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).
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Chong JX,McMillin MJ,Shively KM,Beck AE,Marvin CT,Armenteros JR,Buckingham KJ,Nkinsi NT,Boyle EA,Berry MN,Bocian M,Foulds N,Uzielli ML,Haldeman-Englert C,Hennekam RC,Kaplan P,Kline AD,Mercer CL,Nowaczyk MJ,Klein Wasdoi
10.1016/j.ajhg.2015.01.003subject
Has Abstractpub_date
2015-03-05 00:00:00pages
462-73issue
3eissn
0002-9297issn
1537-6605pii
S0002-9297(15)00011-7journal_volume
96pub_type
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