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Introduction Depending on the location of insertion of the gained region, F8 duplications can have variable clinical impacts from benign impact to severe haemophilia A phenotype. Aim To characterize two large Xq28 duplications involving F8 incidentally detected by chromosome microarray analysis (CMA) in two patients presenting severe intellectual disability but no history of bleeding disorder. Methods Whole genome sequencing (WGS) was performed in order to characterize the two large Xq28 duplications at nucleotide level. Results In patient 1, a 60–73 kb gained region encompassing the exons 23–26 of F8 and SMIM9 was inserted at the int22h‐2 locus following a non‐homologous recombination between int22h‐1 and int22h‐2. We hypothesized that two independent events, micro‐homology‐mediated break‐induced replication (MMBIR) and break‐induced replication (BIR), could be involved in this rearrangement. In patient 2, the CMA found duplication from 101 to 116‐kb long encompassing the exons 16–26 of F8 and SMIM9. The WGS analysis identified a more complex rearrangement with the presence of three genomic junctions. Due to the multiple micro‐homologies observed at breakpoints, a replication‐based mechanism such as fork stalling and template switching (FoSTeS) was greatly suspected. In both cases, these complex rearrangements preserved an intact copy of the F8. Conclusion This study highlights the value of WGS to characterize the genomic junction at the nucleotide level and ultimately better describe the molecular mechanisms involved in Xq28 structural variations. It also emphasizes the importance of specifying the structure of the genomic gain in order to improve genotype‐phenotype correlation and genetic counselling.

We report the clinical and molecular cytogenetic characterization of four unrelated patients from France and Spain, carrying 2p14 microdeletions and presenting with intellectual disability and dysmorphisms. 2p14 microdeletions are very rare. Seven patients have been reported so far harboring deletions including 2p14p15 and encompassing OTX1, whose haploinsufficiency is frequently associated with genitourinary defects. To date, only one patient has been reported carrying a more proximal 2p14 microdeletion which does not include OTX1. Here, we report three further patients carrying proximal 2p14 microdeletions not including OTX1 and one patient carrying a more distal 2p14p15 microdeletion including this gene, providing new insights into the associated phenotypic spectrum. First, our study and a review of the literature showed that 3/4 patients carrying proximal 2p14 microdeletions had sensorineural hearing loss, suggesting the presence of a previously unreported deafness-causing gene in this chromosomal region. Second, one patient developed a progressive cardiomyopathy, suggesting that a cardiac follow-up should be systematically warranted even in the absence of congenital heart disease. We speculate that ACTR2 and MEIS1 might respectively play a role in the pathogenesis of the observed deafness and cardiomyopathy. Third, we observed other previously unreported features such as glaucoma, retinopathy, and mild midline abnormalities including short corpus callosum, hypospadias and anteriorly placed anus. Finally, the patient carrying a 2p14p15 deletion including OTX1 had normal kidneys and genitalia, thus confirming that OTX1 haploinsufficiency is not invariably associated with genitourinary defects. In conclusion, our study contributes significantly to delineate the phenotypic spectrum of 2p14 microdeletions.

The above article was published with inverted author names. Family names was captured first instead of the given names that leads to incorrect citations online. This is now updated here.The Original article has been corrected.

S127 pre-mRNA splicing modifier that increases the levels of functional SMN protein. Jewelfish (NCT03032172) is a multicenter, open-label study of daily oral risdiplam in non-naïve patients with SMA, aged 6 months to 60 years. Jewelfish participants previously received RG7800 (RO6885247), nusinersen (SPINRAZA R), olesoxime or onasemnogene abeparvovec-xioi (ZOLGENSMA R). Jewelfish (N = 174) assesses the safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD) relationship of risdiplam. We have previously presented safety data from 45 patients with SMA (datacut: 28th June 2019) who received risdiplam for up to 28.9 months (nine patients previously received RG7800, 24 patients received nusinersen and 12 patients received olesoxime). No drug-related safety findings leading to withdrawal were reported and there have been no treatment-related safety findings leading to withdrawal in any risdiplam trial (data-cut: 28th June 2019). In an earlier analysis of SMN protein in whole blood from patients in Jewelfish, while patient numbers were limited (n = 18), the magnitude of SMN protein increase (> 2-fold) was comparable to that in SUNFISH Part 1 (NCT02908685) in patients with Types 2 and 3 SMA who had not previously received an SMN2-targeting therapy. We will present updated data on safety and PK/PD from patients within the Jewelfish study, including new patients, and reasons for discontinuing previous treatment regimens. The Jewelfish study is ongoing in sites across Europe and the US.