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Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease.

ABSTRACT: Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (HLA) haplotype findings were compared to a control group (n = 8496). PLINK-based analysis between GCD and NGCD groups did not find consistently significant hits. gnomAD control comparisons, however, showed consistent subgroup associations with DGKZ , ESRRA , and GXYLT1 , genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine.

SUBMITTER: Harris RA

PROVIDER: S-EPMC10528115 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease.

Harris R Alan RA Bush Allyson H AH Eagar Todd N TN Qian Justin J Greenwood Michael P MP Opekun Antone R AR Baldassano Robert R Guthery Stephen L SL Noe Joshua D JD Otley Anthony A Rosh Joel R JR Kugathasan Subra S Kellermayer Richard R

Journal of pediatric gastroenterology and nutrition 20230622 3

Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify sin ...[more]

PMID: 37347142

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Project description:Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.

Dataset Information

Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease.

Publications

Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease.

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