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Mol Genet Metab Rep. 2018 Jun 15;16:23-29. doi: 10.1016/j.ymgmr.2018.06.001. eCollection 2018 Sep.

De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome.

Author information

1
Department of Neurology, Boston University Medical Center, Boston, MA 02118, USA.
2
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
3
Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
4
Harvard Medical School, Boston, MA 02115, USA.
5
Developmental Neuropsychiatry Clinic, Department of Psychiatry, Boston Children's Hospital, Boston, MA 02115, USA.
6
Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA.
7
Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA.
8
Claritas Genomics, Cambridge, MA 02139, USA.
9
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
10
Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
11
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region.
12
Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
13
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
14
Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
15
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract

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

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