De novo Mutations in NALCN Cause a Syndrome of Congenital Contractures of the Limbs and Face with 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 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).

Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchyme

“…This work suggests a mechanism linking observed craniofacial phenotypes of channelopathy patients with disruptions in traditional morphogen signaling. The necessity of ion channels for proper morphogenesis of human structures has been repeatedly documented ( KCNJ2 : Anderson-Tawil syndrome, CACNA1C : Timothy Syndrome, GIRK2 : Keppen-Ludinski syndrome, NALCN : IHPRF1, and CHRNA7: 15q13.3 microdeletion syndrome) ( 8, 9, 12, 13, 15, 30, 51–53 ). Similarly, pharmacological and genetic disruption of ion channels during embryonic development causes morphological abnormalities in animal models ( 54 ).…”

Novel NALCN variant linked to temporal lobe epilepsy

“…Our search of the literature identified 11 patients with seizures harboring NALCN variants (Table 1). All had IHPRF (7), CLIFAHDD (2) or infantile neuraxonal dystrophy (INAD) (2); seizures were never the mode of presentation (Al‐Sayed et al, 2013; Angius et al, 2018; Chong et al, 2015; Gal et al, 2016; García‐Hernández et al, 2021; Köroğlu et al, 2013). In contrast, our two cases only had focal epilepsy without intellectual disability nor any feature remotely resembling IHPRF, CLIFAHDD or INAD.…”

“…Mutations in the NALCN gene have been reported in patients with infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF; MIM 615419) and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD syndrome; MIM 616266) (Angius et al, 2018). A handful of patients with developmental delay/intellectual disability and epilepsy have also been reported (Al‐Sayed et al, 2013; Angius et al, 2018; Chong et al, 2015; Gal et al, 2016; García‐Hernández et al, 2021; Köroğlu et al, 2013). Herein, we report a father and a son featuring focal epilepsy without intellectual disability, expanding the spectrum of NALCN‐related disorders.…”

Novel nonsense mutation in UNC80 in a Turkish patient further validates the sociable skill and severe gastrointestinal problems as part of disease spectrum

“…Two of the four NALCN complex Biallelic deleterious variants in NALCN (MIM 611549) were found to cause infantile hypotonia, psychomotor retardation and characteristics facies 1 (IHPRF1, MIM# 615419) (Koroglu et al, 2013). Monoallelic deleterious variants in NALCN were also found to be causative for congenital contractures in limbs and face, hypotonia, and developmental delay (MIM# 616266) (Chong et al, 2015). Both IHPRF1 and IHPRF2, caused by NALCN and UNC80, respectively, has significantly overlapping clinical features.…”