biostudies-literatureWormser OIsrael Science FoundationIsrael Science Foundation (ISF)The Morris Kahn Family Foundation; Israel Ministry of Science, Technology and Space and the National Knowledge Center for Rare/Orphan Diseases22https://www.ebi.ac.uk/biostudies/studies/S-EPMC10425348biostudies-literatureUnknown8(1)Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chickenNPJ genomic medicineIHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma.PMC104253482034/18Tangeman JAGradstein LGrajales-Esquivel EPerez YDolgin VDrabkin MWormser OHalperin DDel Rio-Tsonis KYogev YBirnbaum RYKamali BFreund OIrron IAkler GBirk OSHadar NfalseIHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma.Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chicken2023-01-01T00:00:00Z2023 Aug2026-05-29T04:55:02.504Z2025-04-20T03:17:31.904ZS-EPMC104253483758033010.1038/s41525-023-00364-x