@article {194,
	title = {De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.},
	journal = {Am J Hum Genet},
	volume = {96},
	year = {2015},
	month = {2015 Mar 05},
	pages = {462-73},
	abstract = {<p>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).</p>},
	keywords = {Arthrogryposis, Contracture, Craniofacial Dysostosis, Cytoskeletal Proteins, Exome, Extremities, Face, Female, Gene Frequency, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Infant, Male, Muscle Hypotonia, Mutation, Missense, Sodium Channels},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2015.01.003},
	author = {Chong, Jessica X and McMillin, Margaret J and Shively, Kathryn M and Beck, Anita E and Marvin, Colby T and Armenteros, Jose R and Buckingham, Kati J and Nkinsi, Naomi T and Boyle, Evan A and Berry, Margaret N and Bocian, Maureen and Foulds, Nicola and Uzielli, Maria Luisa Giovannucci and Haldeman-Englert, Chad and Hennekam, Raoul C M and Kaplan, Paige and Kline, Antonie D and Mercer, Catherine L and Nowaczyk, Malgorzata J M and Klein Wassink-Ruiter, Jolien S and McPherson, Elizabeth W and Moreno, Regina A and Scheuerle, Angela E and Shashi, Vandana and Stevens, Cathy A and Carey, John C and Monteil, Arnaud and Lory, Philippe and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J}
}
