학술논문
TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions.
Document Type
Academic Journal
Author
Hijazi H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Reis LM; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA.; Pehlivan D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.; Bernstein JA; Department of Pediatrics, Division of Medical Genetics, Stanford School of Medicine, Stanford, CA, USA.; Muriello M; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA.; Syverson E; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA.; Bonner D; Department of Pediatrics, Division of Medical Genetics, Stanford School of Medicine, Stanford, CA, USA.; Estiar MA; Department of Human Genetics, McGill University, Montreal, QC, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.; Gan-Or Z; Department of Human Genetics, McGill University, Montreal, QC, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada; Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada.; Rouleau GA; Department of Human Genetics, McGill University, Montreal, QC, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada; Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada.; Lyulcheva E; Liverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Liverpool, UK.; Greenhalgh L; Liverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Liverpool, UK.; Tessarech M; Department of Medical Genetics, Angers University Hospital, Angers, France; Mitovasc Unit, UMR CNRS 6015-INSERM 1083, University of Angers, Angers, France.; Colin E; Department of Medical Genetics, Angers University Hospital, Angers, France; Mitovasc Unit, UMR CNRS 6015-INSERM 1083, University of Angers, Angers, France.; Guichet A; Department of Medical Genetics, Angers University Hospital, Angers, France; Mitovasc Unit, UMR CNRS 6015-INSERM 1083, University of Angers, Angers, France.; Bonneau D; Department of Medical Genetics, Angers University Hospital, Angers, France; Mitovasc Unit, UMR CNRS 6015-INSERM 1083, University of Angers, Angers, France.; van Jaarsveld RH; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.; Lachmeijer AMA; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.; Ruaud L; INSERM UMR1141, Neurodiderot, University of Paris, 75019 Paris, France; APHP.Nord, Robert Debré University Hospital, Department of Genetics, 75019 Paris, France.; Levy J; APHP.Nord, Robert Debré University Hospital, Department of Genetics, 75019 Paris, France.; Tabet AC; APHP.Nord, Robert Debré University Hospital, Department of Genetics, 75019 Paris, France.; Ploski R; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.; Rydzanicz M; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.; Kępczyński Ł; Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, Łódź, Poland.; Połatyńska K; Department of Developmental Neurology an Epileptology, Polish Mother's Memorial Hospital - Research Institute, Łódź, Poland.; Li Y; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Fatih JM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Marafi D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics, Houston, TX, USA.; Coban-Akdemir Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Bi W; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics, Houston, TX, USA.; Gibbs RA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.; Hobson GM; Department of Research, Nemours Children's Health, Wilmington, DE, USA.; Hunter JV; E.B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX, USA.; Carvalho CMB; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Semina EV; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA; Departments of Ophthalmology and Visual Sciences and Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: esemina@mcw.edu.; Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA. Electronic address: jlupski@bcm.edu.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
Subject
Language
English
Abstract
An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion.
Competing Interests: Declaration of interests J.R.L. serves on the Scientific Advisory Board of Baylor Genetics (BG); J.A.R. and W.B. report affiliation with BG. Baylor College of Medicine (BCM) and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs clinical microarray analysis (CMA) and clinical exome sequencing (cES) and molecular diagnostic whole-genome sequencing (WGS). J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. H.H., D.P., Y.L., J.M.F., D.M., J.A.R., Z.H.C.A., W.B., R.A.G., C.M.B.C., J.E.P., and J.R.L. report affiliation with the Department of Molecular and Human Genetics at Baylor College of Medicine. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic and personal genome (CMA, cES, WGS) genomic testing offered in BG. Z.G.O. serves on the scientific advisory boards and receives consultancy fees from Bial Biotech Inc. and Handl Therapeutics. He has received consultancy fees from Neuron23, Ono Therapeutics, and UCB.
(Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests J.R.L. serves on the Scientific Advisory Board of Baylor Genetics (BG); J.A.R. and W.B. report affiliation with BG. Baylor College of Medicine (BCM) and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs clinical microarray analysis (CMA) and clinical exome sequencing (cES) and molecular diagnostic whole-genome sequencing (WGS). J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. H.H., D.P., Y.L., J.M.F., D.M., J.A.R., Z.H.C.A., W.B., R.A.G., C.M.B.C., J.E.P., and J.R.L. report affiliation with the Department of Molecular and Human Genetics at Baylor College of Medicine. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic and personal genome (CMA, cES, WGS) genomic testing offered in BG. Z.G.O. serves on the scientific advisory boards and receives consultancy fees from Bial Biotech Inc. and Handl Therapeutics. He has received consultancy fees from Neuron23, Ono Therapeutics, and UCB.
(Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)