ArticleAmerican journal of human genetics2015
De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.
Article in American journal of human genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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85 citing papers in PubMed, 157 citations in OpenAlex.
- Comment on "Anesthetic management of a 9-year-old girl with Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay syndrome: airway difficulties and postoperative apnea during tendon surgery".Anesthesia and pain medicine · 2026Article
- Review
- A New Variant in the NALCN Channel Is Responsible for Cerebellar Ataxia and Cognitive Impairment.Genes · 2025Article
- The evolving genetic landscape of neuromuscular fetal akinesias.Journal of neuromuscular diseases · 2025Review
- Strabismus in Genetic Syndromes: A Review.Clinical & experimental ophthalmology · 2025Review
- Anesthetic management of a 9-year-old girl with Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay syndrome: airway difficulties and postoperative apnea during tendon surgery.Anesthesia and pain medicine · 2025Article
- Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchymal cells.Nature communications · 2024Article
- Unplugging lateral fenestrations of NALCN reveals a hidden drug binding site within the pore region.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The NaeLife · 2024Article
- Case Report: New presentation of CLIFAHDD syndrome with a novel variant in the NALCN gene and a literature review.Frontiers in pediatrics · 2024Article
- The Modulation by Anesthetics and Analgesics of Respiratory Rhythm in the Nervous System.Current neuropharmacology · 2024Review
- Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome's clinical and molecular spectrum through NALCNFrontiers in genetics · 2024Article
- The NabioRxiv : the preprint server for biology · 2023Article
- Rare variants inHGG advances · 2023Article
- BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.European journal of human genetics : EJHG · 2023Article
- New presentation of CLIFAHDD syndrome with a novel variant inClinical case reports · 2023Article
- Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics.Molecular aspects of medicine · 2023Review
- Clinically diverse and perinatally lethal syndromes with urorectal septum malformation sequence.American journal of medical genetics. Part A · 2023Review
- Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.Physiological reviews · 2023Review
- Awareness about Patterson syndrome among dental students.Journal of advanced pharmaceutical technology & research · 2022Article
25 more citing papers are in PubMed but not listed here.
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34 authors at 19 institutions in 7 countries.
Funding
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 individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 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 NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations 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 affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.