Mutations in CRLF1 cause familial achalasia

Area of Science:

• Genetics
• Molecular Biology
• Pediatrics

Background:

• Early-onset achalasia is a rare esophageal motility disorder.
• Cytokine receptor-like factor 1 (CRLF1) mutations are associated with Crisponi/cold-induced sweating syndrome (CS/CISS1).
• CS/CISS1 can present with feeding difficulties, a symptom shared with achalasia.

Purpose of the Study:

• To investigate the genetic basis of early-onset achalasia in a Libyan family.
• To determine the role of CRLF1 gene variants in affected siblings.

Main Methods:

• Next-generation sequencing (NGS) of approximately 5000 disease-associated genes.
• Segregation analysis within the family.
• Functional assessment of CRLF1 protein secretion in transfected cells.

Main Results:

• Identified compound heterozygous variants in the CRLF1 gene in affected siblings.
• The c.713dupC variant was previously reported in CS/CISS1 patients.
• The novel c.178T>A variant impaired CRLF1 protein secretion, suggesting pathogenicity.
• Segregation analysis confirmed inheritance patterns consistent with autosomal recessive inheritance.

Conclusions:

• CRLF1 gene mutations should be considered in cases of early-onset achalasia, even in the absence of other CS/CISS1 symptoms.
• This expands the phenotypic spectrum associated with CRLF1 pathogenic variants.
• Highlights the importance of genetic testing in diagnosing rare pediatric disorders.