title: De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.
abstract: Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Jessica X
authors: JX
authors: Chong
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Margaret J
authors: MJ
authors: McMillin
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Kathryn M
authors: KM
authors: Shively
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Anita E
authors: AE
authors: Beck
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Colby T
authors: CT
authors: Marvin
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Jose R
authors: JR
authors: Armenteros
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Kati J
authors: KJ
authors: Buckingham
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Naomi T
authors: NT
authors: Nkinsi
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Evan A
authors: EA
authors: Boyle
authors: Department of Pediatrics, Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors: Margaret N
authors: MN
authors: Berry
authors: Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California Irvine, Orange, CA 92868 USA.
authors: Maureen
authors: M
authors: Bocian
authors: Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK; Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK.
authors: Nicola
authors: N
authors: Foulds
authors: Genetics and Molecular Medicine, Dipartimento di Scienz, University of Florence, 6 Viale G. Pieraccini, 50139 Florence, Italy.
authors: Maria Luisa Giovannucci
authors: ML
authors: Uzielli
authors: Department of Pediatrics, Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors: Chad
authors: C
authors: Haldeman-Englert
authors: Department of Pediatrics, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, the Netherlands.
authors: Raoul C M
authors: RC
authors: Hennekam
authors: Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Paige
authors: P
authors: Kaplan
authors: Department of Pediatrics, Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.
authors: Antonie D
authors: AD
authors: Kline
authors: Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK; Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK.
authors: Catherine L
authors: CL
authors: Mercer
authors: Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
authors: Malgorzata J M
authors: MJ
authors: Nowaczyk
authors: Department of Genetics, University Medical Centre Groningen, 9700 RB, Groningen, the Netherlands.
authors: Jolien S
authors: JS
authors: Klein Wassink-Ruiter
authors: Department of Medical Genetics, Marshfield Clinic, Marshfield, WI 54449, USA.
authors: Elizabeth W
authors: EW
authors: McPherson
authors: Departamento de Ciencias Básicas, Facultad de Medicina, Universidad de la Frontera, Temuco 4811230, Chile.
authors: Regina A
authors: RA
authors: Moreno
authors: Department of Pediatrics, Division of Genetics and Metabolism, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Angela E
authors: AE
authors: Scheuerle
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA.
authors: Vandana
authors: V
authors: Shashi
authors: Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, TN 37403, USA.
authors: Cathy A
authors: CA
authors: Stevens
authors: Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.
authors: John C
authors: JC
authors: Carey
authors: Institut de Génomique Fonctionelle, LabEx "Ion Channel Science and Therapeutics," Centre National de la Recherche Scientifique UMR 5203, Montpelier F-34094, France; Département de Physiologie, Université Montpellier, Montpellier F34094, France; Institut National de la Santé et de la Recherche Médicale, Paris, France.
authors: Arnaud
authors: A
authors: Monteil
authors: Institut de Génomique Fonctionelle, LabEx "Ion Channel Science and Therapeutics," Centre National de la Recherche Scientifique UMR 5203, Montpelier F-34094, France; Département de Physiologie, Université Montpellier, Montpellier F34094, France; Institut National de la Santé et de la Recherche Médicale, Paris, France.
authors: Philippe
authors: P
authors: Lory
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Holly K
authors: HK
authors: Tabor
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Joshua D
authors: JD
authors: Smith
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Jay
authors: J
authors: Shendure
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Deborah A
authors: DA
authors: Nickerson
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: mbamshad@uw.edu.
authors: Michael J
authors: MJ
authors: Bamshad
mesh_terms: D001176:Arthrogryposis / Q000235:genetics; D003286:Contracture / Q000235:genetics*; D003394:Craniofacial Dysostosis / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005121:Extremities / Q000503:physiopathology*; D005145:Face / Q000002:abnormalities*; D005260:Female; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007223:Infant; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins; D009123:Muscle Hypotonia / Q000235:genetics*; D020125:Mutation, Missense; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D007473:Ion Channels; C510594:MYH3 polypeptide, human; D008565:Membrane Proteins; C544681:NALCN protein, human; D015222:Sodium Channels