Familial intestinal degenerative neuropathy with chronic intestinal pseudo-obstruction linked to a gene locus with duplication in chromosome 9

• Published in: Scandinavian journal of gastroenterology Vol. 54; no. 12; pp. 1441 - 1447
• Main Authors: Abrahamsson, Hasse, Ahlfors, Frida, Fransson, Susanne, Nilsson, Staffan, Linander, Hans, Martinsson, Tommy
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02-12-2019
• Subjects: Chronic intestinal pseudo-obstruction; diagnosis; disease expressivity; familial intestinal degenerative; familial intestinal degenerative neuropathy; Gastroenterologi; Gastroenterology & Hepatology; Gastroenterology and Hepatology; gene duplication; myopathy; neuropathy; Chronic intestinal pseudo-obstruction; familial intestinal degenerative neuropathy; gene duplication; disease expressivity
• ISSN: 0036-5521; 1502-7708
• DOI: 10.1080/00365521.2019.1697741

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.