Mutations in CRLF1 cause familial achalasia

Abstract

We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor-like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.

Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia

“…Among these IA-affected individuals, we did not identify any variants previously reported in familial IAs or rare loss-of-function variants in genes with achalasia phenotype in a mouse model (Table S3). [23][24][25][26][27][28][29][30][31][32][33] Principal component analysis and quantile-quantile (Q-Q) plots of genome-wide association test statistics revealed no inflation; thus, substantial cryptic population substructure and differing genotypic variants between the affected individuals and control subjects were unlikely in the discovery stages (l ¼ 0.92, Figure S2B).…”

CRLF1 and CLCF1 in Development, Health and Disease

“…Motoneurons are involved in the contraction and relaxation of muscles, and severe contractions of the facial muscles and orofacial weakness are characteristic features of CS/CISS. Interestingly, in this respect, mutations in CRLF1 have also been found in patients with familial achalasia, suggesting a role of CRLF1 signalling in the relaxation of the lower oesophageal sphincter [42].…”

Achalasia: A syndrome

“…2 Also, genetic conditions and paraneoplastic manifestations may also lead to the achalasia symptoms. 3,4 For years, achalasia has been treated as a sole disease, and most of the efforts have been on classifying this condition, instead of revealing each specific etiology. Firstly, the esophagogram classifications were used to guide the therapy.…”