A New Variant in the NALCN Channel Is Responsible for Cerebellar Ataxia and Cognitive Impairment

TL;DR

A new mutation in the NALCN gene is linked to a milder, later-onset form of a rare neurodevelopmental disorder.

Contribution

A novel NALCN variant is identified, expanding the known clinical spectrum of CLIFAHDD syndrome.

Findings

A de novo missense variant c.1514A>T; p.(Lys505Met) in NALCN was found to be likely pathogenic.

The variant affects a critical residue in the NALCN channel, possibly altering its function and regulation.

The patient's milder and later-onset symptoms suggest a broader clinical spectrum for CLIFAHDD syndrome.

Abstract

Background/Objectives: CLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Methods and Results: Whole Exome Sequencing (WES) identified a novel missense variant c.1514A>T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. Conclusions: The patient’s milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity.

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