Case Report: Novel Biallelic Variants in DNAJC21 Causing an Inherited Bone Marrow Failure Spectrum Phenotype: An Odyssey to Diagnosis.

Bone marrow failure represents an umbrella diagnosis for several life-threatening disorders. In many people, the etiology remains unknown for a long time, leading to an odyssey to diagnosis, with numerous tests performed and sometimes inappropriate treatment. Biallelic pathogenic variants in the DNAJC21 gene were recently discovered to cause bone marrow failure syndrome type 3, having phenotypic overlap with Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia. Herein, we report an 8-year-old boy, with normal intellect, presenting bone marrow failure; growth retardation; failure to thrive; recurrent infections (including sepsis); cryptorchidia; skeletal, skin, teeth, and hair abnormalities; joint hypermobility; eczema; palpebral ptosis; high myopia; rod-cone retinal dystrophy; and short telomeres. He underwent several tests and evaluations, including genetic investigations (panel and exome sequencing), before the DNAJC21 gene was known to cause disease. Whole-genome sequencing performed at the age of 7 years, identified two novel, pathogenic, and compound heterozygous variants in the DNAJC21 gene: NM_001012339.3:c.148C>T (stopgain-maternal origin), p.Gln50∗ and c.643_644delinsTTT (frameshift paternal origin), and p.Lys215Phefs∗71. He received aggressive treatments for his multisystem disease: blood cell transfusions, high-dose corticosteroids, immunoglobulins, multiple antibiotics, vitamins, growth hormone, and others. However, allogeneic hematopoietic stem cell transplantation was avoided. The clinical evolution of bone marrow failure and recurrent infections stabilized with age, yet the myopia progressed. Exocrine pancreatic insufficiency was not detected. This report widens the molecular and clinical understanding of bone marrow failure syndrome type 3. Genome sequencing directed a precise diagnosis that improved patient management and enabled family genetic counseling.

Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels.

The benefit of reporting unsolicited findings in Next Generation Sequencing (NGS) related to cancer genes in children may have implications for family members, nevertheless, could also cause distress. We aimed to retrospectively investigate germline variants in 94 genes implicated in oncogenesis, in patients referred to NGS testing for various rare genetic diseases and reevaluate the utility of reporting different classes of pathogenicity. We used in silico prediction software to classify variants and conducted manual review to examine unsolicited findings frequencies in 145 children with rare diseases, that underwent sequencing - using a 4813 gene panel. The anonymized reanalysis revealed 18250 variants, of which 126 were considered after filtering. Six pathogenic variants (in BRCA1,BMPR1A,FANCA,FANCC,NBN genes) with cancer related phenotype and three unsolicited variants (in BRCA2,PALB2,RAD50 genes) were reported to patients. Additionally, three unsolicited variants in ATR, BLM (in two individuals), and FANCB genes presented potential cancer susceptibility, were not reported to patients. In retrospect, 4.8% (7/145) of individuals in our cohort had unsolicited NGS findings related to cancer. More efforts are needed to create an updatable consensus in reporting variants in cancer predisposing genes, especially for children. Consent process is crucial to inform of both value and risk of additional genetic information.

Single Nucleotide Polymorphisms in PEMT and MTHFR Genes are Associated with Omega 3 and 6 Fatty Acid Levels in the Red Blood Cells of Children with Obesity.

Polyunsaturated fatty acids (PUFAs) play important roles in health and disease. PUFA levels are influenced by nutrition and genetic factors. The relationship between PUFA composition in red blood cells (RBCs) and genetic variations involved in PUFA metabolism has not been investigated in children with obesity. This study evaluated the association between several genetic variations and PUFA levels in RBCs in children with obesity. One hundred ninety-six children with obesity (101 females, 95 males) were evaluated using anthropometric measurements, dietary intakes, plasma and RBC PUFA quantification, blood biochemistry, and 55 single nucleotide polymorphisms within 14 genes. phosphatidylethanolamine N-methyltransferase (PEMT) rs1109859 and methylenetetrahydrofolate reductase gene (MTHFR) rs4846052 genotypes were associated with PUFA levels in RBCs. PUFA intake did not influence the RBC eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels. Higher RBC DHA and EPA levels were observed for PEMT rs1109859 GG and GA genotypes versus the AA genotype. Higher levels of RBC DHA, EPA, arachidonic acid (ARA), and linoleic acid (LA) and were observed for MTHFR rs4846052 TT genotype versus TC and CC genotypes. Genetic variations in PEMT rs1109859 and MTHFR rs4846052 were associated with different PUFA levels in RBC membranes and are estimators for PUFA species in RBCs. Further research is needed to establish whether these genotype-specific alterations are specific to overweight children.

Clinical relevance of retinal structure in children with laser-treated retinopathy of prematurity versus controls - using optical coherence tomography.

PURPOSE: We aimed to assess the macular anatomy using spectral domain optical coherence tomography (SD-OCT), in children born preterm who had laser-treated retinopathy of prematurity (ROP), and to investigate the relationship between structural changes in macula and visual function. METHODS: Thirty-seven 3-8 years old children were included in the study in two groups: 20 children born preterm [(<34 weeks of gestation, birthweight (BW) <2000 g)] who had laser-treated ROP in the Neonatology Department, Municipal Clinical Emergency Hospital of Timisoara, Romania; and 17 controls (children born at term, without eye disease, matched for age and gender). Spectral domain optical coherence tomography (SD-OCT) imaging (Spectralis OCT) was performed at central fovea and 1 mm nasally. RESULTS: In the ROP group (total 34 eyes), we included both eyes in 14 children, and on one eye in six other children. In the control group, both eyes for all 17 children were included. Central fovea thickness (CFT) was significantly higher in children born preterm and with laser-treated ROP as compared to controls (275 ± 34.8 µm versus 224 ± 27.2 µm; p < 0.001). The laser-treated eyes with ROP had mean best-corrected visual acuity (BCVA) = 0.19 logMAR (20/31 Snellen); 35% had BCVA ≥0.3 logMAR (20/40 Snellen). In receiver operating characteristic curve (ROC) analysis, with BCVA as static variable (category 0 = BCVA ≤0.3 logMAR), the CFT cut-off was 257 µm (sensitivity: 0.917; specificity: 0.661; area under the curve: 0.810, p = 0.001). CONCLUSION: Years after the laser intervention, central fovea was significantly thicker in ROP laser-treated children born preterm when compared to controls. Central fovea thickness (CFT) correlated strongly and inversely with BW and gestational age (GA) at birth, while a CFT value above 257 µm was suggestive for suboptimal visual acuity. The proposed cut-off value needs to be validated in future larger studies.