title: Exome analysis of Smith-Magenis-like syndrome cohort identifies de novo likely pathogenic variants.
abstract: Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region. This can help clarify NDN's role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Seth I
authors.initials: SI
authors.lastname: Berger
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Ciccone
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Simon
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: May Christine
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA, 22042, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Billington
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Office of Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive MSC 1851, Building 10, 10-C103, Bethesda, MD, 20892, USA.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Introne
authors.affiliation: Children's National Medical Center, Washington, DC, 20010, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gropman
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, 20007, USA.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Blancato
authors.affiliation: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Rockville, MD, 20892, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Office of Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive MSC 1851, Building 10, 10-C103, Bethesda, MD, 20892, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.affiliation: Office of Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive MSC 1851, Building 10, 10-C103, Bethesda, MD, 20892, USA. acmsmith@nih.gov.
authors.forename: Ann C M
authors.initials: ACM
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002675:Child, Preschool; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D059472:Exome; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D058496:Smith-Magenis Syndrome / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C116013:DEAF1 protein, human; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human; C000612102:NDN protein, human; D009687:Nuclear Proteins; C431552:RAI1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins