CLCF1 – Cold-induced Sweating Syndrome 1

Cold-induced sweating syndrome 1 (CISS1) is a rare autosomal recessive disorder characterised by neonatal bulbar dysfunction with feeding difficulties, episodic hyperthermia, exaggerated startle responses, and later-onset scoliosis and cold-induced hyperhidrosis. Two genetic subtypes are recognised: CISS1 due to CRLF1 deficiency and CISS2 due to CLCF1 deficiency. Biallelic CLCF1 variants produce a clinically indistinguishable phenotype, confirming locus heterogeneity in CISS ([PMID:20400119]).

Genetic evidence for CLCF1 involvement includes three unrelated probands with compound heterozygous variants. Two patients in the 2010 cohort harboured c.676T>C (p.Ter226Arg) and c.46T>C (p.Cys16Arg), while a 2006 report described a patient with c.321C>A (p.Tyr107Ter) and c.590G>T (p.Arg197Leu) disrupting CLCF1 function ([PMID:20400119], [PMID:16782820]). No extended pedigrees were reported, but the presence of two pathogenic alleles in each proband and absence of heterozygous phenotype support autosomal recessive inheritance.

The variant spectrum comprises premature termination codons (c.321C>A (p.Tyr107Ter), c.676T>C (p.Ter226Arg)) and missense substitutions (c.46T>C (p.Cys16Arg), c.590G>T (p.Arg197Leu)). No recurrent or founder alleles have been documented to date. These alleles are absent from population databases and segregate in trans in affected individuals.

Functional assays demonstrate that p.Arg197Leu abolishes CLCF1 binding to the CNTF receptor alpha component (CNTFRα), preventing downstream JAK/STAT signaling. Structural and docking analyses reveal that the Arg197Leu substitution destabilises the CLC–CNTFRα interface, recapitulating the loss of composite cytokine activity observed in CISS ([PMID:16782820]).

Collectively, genetic and experimental data support a Moderate-level clinical validity for the CLCF1–CISS1 association. Three unrelated probands with biallelic LoF and missense variants and concordant functional disruption fulfill criteria for a Moderate classification under ClinGen guidelines.

Key Take-home: Biallelic CLCF1 variants cause autosomal recessive cold-induced sweating syndrome, guiding molecular diagnosis and potential therapeutic targeting.

References

• Journal of the neurological sciences • 2010 • Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases. PMID:20400119
• Proceedings of the National Academy of Sciences of the United States of America • 2006 • Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient. PMID:16782820

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