Case Report: Congenital Brain Dysplasia, Developmental Delay and Intellectual Disability in a Patient With a 7q35-7q36.3 Deletion

7q terminal deletion syndrome is a rare condition presenting with multiple congenital malformations, including abnormal brain and facial structures, developmental delay, intellectual disability, abnormal limbs, and sacral anomalies. At least 40 OMIM genes located in the 7q34-7q36.3 region act as candidate genes for these phenotypes, of which SHH, EN2, KCNH2, RHEB, HLXB9, EZH2, MNX1 and LIMR1 may be the most important. In this study, we discuss the case of a 2.5-year-old male patient with multiple malformations, congenital brain dysplasia, developmental delay, and intellectual disability. A high-resolution genome-wide single nucleotide polymorphism array and real-time polymerase chain reaction were performed to detect genetic lesions. A de novo 9.4 Mb deletion in chromosome region 7q35-7q36.3 (chr7:147,493,985–156,774,460) was found. This chromosome region contains 68 genes, some of which are candidate genes for each phenotype. To the best of our knowledge, this is a rare case report of 7q terminal deletion syndrome in a Chinese patient. Our study identifies a rare phenotype in terms of brain structure abnormalities and cerebellar sulcus widening in patients with deletion in 7q35-7q36.3.

Clinical report of a neonate carrying a large deletion in the 10p15.3p13 region and review of the literature

Background Terminal deletion of chromosome 10p is a rare chromosomal abnormality. We report a neonatal case with a large deletion of 10p15.3p13 diagnosed early because of severe clinical manifestations. Case presentation Our patient presented with specific facial features, hypoparathyroidism, sen sorineural deafness, renal abnormalities, and developmental retardation, and carried a 12.6 Mb deletion in the 10p15.3 p13 region. The terminal 10p deletion involved in our patient is the second largest reported terminal deletion reported to date, and includes the ZMYND11 and GATA3 genes and a partial critical region of the DiGeorge syndrome 2 gene (DGS2). Conclusion On the basis of a literature review, this terminal 10p deletion in the present case is responsible for a specific contiguous gene syndrome. This rare case may help the understanding of the genotype–phenotype spectrum of terminal deletion of chromosome 10p.

Potential Prognostic Significance of Patterns of Deletion (13q) in Plasma Cell Myelomas—Reappraisal of a Perennial Bone of Contention

Deletion 13q is recommended in the initial cytogenetic workup of myeloma patients. The patterns of this abnormality have been shown to have differential prognostic value. The presence of monosomy 13 is associated with a significantly poor progression-free survival, while interstitial deletion 13q is associated with significant improvement in the overall survival. We analyzed the patterns of 13q abnormalities on fluorescent in situ hybridization (FISH) assay results in myeloma patients. Deletion 13q abnormalities were observed in 38% (55 of 138) of the myeloma patients. Ten (18%) and 44 (80%) patients showed interstitial deletion and terminal deletion, respectively. One had a mosaic of both the patterns. Nine of the ten patients with interstitial deletions were males. For terminal deletion 13q, there appeared to be a slight female predilection, with a male to female ratio of 0.83:1. Half of the patients with deletion 13q had coexistent cytogenetic abnormalities. We suggest a baseline FISH for deletion 13q and specification of the type of abnormality (terminal vs. interstitial) in patients with myeloma. Based on our observation in conjunction with the available literature, further studies in a large cohort of patients with survival data are warranted to clearly delineate the role of deletion 13q in myeloma.

Deletion of LBR N-terminal domains recapitulates Pelger-Huet anomaly phenotypes in mouse without disrupting X chromosome inactivation

Mutations in the gene encoding Lamin B receptor (LBR), a nuclear-membrane protein with sterol reductase activity, have been linked to rare human disorders. Phenotypes range from a benign blood disorder, such as Pelger-Huet anomaly (PHA), affecting the morphology and chromatin organization of white blood cells, to embryonic lethality as for Greenberg dysplasia (GRBGD). Existing PHA mouse models do not fully recapitulate the human phenotypes, hindering efforts to understand the molecular etiology of this disorder. Here we show, using CRISPR/Cas-9 gene editing technology, that a 236bp N-terminal deletion in the mouse Lbr gene, generating a protein missing the N-terminal domains of LBR, presents a superior model of human PHA. Further, we address recent reports of a link between Lbr and defects in X chromosome inactivation (XCI) and show that our mouse mutant displays minor X chromosome inactivation defects that do not lead to any overt phenotypes in vivo. We suggest that our N-terminal deletion model provides a valuable pre-clinical tool to the research community and will aid in further understanding the etiology of PHA and the diverse functions of LBR.

The C-Terminal Domain of Nefmut Is Dispensable for the CD8+ T Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles

Intramuscular injection of DNA vectors expressing the extracellular vesicle (EV)-anchoring protein Nefmut fused at its C-terminus to viral and tumor antigens elicit a potent, effective, and anti-tolerogenic CD8+ T cell immunity against the heterologous antigen. The immune response is induced through the production of EVs incorporating Nefmut-derivatives released by muscle cells. In the perspective of a possible translation into the clinic of the Nefmut-based vaccine platform, we aimed at increasing its safety profile by identifying the minimal part of Nefmut retaining the EV-anchoring protein property. We found that a C-terminal deletion of 29-amino acids did not affect the ability of Nefmut to associate with EVs. The EV-anchoring function was also preserved when antigens from both HPV16 (i.e., E6 and E7) and SARS-CoV-2 (i.e., S1 and S2) were fused to its C-terminus. Most important, the Nefmut C-terminal deletion did not affect levels, quality, and diffusion at distal sites of the antigen-specific CD8+ T immunity. We concluded that the C-terminal Nefmut truncation does not influence stability, EV-anchoring, and CD8+ T cell immunogenicity of the fused antigen. Hence, the C-terminal deleted Nefmut may represent a safer alternative to the full-length isoform for vaccines in humans.

IUGR is Commonly Observed among Prenatally Diagnosed Chromosome 4p Deletion Syndrome

Objective: our study aimed at retrospectively assessing the abnormal prenatal ultrasound findings of chromosome 4p deletion syndrome. Methods: 21 cases with abnormal sonographic signs revealed 4p deletion by Chromosome Microarray (CMA) in this retrospective analysis. Clinical information and molecular basis of this cohort were compared with those from other two groups in China, the critical region related to special ultrasound findings was mapped with the smallest regions of overlap. Results: This is the largest prenatal series to evaluate the prenatal ultrasound features of 4p deletion syndrome detected by CMA. Firstly we refined the relationship between the genomic coordinates with IUGR in chromosome 4p terminal deletion syndrome. Additional chromosomal abnormalities was identified in 12 cases. Intrauterine embryonic arrest was diagnosed at first trimester for 9 cases. The most consistent ultrasound indicator was IUGR (95.5%), and the smallest region response for IUGR correspond to a 2.05Mb at 4p16.3-pter (chr4: 68,345-2,121,057, hg19). Increased Nuchal Translucency (NT) could be a risk factor for predicting WHS at first-trimester pregnancy with the rate of 16.6% from our data. A 3.6Mb microdeletion located at 4p16.3-pter (chr4: 68,345-3,753,422, hg19) might be the candidate region associated with increased NT. Conclusion: We identified IUGR as the most common feature in prenatal 4p terminal deletion and Wolf-Hirschhorn syndrome. The existence of additional CNVs may contribution to possible explanations for the clinical heterogeneity of this syndrome. Prenatal findings of IUGR, increased NT or early spontaneous abortion should warrant the diagnosis of 4p terminal deletion WHS.

CD8+ T cell immunogenicity induced by endogenous EVs engineered by antigens fused to a truncated Nefmut EV-anchoring protein

Intramuscular injection of DNA vectors expressing the extracellular vesicle (EV)-anchoring protein Nefmut fused at its C-terminus to viral and tumor antigens elicits a potent, effective, and anti-tolerogenic CD8+ T cell immunity against the heterologous antigen. The immune response is induced through the production of EVs incorporating Nefmut-derivatives released by muscle cells. In the perspective to a possible translation into the clinic of the Nefmut-based vaccine platform, we aimed at increasing its safety profile by identifying the minimal part of Nefmut retaining the EV-anchoring protein property. We found that a C-terminal deletion of 29-amino acids did not affect the ability of Nefmut to associate with EVs. Furthermore, the EV-anchoring function was preserved when antigens from both HPV16 (i.e., E6 and E7) and SARS-CoV-2 (i.e., S1 and S2) were fused to its C-terminus. By analyzing the immune responses induced after intramuscular injection of DNA vectors expressing fusion products based on the four viral antigens, we found that the Nefmut C-terminal deletion did not impact on the levels of antigen –specific CD8+ T lymphocytes as evaluated by IFN-γ EliSpot analysis and intracellular cytokine staining. In addition, immune responses at distal sites remained unaffected, as indicated by the similar percentages of SARS-CoV-2 S1- and S2-specific CD8+ T cells detected in spleens and lung airways of mice injected with DNA vectors expressing the viral antigens fused with either Nefmut or NefmutPL.We concluded that the C-terminal Nefmut truncation does not affect stability, EV-anchoring, and CD8+ T cell immunogenicity of the fused antigen. Hence, NefmutPL represents a safer alternative to full-length Nefmut for the design of CD8+ T cell vaccines for humans.