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).

DOI: 10.1016/j.ajhg.2015.01.003

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@article{Chong2015DeNM, title={De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.}, author={Jessica X Chong and Margaret J. McMillin and Kathryn M B Shively and Anita E. Beck and Colby T. Marvin and Jose R Armenteros and Kati J. Buckingham and Naomi T Nkinsi and Evan A. Boyle and Margaret N Berry and Maureen E Bocian and Nicola C. Foulds and Maria Luisa Giovannucci Uzielli and Chad R Haldeman-Englert and Raoul C. M. Hennekam and Paige B. Kaplan and Antonie D. Kline and Catherine L Mercer and Małgorzata J M Nowaczyk and Jolien S Klein Wassink-Ruiter and Elizabeth McPherson and Regina A Moreno and Angela E. Scheuerle and Vandana Shashi and Cathy A. Stevens and John C Carey and Arnaud Monteil and Philippe Lory and Holly K Tabor and Joshua D. Smith and Jay Shendure and Deborah A. Nickerson and Michael Bamshad}, journal={American journal of human genetics}, year={2015}, volume={96 3}, pages={462-73} }