NALCN – CLIFAHDD Syndrome

Congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD syndrome) is an autosomal dominant neurodevelopmental disorder caused by de novo missense variants in the sodium leak channel gene NALCN (HGNC:19082; MONDO:0014556).

Genetic evidence includes at least 14 unrelated probands with heterozygous de novo missense variants clustering in or near the S5/S6 pore-forming segments of NALCN ([PMID:25683120]), a severe neonatal case carrying c.1768C>T (p.Leu590Phe) ([PMID:27558372]), and a Chinese infant with c.4300A>G (p.Ile1434Val) ([PMID:35911839]), totaling 16 de novo cases. All reported variants are missense, with no reported familial transmission, consistent with a fully penetrant dominant mechanism.

Variant spectrum is restricted to missense changes affecting channel gating domains; no loss-of-function or splice variants have been linked to CLIFAHDD. A representative variant is c.1768C>T (p.Leu590Phe), which abolishes channel selectivity and leads to hyperexcitability in functional models.

Functional studies demonstrate dominant-negative and gain-of-function effects: in vitro expression of CLIFAHDD mutants nearly abolishes wild-type NALCN protein levels ([PMID:25683120]) and electrophysiological recordings in NG108-15 cells show increased current density and slower inactivation for variants such as p.Leu509Ser and p.Tyr578Ser ([PMID:31409833]). In C. elegans, the orthologous p.Leu590Phe mutation causes neuronal hyperactivity and uncoordinated movement, confirming a gain-of-function mechanism ([PMID:27558372]).

No conflicting reports dispute the association; evidence has been replicated across multiple cohorts and functional platforms. Additional heterozygous phenotypes (e.g., CAPCACH) expand the clinical spectrum but do not weaken the gene–disease link for CLIFAHDD.

Integrating genetic and experimental data supports a Definitive gene–disease association. NALCN testing should be considered for patients with congenital arthrogryposis, hypotonia, and developmental delay, and functional assays may guide variant interpretation.

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
• Neurology • 2016 • NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations. PMID:27558372
• Frontiers in pediatrics • 2022 • Case Report: A de novo Variant in NALCN Associated With CLIFAHDD Syndrome in a Chinese Infant. PMID:35911839
• 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

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