NALCN – Freeman-Sheldon syndrome

Freeman-Sheldon syndrome, also known as distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition typically caused by mutations in MYH3 and characterized by congenital contractures of the face and limbs with preserved cognition. A distinct subset of patients presenting with DA2A plus severe hypotonia and global developmental delay has been delineated as CLIFAHDD syndrome, expanding the phenotypic spectrum associated with congenital arthrogryposis. Recent exome sequencing efforts have implicated heterozygous NALCN variants in this atypical form, suggesting a novel genetic etiology overlapping Freeman-Sheldon syndrome.

In an initial cohort of five individuals diagnosed with DA2A and neurological abnormalities, de novo missense mutations in NALCN were identified in four families. Targeted screening of 202 DA-affected individuals and concurrent exome sequencing of six additional DA cases uncovered NALCN mutations in ten further families, for a total of 14 unrelated probands (PMID:25683120). All variants arose de novo and followed an autosomal-dominant inheritance pattern with no additional affected relatives.

The spectrum of NALCN variants in CLIFAHDD syndrome comprises 14 distinct missense changes clustering in or near the S5 and S6 pore-forming transmembrane segments of the channel. A recurrent variant, c.518G>T (p.Arg173Leu), has been observed among unrelated cases and underscores hotspot pathogenicity within the pore region. These findings highlight genotype-phenotype correlations that distinguish dominant CLIFAHDD alleles from recessive loss-of-function variants.

Functional studies demonstrate that CLIFAHDD-associated NALCN mutations nearly abolish wild-type channel expression, indicating a dominant-negative effect (PMID:25683120). Heterologous expression in NG108-15 cells revealed that representative CLIFAHDD mutants p.Leu509Ser and p.Tyr578Ser exhibit increased current densities and slower inactivation, consistent with gain-of-function properties (PMID:31409833). In Caenorhabditis elegans, the orthologous c.1768C>T (p.Leu590Phe) mutation produces severe hypercontraction and uncoordinated movement, corroborating a gain-of-function mechanism in vivo (PMID:27558372).

In contrast, homozygous or compound heterozygous loss-of-function NALCN mutations cause an autosomal-recessive syndrome of profound hypotonia, intellectual disability, and speech impairment (IHPRF1) (PMID:24075186). This allelic and mechanistic heterogeneity illustrates that divergent NALCN mutational classes yield distinct neurodevelopmental phenotypes.

Collectively, the association between heterozygous NALCN missense variants and DA2A-like contractures with neurological involvement merits a Moderate ClinGen classification. Fourteen de novo probands with consistent dominant-negative/gain-of-function evidence support pathogenicity, though extended segregation data remain limited. Key Take-home: NALCN mutational screening should be considered in patients with DA2A features accompanied by hypotonia or developmental delay.

References

• American journal of human genetics • 2015 • De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. PMID:25683120
• Scientific reports • 2019 • Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties. PMID:31409833
• Neurology • 2016 • NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations. PMID:27558372
• American journal of human genetics • 2013 • Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay. PMID:24075186

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