Familial intestinal degenerative neuropathy with chronic intestinal pseudo-obstruction linked to a gene locus with duplication in chromosome 9. (2nd December 2019)

• Record Type: Journal Article
• Authors: Abrahamsson, Hasse; Ahlfors, Frida; Fransson, Susanne; Nilsson, Staffan; Linander, Hans; Martinsson, Tommy
• Is Part Of: Scandinavian journal of gastroenterology. Volume 54:Number 12(2019)
• Page Start: 1441
• Page End: 1447
• Publication Date: 2019-12-02
• Subjects: Chronic intestinal pseudo-obstruction -- familial intestinal degenerative neuropathy -- gene duplication -- disease expressivity; Gastroenterology -- Periodicals; Digestive organs -- Diseases -- Periodicals; 616.33
• DOI: 10.1080/00365521.2019.1697741
• Languages: English
• ISSNs: 0036-5521

Abstract

Abstract: Background: Intestinal degenerative neuropathy without extra-intestinal involvement occurs as familial forms (FIDN) but the genetics behind is unknown. We studied a Swedish family with autosomal dominant disease and several cases of chronic intestinal pseudo-obstruction (CIP). Methods: We included 33 members of a family sharing a male ancestor. Chronic intestinal symptoms including diarrhoea occurred in 11, four had severe CIP. DNA was analysed with SNP-microarray (Affymetrix), linkage (Allegro Software) and gene dosage (CNAG 3.0). Results: Genetic linkage was found to the short arm of Ch9 to a 9.7 Mb region with 45 protein-coding genes, 22 of which were duplicated (1.2 Mb duplication) (dup(9)(p21.3) with breaking point in the FOCAD -gene. Lod score for the region was 3.4. Fourteen subjects were duplication carriers including all 11 subjects having severe chronic symptoms/CIP. Nineteen subjects had no duplication. The occurrence of gastrointestinal symptoms in the family was strongly linked to duplication carrier-ship ( p = .0005). The two branches of the family had separate maternal ancestors (A and B). Including the previous generation, severe disease (overt CIP and/or death from intestinal failure) was assessed to occur in 100% (5/5) of duplication carriers in branch A and in 21% (3/14) in branch B ( p = .005). In branch B the onset of symptoms was later (median 38 vs. 24 yrs) and three duplication carriers were symptom-free. Conclusions: In this family with autosomal dominant hereditary intestinal neuropathy, the disorder is linked to a 9.7 Mb region in Ch9 including a 1.2 Mb duplication. There is a significant difference in disease expressivity between family branches, seemingly related to separate maternal ancestors.