We present a 12-year-old girl with de novo karyotype 46,XX,del(12)(p11.1p12.1). Array CGH revealed in addition to a 10.466 Mb interstitial deletion on 12p11.1→12p12.1 a 0.191 Mb deletion on 2p16.3. The girl presented with mild facial dysmorphism consisting of microcephaly, hypertelorism, downslanting palpebral fissures, strabismus, broad nasal base, bulbous nose, short philtrum, micro/retrognathia, irregular tooth arrangement, phalangeal deformity in distal phalanges of hands, 5th finger camptodactyly, brachydactyly in feet, history of joint hypermobility, and scoliosis. She was considered to have mild to moderate mental retardation and ascertained for an autism spectrum disorder(ASD). Short arm of chromosome 12 interstitial deletions are rarely reported whereas point mutations and deletions of NRXN1, which is located on chromosome 2p16.3, are associated with ASDs. In this article we present and discuss the phenotypic consequences of a patient who was affected by deletions of two different chromosomal regions.
Background
The expansion of therapeutic options in IBD brought forward a need to personalise treatment. Gut inflammation in inflammatory bowel disease (IBD) patients has been associated with reduced microbial richness and abundance of SCFA producers. We aimed to explore the longitudinal impact of treatment on the inflammatory burden and faecal microbiota in patients with CD and UC, treated with anti-tumour necrosis factor (anti-TNF) therapy, vedolizumab (VDZ) or ustekinumab (UST).
Methods
We analysed faecal samples from 349 IBD patients (112 UC, 237 CD) initiating biological therapy (anti-TNF; VDZ; UST), regardless baseline disease activity, between 2010 and 2019 at a tertiary referral centre. Samples were collected at week 0, 14 and 24. Microbiota phylogenetic profiling was conducted by 16S rRNA gene sequencing and faecal cell counts were determined using flow cytometry. Moisture levels were measured using lyophilisation. Disease activity and response were assessed by faecal calprotectin (FCal). Statistics were performed in R, v3.5.1. Enterotyping was based on the Dirichlet multinomial mixtures approach.
Results
Faecal microbiota profiles showed high diversity, with samples classified into all four enterotypes (Fig1), although Bact2 was 6- to 10-fold more prevalent in patients compared with controls (Fig2). The variation in faecal microbiota composition was explained (multivariate dbRDA) by diagnosis (R2 = 1.2%, p = 1.00E−04), timepoint (R2 = 0.52, p = 0.006), significantly by age, gender and faecal moisture. The full model only explained 2.85% of the microbiota variation.
A slight non-significant decrease in the Bact2 enterotype prevalence was observed in the CD, but not in the UC cohort, during treatment.
A significant decrease in FCal concentrations (w0 vs. 14, UC p = 5.12E-08, CD p = 2.56E−08; week 0 vs. 24: CD p = 4.86E-08) was observed with treatment, accompanied by a significant increase in cellcounts (w0 vs. 14: UC p = 0.024, CD p = 0.0022; week 0 vs. 24: CD p = 0.0201) (Figure 3). No significant change in Bact2 prevalence was found during treatment.
Only treatment-associated variables—week of treatment (p = 2.4E−18), diagnosis (0.0005) and timepoint (p = 0.0073)—were significant predictors for response, while microbiota-associated variables (enterotype, cell counts and faecal moisture) not. Baseline samples were associated with higher FCal levels. This suggests that the response time of the microbiota to treatment may be higher than the host inflammatory response.
Conclusion
The prevalence of the inflammatory Bact2 enterotype was 5- to 10-fold higher in CD and UC patients as compared with controls. Although initiation of biological therapies leads to a decrease in inflammation levels as witnessed by faecal calprotectin and increase in microbial richness, a shift in enterotypes did not occur.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.