Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, $70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

Objective:Glucocorticoids (GCs) are the key drugs for the treatment of pediatric acute lymphoblastic leukemia (ALL). Herein, investigation of the relationship between the N363S and BclI polymorphisms of the GC receptor gene (NR3C1) and the side effects of GCs during pediatric ALL therapy was aimed.Materials and Methods:N363S and BclI polymorphisms were analyzed in 49 patients with ALL treated between 2000 and 2012. The control group consisted of 46 patients with benign disorders. The side effects of GCs noted during the induction and reinduction periods were evaluated retrospectively according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0.Results:The BclI allele and genotype frequencies were found similar in the two groups. No N363S polymorphism was detected in either of the groups. During induction, dyspepsia was found more frequently in the CG than in the CC (wild-type) genotype (36.4% vs. 5.3%, p=0.018) and depression symptoms more frequent in patients with the G allele (CG+GG) than the CC genotype (39.3% vs. 10.5%, p=0.031). During reinduction, Cushingoid changes, dyspepsia, and depression symptoms were more frequent in patients with the G allele (CG+GG) than in patients with the CC genotype (48.1% vs. 17.6%, p=0.041; 29.6% vs. 0.0%, p=0.016; 40.7% vs. 11.8%, p=0.040, respectively).Conclusion:In our study, patients with the BclI polymorphism were found to have developed more frequent side effects. We think that the BclI polymorphism should be considered while designing individualized therapies in childhood ALL.

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ABSTRACT.Purpose: To investigate genetic prothrombotic factors (factor V Leiden and prothrombin gene G20210A mutations) and their relation with retinal vascular occlusions in ocular Behc¸et disease. Methods: Thirty Behc¸et patients were prospectively recruited into the study. Their mean age was 34.2 AE 8.3 years. All patients underwent complete ophthalmic examination and fluorescein angiography. Of the 30 patients, 15 (16 eyes) had retinal vascular occlusion. Patients were tested for the presence of factor V Leiden and prothrombin gene G20210A mutations by polymerase chain reaction. The results were compared with the frequencies of factor V Leiden in 285 and prothrombin gene G20210A mutation in 182 healthy members of the Turkish population. Results: The prevalence of factor V Leiden mutation was significantly higher in ocular Behc¸et patients (12/30, 40%), compared with healthy control subjects (28/285, 9.8%) (p < 0.001). Of the 12 Behc¸et patients with factor V Leiden mutation, eight had retinal vascular occlusion. The prevalence of factor V Leiden was 53.3% (8/15) of the 15 patients with retinal vascular occlusion and 26.7% (4/15) of the remaining 15 patients without vascular occlusion. Prothrombin gene mutation was detected in none of Behc¸et patients compared with 2.7% (5/182) of the control group. Conclusion: These data suggest that factor V Leiden may be an additional risk factor in ocular Behc¸et disease, whereas factor II mutations do not seem to be relevant.

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