TY - JOUR T1 - <em>De novo</em> Mutations in <em>NALCN</em> Cause a Syndrome of Congenital Contractures of the Limbs and Face with Hypotonia, and Developmental Delay JF - bioRxiv DO - 10.1101/013656 SP - 013656 AU - Jessica X. Chong AU - Margaret J. McMillin AU - Kathryn M. Shively AU - Anita E. Beck AU - Colby T. Marvin AU - Jose R. Armenteros AU - Kati J. Buckingham AU - Naomi T. Nkinsi AU - Evan A. Boyle AU - Margaret N. Berry AU - Maureen Bocian AU - Nicola Foulds AU - Maria Luisa Giovannucci Uzielli AU - Chad Haldeman-Englert AU - Raoul C.M. Hennekam AU - Paige Kaplan AU - Antonie D. Kline AU - Catherine L. Mercer AU - Malgorzata J.M. Nowaczyk AU - Jolien S. Klein Wassink-Ruiter AU - Elizabeth W. McPherson AU - Regina A. Moreno AU - Angela E. Scheuerle AU - Vandana Shashi AU - Cathy A. Stevens AU - John C. Carey AU - Arnaud Monteil AU - Philippe Lory AU - Holly K. Tabor AU - Joshua D. Smith AU - Jay Shendure AU - Deborah A. Nickerson AU - Michael J. Bamshad Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/01/11/013656.abstract N2 - 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 simplex cases putatively diagnosed with “DA2A with severe neurological abnormalities” in which the proband had Congenital Contractures of the LImbs and FAce, Hypotonia, and global Developmental Delay often resulting in early death, a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in sodium leak channel, nonselective (NALCN) in four families with CLIFAHDD syndrome. Using molecular inversion probes to screen NALCN in a cohort of 202 DA cases as well as concurrent exome sequencing of six other DA cases revealed NALCN mutations in ten additional families with “atypical” forms of DA. All fourteen 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 mutant NALCN nearly abolished the expression of wildtype NALCN, suggesting that mutations 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 with an autosomal recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition with varied though overlapping phenotypic features perhaps depending on the type of mutation and affected protein domain(s). ER -