Chronic Atrial And Intestinal Dysrhythmia

A number sign (#) is used with this entry because of evidence that chronic atrial and intestinal dysrhythmia (CAID) is caused by homozygous mutation in the SGOL1 gene (609168) on chromosome 3p24.

Clinical Features

Chetaille et al. (2014) identified 16 French Canadian patients and 1 Swedish patient from 14 families in whom dysregulation of the cardiac sinus node and chronic intestinal pseudoobstruction cooccurred. In all but 1 patient, onset of symptoms occurred in the first or second decade of life. Cardiac features included sick sinus syndrome (SSS), manifested as sinus bradycardia in all 17 patients, 4 of whom exhibited junctional escape rhythms; atrial dysrhythmias in 6 patients, consisting of atrial flutter in 5 and atrial fibrillation in 1; and valve anomalies in 7 patients, involving the aortic valve in 4, the mitral valve in 2, and the pulmonary valve in 1. Pacemakers were implanted in 10 of the 17 patients. Intestinal pseudoobstruction was present in all patients and was reported to be myogenic in 2 patients, neurogenic in 1 patient, and mixed in 3 patients. Total parenteral nutrition was required in all but 1 of the patients. C-band karyotype analysis revealed heterochromatin repulsion at the centromere, resulting in the typical 'railroad track' appearance of a centromeric cohesion defect, without signs of aneuploidy. Full-thickness gastrointestinal biopsies showed characteristic anomalies in the enteric nervous system, including hypoplastic ganglia and mislocalization of ganglia and Cajal cells in the circular and longitudinal smooth muscle layers. Hallmarks of TGF-beta (TGFB1; 190180) activation were observed, including abundant T cells and extensive fibrosis in the intestinal smooth muscle layers; there was also thinning of smooth muscle layers with fragmentation of smooth muscle fiber architecture. None of the patients showed clinical evidence of other congenital anomalies or manifestations of known cohesinopathies.

Molecular Genetics

From a cohort of 1 Swedish patient and 16 French Canadian patients with chronic atrial and intestinal dysrhythmia, Chetaille et al. (2014) performed whole-exome sequencing in 3 unrelated probands and identified 1 homozygous pathogenic variant shared by all 3 probands, a missense mutation in the SGOL1 gene (K23E; 609168.0001) The mutation was extremely rare, with a minor allele frequency of less than 1% in public databases, and was not found in 360 French Canadian control exomes. Sanger sequencing confirmed the homozygous mutation in the CAID patients and segregation with disease in their families; the mutation was not found in 11 pediatric cases of SSS without chronic intestinal pseudoobstruction (CIPO) or in 43 pediatric cases of CIPO without SSS. Haplotype analysis revealed a 700-kb disease-associated haplotype shared by the Swedish and French Canadian patients, without rare copy number variations. All the French Canadian patients shared a common ancestral haplotype for the SGOL1 gene, the age of which was estimated at 13 generations; allele-dropping analysis identified a likely founder couple, married in France in 1620, which supported a transatlantic founder effect in the 17th century when Nouvelle France was settled. The haplotype sharing between the Swedish and French Canadian patients suggested common ancestry at about 30 generations, or 900 years, earlier.