Two sisters with cardiac‐urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

Abstract Background Cardiac‐urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin‐related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. Case Presentation We present case reports of two siblings of unrelated parents in whom whole‐exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. Conclusions To our knowledge, this is the first published case of familial cardiac‐urogenital syndrome indicating gonadal mosaicism

Prognostic Impact of Peripheral Blood Involvement during Early Time Points of Childhood ALL Treatment.

Abstract Minimal residual disease (MRD) testing performed on bone marrow (BM) samples has become a part of the risk group stratification procedure in several of the most progressive acute lymphoblastic leukemia (ALL) treatment protocols. MRD testing of peripheral blood (PB) instead of BM is not routinely performed, although PB sampling could cause less discomfort especially in children. It is well established that the level of MRD in PB and BM correlates well in T-ALL; the data concerning B-cell precursor (BCP)-ALL remain controversial, with most studies lacking sufficient number of samples taken during the early phase of treatment with quantifiable MRD in both compartments. We simultaneously evaluated MRD in BM and PB using immunoglobulin and T-cell receptor gene-based RQ-PCR. 221 paired samples from 47 children with BCP-ALL treated according to the Berlin-Frankfurt-Muenster (BFM) ALL IC-BFM 2002 protocol were taken at diagnosis (dg, n=47), day 8 (d8, n=39), day 15 (d15, n=44), day 33 (d33, n=34), week 12 (w12, n=31) and at the end of maintenance therapy (post-MT, n=26). As in the BM at d15, patients with lower MRD in PB at d15 were more likely to achieve MRD negativity in BM at d33 in the univariate analysis (p=0.01, Mann Whitney). Patients younger than 10 yrs had lower MRD in PB at d8 and at d15 than other patients (p=0.03 and p=0.01, respectively). Unlike in BM, patients with hyperdiploidy had lower MRD in PB at d15 than other patients excluding TEL/AML1 cases (p=0.05). There were no significant associations with diagnostic white blood cell count (WBC), sex, immunophenotype (cALL/prae-B ALL) or presence of TEL/AML1 fusion at any time point. Patients with MRD&amp;lt;1E-04 in PB at d15 had a 5-year relapse-free survival (RFS) of 100% vs. 62.5±9.9% for those with a higher MRD (p=0.0089). No such threshold could be set for dg, d8 and d33 PB MRD level. Low numbers of MRD-positive results at w12 and post-MT samples precluded statistical analysis. In 125 paired samples MRD was detected in both tissues, in 18 pairs in BM only and in 5 pairs in PB only. MRD levels in PB varied greatly and were a mean of 149-fold lower than in BM (range 0.04–8293). We next examined the prognostic impact of BM/PB MRD ratio. Patients having MRD levels in PB similar to those in BM (BM/PB MRD&amp;lt;10) at d8 and d15 were more likely to relapse (d8: RFS 88.1±6.4% vs. 61.5±13.5%, p=0.04; d15: RFS 89.5±5.7% vs. 54.5±15%, p=0.01). No such relationship was observed for dg or d33. In conclusion, our data show that in childhood BCP-ALL, MRD in PB is not simply proportional to the BM level and provides additional prognostic information. A higher relapse rate in patients with PB MRD level similar to that in BM suggests that leukemic blasts with the propensity for massive escape from BM to PB during the induction treatment have a great potential for giving rise to relapse.</jats:p

Molecular Characterization of <b>β</b>-Thalassemia in the Czech and Slovak Populations: Mediterranean, Asian and Unique Mutations

<p>β-Thalassemia (β-thal) is considered rare in Central Europe. As in other malaria-free regions, the presence of β-thal in Central Europe reflects historical and recent immigration, and demographic changes that have influenced the genetic variability of the current populations living in this area. This study assesses the frequency and spectrum of mutations on the β-globin gene in Czech and Slovak subjects with clinical symptoms of thalassemia. The results of the initial part of this research were published more than two decades ago; the aim of this study was to update these original reports. During the period from 2002 to 2015, 400 cases from Czech and Slovak hematological centers were analyzed. Twenty-nine β-thal mutations, identified in 356 heterozygotes from 218 unrelated families, involve five unique mutations including a recently described insertion of a transposable L1 element into the β-globin gene. One mutation described here is reported for the first time. Most of the mutations were of Mediterranean origin and accounted for 82.0% of cases. All but one case studied were heterozygous carriers, manifesting β-thal minor, with rare exceptions represented by the rare (β⁰) codons 46/47 (+G) (<i>HBB</i>: c.142_142dupG) mutation associated with an α-globin gene quadruplication and by dominantly inherited β-thal with a more severe phenotype. One double heterozygous β-thal patient was a recent immigrant from Moldavia. The list of δβ-thal alleles (26 carriers, 16 families) contains Hb Lepore and two types of δβ⁰-thal deletions. In the past, genetic drift and migration as well as recent immigrations were responsible for the introduction of Mediterranean alleles, while several mutations described in single families were of local origin.</p

Oral Microbiota Composition and Antimicrobial Antibody Response in Patients with Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) is the most common disease of the oral mucosa, and it has been recently associated with bacterial and fungal dysbiosis. To study this link further, we investigated microbial shifts during RAS manifestation at an ulcer site, in its surroundings, and at an unaffected site, compared with healed mucosa in RAS patients and healthy controls. We sampled microbes from five distinct sites in the oral cavity. The one site with the most pronounced differences in microbial alpha and beta diversity between RAS patients and healthy controls was the lower labial mucosa. Detailed analysis of this particular oral site revealed strict association of the genus Selenomonas with healed mucosa of RAS patients, whereas the class Clostridia and genera Lachnoanaerobaculum, Cardiobacterium, Leptotrichia, and Fusobacterium were associated with the presence of an active ulcer. Furthermore, active ulcers were dominated by Malassezia, which were negatively correlated with Streptococcus and Haemophilus and positively correlated with Porphyromonas species. In addition, RAS patients showed increased serum levels of IgG against Mogibacterium timidum compared with healthy controls. Our study demonstrates that the composition of bacteria and fungi colonizing healthy oral mucosa is changed in active RAS ulcers, and that this alteration persists to some extent even after the ulcer is healed