title: 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.
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Busch
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Žarković
authors.affiliation: Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Lowe
authors.affiliation: Clinic of General Pediatrics, University Hospital Bonn, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Jankofsky
authors.affiliation: Clinic of General Pediatrics, University Hospital Bonn, Bonn, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Ganschow
authors.affiliation: Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Buers
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Kurth
authors.affiliation: Department of Neonatology and Pediatric Intensive Care, University Hospital Bonn, Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Reutter
authors.affiliation: Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Rutsch
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: C A
authors.initials: CA
authors.lastname: Hübner
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D003645:Death, Sudden; D004931:Esophageal Achalasia / Q000235:genetics* / Q000503:physiopathology; D019066:Facies; D020022:Genetic Predisposition to Disease; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D006945:Hyperhidrosis / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D018121:Receptors, Cytokine / Q000235:genetics*; D014313:Trismus / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology
chemical_list: D018121:Receptors, Cytokine; C113554:cytokine-like factor-1
keywords: CRLF1; Crisponi syndrome; NGS; feeding difficulties