetrics and Gynecology, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada., Brandt T; GeneDx, Inc., Gaithersburg, Maryland., Chitayat DA; Department of Obstetrics and Gynecology, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada., DeFilippo CP; Division of Genomic Medicine, Department of Pediatrics, MIND Institute, University of California-Davis, Sacramento, California., Douglas GV; GeneDx, Inc., Gaithersburg, Maryland., Dubbs HA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Elloumi HZ; GeneDx, Inc., Gaithersburg, Maryland., Glassford MR; Division of Pediatric Genetics, Metabolism and Genomic Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan., Hannibal MC; Division of Pediatric Genetics, Metabolism and Genomic Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan., Héron B; Hôpital Armand Trousseau, Service de Neurologie Pédiatrique, Paris, France., Kim LE; Department of Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, Ontario, Canada., Marco EJ; Department of Neurodevelopmental Medicine, CorticaCare, San Diego, California., Mignot C; Clinical Genetic Department, Pitié Salpétrière University Hospital, Paris, France., Monaghan KG; GeneDx, Inc., Gaithersburg, Maryland., Myers KA; Division of Neurology, Department of Pediatrics, McGill University Health Centre, Montreal, Canada., Parikh S; Department of Mitochondrial Medicine & Genetics, Cleveland Clinic, Cleveland, Ohio., Quinonez SC; Division of Pediatric Genetics, Metabolism and Genomic Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan., Rajabi F; Division of Genetics and Genomics, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts., Shankar SP; Division of Genomic Medicine, Department of Pediatrics, MIND Institute, University of California-Davis, Sacramento, California., Shinawi MS; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri., van de Kamp JJP; Clinical Genetics, Amsterdam University Medical Centers, Amsterdam Netherlands., Veerapandiyan A; Division of Neurology, Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Arkansas., Waldman AT; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Graf WD; Division of Neurology, Department of Pediatrics, Connecticut Children's, University of Connecticut, Farmington, Connecticut. Electronic address: wgraf@connecticutchildrens.org.
Jazyk: angličtina
Zdroj: Pediatric neurology [Pediatr Neurol] 2022 Jan; Vol. 126, pp. 65-73. Date of Electronic Publication: 2021 Oct 18.
DOI: 10.1016/j.pediatrneurol.2021.10.008
Abstrakt: Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants.
Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant.
Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05).
Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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