De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia

Abstract

Three recessive mutations in the sodium leak channel, nonselective (NALCN) have been reported to cause intellectual disability and hypotonia. In addition, 14 de novo heterozygous mutations have been identified in 15 patients with arthrogryposis and neurodevelopmental impairment. Here, we report three patients with neurodevelopmental disease and hypotonia, harboring one recurrent (p.R1181Q) and two novel mutations (p.L312V and p.V1020F) occurring de novo in NALCN. Mutation p.L312 is located in the pore forming S6 region of domain I and p.V1020F in the S5 region of domain III. Mutation p.R1181Q is in a linker region. Mapping these three mutations to a model of NALCN showed p.Leu312 and p.Val1020 positioned in the hydrophobic core of the pore modules, indicating these two mutations may affect the gating function of NALCN. Although p.R1181Q is unlikely to affect the ion channel structure, previous studies have shown that an analogous mutation in Caenorhabditis elegans produced a phenotype with a coiling locomotion, suggesting that p.R1181Q could also affect NALCN function. Our three patients showed profound intellectual disability and growth delay, facial dysmorphologies and hypotonia. The present data support previous work suggesting heterozygous NALCN mutations lead to syndromic neurodevelopmental impairment.

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

“…The detected variant of NALCN (c.1789G > A, p.V597I) with a de novo condition is strongly considered to be responsible for our patient's disease for the following four reasons. 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.…”

“…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.…”

Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants

“…For example, the 178 bp deletion in NALCN (a gene related with adductive thumbs) disrupted an ADE in the cerebellum and exhibited a sharp difference in enhancer activities between monkeys and apes ( Figure 5F and Table S26). It was reported that NALCN was also associated with neurodevelopmental diseases (Bramswig, et al 2018) and the mutation of NALCN leads to syndromic neurodevelopmental impairment (Fukai, et al 2016). Another example is the ASSV (242 bp deletion) within an ADE in PcGm in TLN2 ( Figure 5A), a brain-function-related gene (Gusareva, et al 2018;Mendez-David, et al 2017).…”

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

“…We first evaluated whether the deletion could unmask recessive alleles, and found no rare pathogenic mutations within the seven 16p12.1 genes on the non-deleted chromosome (Table S7) 55,85,86 . Further, in another family (family GL_011), a rare deletion in 2p16.3 inherited from a non-16p12.1 carrier parent, encompassing NRXN1, was also identified in a proband.…”