De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome
Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5 years of age manifested perseverations that interfer...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-09-01
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| Series: | Molecular Genetics and Metabolism Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426918300648 |
| _version_ | 1811283511288528896 |
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| author | Alcy Torres Catherine A. Brownstein Sahil K. Tembulkar Kelsey Graber Casie Genetti Robin J. Kleiman Kathleen J. Sweadner Chrystal Mavros Kevin X. Liu Niklas Smedemark-Margulies Kiran Maski Edward Yang Pankaj B. Agrawal Jiahai Shi Alan H. Beggs Eugene D'Angelo Sarah Hope Lincoln Devon Carroll Fatma Dedeoglu William A. Gahl Catherine M. Biggs Kathryn J. Swoboda Gerard T. Berry Joseph Gonzalez-Heydrich |
| author_facet | Alcy Torres Catherine A. Brownstein Sahil K. Tembulkar Kelsey Graber Casie Genetti Robin J. Kleiman Kathleen J. Sweadner Chrystal Mavros Kevin X. Liu Niklas Smedemark-Margulies Kiran Maski Edward Yang Pankaj B. Agrawal Jiahai Shi Alan H. Beggs Eugene D'Angelo Sarah Hope Lincoln Devon Carroll Fatma Dedeoglu William A. Gahl Catherine M. Biggs Kathryn J. Swoboda Gerard T. Berry Joseph Gonzalez-Heydrich |
| author_sort | Alcy Torres |
| collection | DOAJ |
| description | Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5 years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype. Keywords: Autism spectrum disorder, Fatigue, Sleep disorder |
| first_indexed | 2024-04-13T02:12:56Z |
| format | Article |
| id | doaj.art-a07a4ebf62e64ec0ae48dd05176df7a0 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-04-13T02:12:56Z |
| publishDate | 2018-09-01 |
| publisher | Elsevier |
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| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-a07a4ebf62e64ec0ae48dd05176df7a02022-12-22T03:07:14ZengElsevierMolecular Genetics and Metabolism Reports2214-42692018-09-01162329De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndromeAlcy Torres0Catherine A. Brownstein1Sahil K. Tembulkar2Kelsey Graber3Casie Genetti4Robin J. Kleiman5Kathleen J. Sweadner6Chrystal Mavros7Kevin X. Liu8Niklas Smedemark-Margulies9Kiran Maski10Edward Yang11Pankaj B. Agrawal12Jiahai Shi13Alan H. Beggs14Eugene D'Angelo15Sarah Hope Lincoln16Devon Carroll17Fatma Dedeoglu18William A. Gahl19Catherine M. Biggs20Kathryn J. Swoboda21Gerard T. Berry22Joseph Gonzalez-Heydrich23Department of Neurology, Boston University Medical Center, Boston, MA 02118, USADivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Corresponding author at: Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Developmental Neuropsychiatry Clinic, Department of Psychiatry, Boston Children's Hospital, Boston, MA 02115, USATommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Developmental Neuropsychiatry Clinic, Department of Psychiatry, Boston Children's Hospital, Boston, MA 02115, USADivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USAHarvard Medical School, Boston, MA 02115, USA; Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USAHarvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USADivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USAHarvard Medical School, Boston, MA 02115, USAClaritas Genomics, Cambridge, MA 02139, USAHarvard Medical School, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USAHarvard Medical School, Boston, MA 02115, USA; Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USADivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USADepartment of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative RegionDivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USATommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Developmental Neuropsychiatry Clinic, Department of Psychiatry, Boston Children's Hospital, Boston, MA 02115, USAHarvard Medical School, Boston, MA 02115, USA; Developmental Neuropsychiatry Clinic, Department of Psychiatry, Boston Children's Hospital, Boston, MA 02115, USADevelopmental Neuropsychiatry Clinic, Department of Psychiatry, Boston Children's Hospital, Boston, MA 02115, USADivision of Immunology, Boston Children's Hospital, Boston, MA 02115, USANational Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAHarvard Medical School, Boston, MA 02115, USA; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, CanadaHarvard Medical School, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USADivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USADivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Corresponding author at: Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5 years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype. Keywords: Autism spectrum disorder, Fatigue, Sleep disorderhttp://www.sciencedirect.com/science/article/pii/S2214426918300648 |
| spellingShingle | Alcy Torres Catherine A. Brownstein Sahil K. Tembulkar Kelsey Graber Casie Genetti Robin J. Kleiman Kathleen J. Sweadner Chrystal Mavros Kevin X. Liu Niklas Smedemark-Margulies Kiran Maski Edward Yang Pankaj B. Agrawal Jiahai Shi Alan H. Beggs Eugene D'Angelo Sarah Hope Lincoln Devon Carroll Fatma Dedeoglu William A. Gahl Catherine M. Biggs Kathryn J. Swoboda Gerard T. Berry Joseph Gonzalez-Heydrich De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome Molecular Genetics and Metabolism Reports |
| title | De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome |
| title_full | De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome |
| title_fullStr | De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome |
| title_full_unstemmed | De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome |
| title_short | De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome |
| title_sort | de novo atp1a3 and compound heterozygous nlrp3 mutations in a child with autism spectrum disorder episodic fatigue and somnolence and muckle wells syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2214426918300648 |
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