Deletion of a distant-acting enhancer on Chr16p13.3 causes recessive Intractable Diarrhea of Infancy Syndrome. D. Oz-Levi1, I. Bar-Joseph3,4, T. Olender1, EK. Ruzzo5, D. Yagel3, H. Reznik-Wolf3,4, A. Alkelai1, R. Milgrom1, C. Hartman6, R. Shamir6, R. Kleta7,8, L. Pennacchio9, DB. Goldstein5, E. Pras3,4, Y. Anikster2,4, D. Lancet1 1) molecular genetics, weizmann institute of science, Rehovot, Rehovot, Israel; 2) Edmond and Lily Safra Childrens Hospital, Sheba Medical Center, Ramat Gan, Israel; 3) The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel; 4) The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 5) Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA; 6) Schneider childrens Medical Center, PetachTikva, Israel; 7) Centre for Nephrology, University College London, London, UK; 8) Institute of Child Health, University College London, London, UK; 9) Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
We report on ten patients from eight seemingly unrelated families of Jewish Iraqi origin who presented with a recessive form of Intractable Diarrhea of Infancy Syndrome (IDIS). This is an early onset non-infectious malabsorptive diarrhea starting within the first few weeks of life, and the patients receive prolonged intravenous nutrition. Exome sequencing together with homozygosity mapping identified two independent deletion alleles of noncoding DNA (deltaS, deltaL) on 16p13.3, overlapping with falsely predicted exons and present homozygously or as compound heterozygote. The 1500bp overlap region of deltaS, deltaL was tested in a transgenic embryonic mouse assay and found to act as a robust enhancer in the stomach, duodenum and pancreas at days e11.5 to e13.5. Candidate target genes in the vicinity of this enhancer, C16ORF91, the CCSMST1 protein precursor; UNKL, a RING finger transcription factor and CCDC154, a scantly annotated coiled-coil protein, are being scrutinized. One hypothesized mechanism of action being considered is that embryonic modified expression of a transcription factor could interfere with a developmental process, leading to adult abnormal gastrointestinal function. Currently, isolation of enhancer positive intestinal cells at e13.5 followed by RNA-seq is in progress to uncover gene expression changes and help identify the target gene. Beyond, mouse homozygous knockout of the enhancer would reveal its role in gastrointestinal dysfunction. Our findings constitute a rare case of noncoding deletion underlying human disease etiology, a finding likely to become more widespread with the increasing use of whole genome sequencing.
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