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DBA genotype-phenotype associated with RPL35A
leading to immunodeficiency in that case.15 However, only 12 cases in our cohort with available clinical information and a large deletion also had deletion of RNF168. Furthermore, cases of large deletions in our study that did not overlap with 3q29 co-ordinates (n=4) also had evi- dence of steroid-resistance and/or RBC transfusion-depen- dence (4 of 4 cases) and neutropenia requiring treatment (3 of 4 cases).
It is possible that genes in close proximity to RPL35A but not in the 3q29 deletion syndrome region may contribute to the DBA phenotypes described here. Possible candidate genes could include the closest neighbors and most fre- quently deleted genes LMLN and IQCG along with RPL35A. These genes were deleted in 15 and 17 of 17 large deletion cases with available co-ordinates, respectively. LMLN is a zinc-metalloprotease, and its protein product is invadolysin.47,48 Antibodies to invadolysin have been shown to concentrate in the edge of macrophage migration, and Drosophila mutants lacking this gene show abnormal cell migration during development.47,48 IQCG has been observed in a somatic fusion with NUP98 in T-cell acute lymphoblastic leukemia and acute myeloid leukemia. This fusion protein has been hypothesized to block differentia- tion of hematopoietic stem cells.49-51 IQCG knockout zebrafish had severely impaired levels of neutrophils, monocytes, macrophages, and lymphocytes.49 Further stud- ies with functional data are warranted to determine the effect of other gene deletions on the phenotype characteris- tics of patients with large deletions which include RPL35A.
In summary, we compiled the largest cohort of DBA cases with RPL35A pathogenic variants to date. Our study is limited by small sample size, retrospective, and non-uniformity of assessment, phenotype coded as absent if not specifically mentioned in patient records, and limited family data. Since our cohort is made up of European and North American cases, the genotype-phe- notype relationships may have limited generalizability. We could not examine the impact of a familial compo- nent on variation in phenotypes since we only had two families with >1 case per family. We were also limited to the 45 cases from our multi-institutional collaboration for genotype-phenotype analysis, excluding all variants found in the literature due to insufficient phenotypic data. Future studies evaluating genotype-phenotype rela- tionships in rare diseases would benefit from detailed clinical information (as in Online Supplementary Table S4) in publications. Moreover, 30 cases included here have never been published, underscoring the importance of reporting all available cases of rare diseases to better characterize the genotype, phenotype, and potential eti-
ology of these diseases. It is also important to include deletion analysis in molecular characterization of patients with DBA, since large deletions may not be identified on standard IBMFS gene panel testing or exome sequencing analysis.
Patients with DBA due to large deletions in RPL35A have a complex, multi-system disease phenotype with a high frequency of hematologic as well as non-hematologic problems that is clinically different from DBA associated with other pathogenic variants in RPL35A. Distinction of this subtype of DBA with RPL35A haploinsufficiency due to large deletion is important for patient management, and evaluations should include thorough investigation for immunodeficiency, GI problems, developmental delays and intellectual disabilities including neuropsychiatric problems. Identification of patients with large deletions in RPL35A should trigger early comprehensive assessment by pediatric specialists to provide optimal multidiscipli- nary care.
Disclosures
DP and JV are supported by the Czech Ministry of Health Grant 16-32105A. AK is consultant of CELGENE and Novartis and and Vifor Pharma and receives Honoraria from CELGENE, Novartis and ApoPharma; CN is a consultant and is on the advi- sory committee for Celgene; all other authors have no conflicts of interest.
Contributions
DMG and NG wrote the manuscript and performed data analyses; NG, BPA and SAS supervised the study; all authors provided data on the patients in their studies and are responsible for the reported research and have participated in the concept and design, analysis and interpretation of data, and revising the man- uscript, and approved the submitted manuscript.
Acknowledgments
We are indebted to the participating families, whose generosity and co-operation have made this study possible.
Funding
This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute; the Czech DBA registry is sup- ported by the Czech Ministry of Health Grant 16-32105A: we acknowledge the contributions made by Ann Carr MS, CGC, Lisa Leathwood, RN, and Maureen Risch, RN provided through contract HHSN261201100018C with Westat Inc. (Rockville, MD, USA); this work utilized the computational resources of the NIH High Performance Computing Biowulf cluster.
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