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).

A de novo mutation in the NALCN gene in an adult patient with cerebellar ataxia associated with intellectual disability and arthrogryposis

“…First, patients reported with mutations in NALCN have similar clinical features to our patient (3)(4)(5). Second, Sanger sequencing confirmed that the patient had this missense mutation, and that the unaffected parents and sister did not have (Fig.…”

“…Recessive mutations predominantly cause hypotonia and severe intellectual disabilities like infantile neuroaxonal dystrophy (1,2). Meanwhile, dominant mutations are all de novo, and cause congenital contractures of the limbs and face, hypotonia, and global developmental delay syndrome, or intellectual disability, ataxia and arthrogryposis (3)(4)(5). Thus, both recessive and dominant mutations might cause a severe phenotype in childhood.…”

Freeman-Sheldon syndrome in a 29-year-old woman presenting with rare and previously undescribed features

“…Sensory impairments may have artificially reduced some scores for patients with FSS who were considered ‘average’ or ‘borderline’. While certain patients with FSS with mental retardation, hypotonia and early death exhibit missense allelic variations in the sodium leak channel, non-selective (NALCN),22 our clinical experience with many patients of different ages and socioeconomic backgrounds has shown that higher intelligence, relative to other family members, may represent a strong feature in a subset of patients with FSS without NALCN allelic variations or repeated hypoxia. Higher intelligence in this subset of patients with FSS may be the first association of higher intelligence with a pathological entity, and after many years of observation, we feel this possible association can no longer be ignored and warrants further inquiry.…”

A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders

“…These infants were found to have mutations in NALCN and KIAA0586, respectively, with both genes having been associated with disease this year. [26][27][28][29] NGS panel containing known disease genes performed for these two infants in 2014 would have returned a negative result. Identifying the causative mutations would have required retesting because new genes were described in the literature and incorporated into commercially available tests.…”