Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort

Most histone methyltransferases (HMTase) harbor a predicted Su(var)3–9, Enhancer-of-zeste, Trithorax (SET) domain, which transfers a methyl group to a lysine residue in their substrates. Mutations of the SET domains were reported to cause intellectual disability syndromes such as Sotos, Weaver, or Kabuki syndromes. Sotos syndrome is an overgrowth syndrome with intellectual disability caused by haploinsufficiency of the nuclear receptor binding SET domain protein 1 (NSD1) gene, an HMTase at 5q35.2–35.3. Here, we analyzed NSD1 in 34 Brazilian Sotos patients and identified three novel and eight known mutations. Using protein modeling and bioinformatic approaches, we evaluated the effects of one novel (I2007F) and 21 previously reported missense mutations in the SET domain. For the I2007F mutation, we observed conformational change and loss of structural stability in Molecular Dynamics (MD) simulations which may lead to loss-of-function of the SET domain. For six mutations near the ligand-binding site we observed in simulations steric clashes with neighboring side chains near the substrate S-Adenosyl methionine (SAM) binding site, which may disrupt the enzymatic activity of NSD1. These results point to a structural mechanism underlying the pathology of the NSD1 missense mutations in the SET domain in Sotos syndrome. NSD1 mutations were identified in only 32% of the Brazilian Sotos patients in our study cohort suggesting other genes (including unknown disease genes) underlie the molecular etiology for the majority of these patients. Our studies also found NSD1 expression to be profound in human fetal brain and cerebellum, accounting for prenatal onset and hypoplasia of cerebellar vermis seen in Sotos syndrome

Pneumothorax after CT-guided transthoracic lung biopsy: A comparison between immediate and delayed occurrence.

BackgroundIn CT-guided transthoracic lung biopsy (CTLB), pneumothorax can occur as a late complication (delayed pneumothorax). The incidence, risk factors, and clinical significance of delayed pneumothorax are not well known.ObjectivesTo compare the risk factors for immediate and delayed pneumothorax after CTLB and to know their clinical significance.MethodsImages and medical records of 536 consecutive patients who underwent CTLB were reviewed. All biopsies were performed as inpatient procedures. Follow-up chest radiographs were obtained at least twice at 4 h after procedure and before discharge. Risk factors for immediate and delayed pneumothorax were assessed based on patient-, lesion-, and procedure-related variables. Rates of chest tube insertion were also compared.ResultsPneumothorax developed in 161 patients (30.0%) including 135 (25.2%) immediate and 26 (4.9%) delayed cases. Lesion size was an independent risk factor for both immediate and delayed pneumothorax (OR = 0.813; CI = 0.717-0.922 and OR = 0.610; CI = 0.441-0.844, respectively). While emphysema, lower lobe location, and long intrapulmonary biopsy track were risk factors (OR = 1.981; CI = 1.172-3.344, OR = 3.505; CI = 2.718-5.650, and OR = 1.330; CI = 1.132-1.563, respectively) for immediate pneumothorax, upper lobe location and increased number of pleural punctures were independent risk factors (OR = 5.756; CI = 1.634-20.274 and OR = 3.738; CI = 1.860-7.511, respectively) for delayed pneumothorax. The rate of chest tube insertion was significantly (p ConclusionPneumothorax tends to occur immediately after CTLB in patients with emphysema, lower lobe lesion, and long intrapulmonary biopsy track. Further attention and warnings are needed for those with multiple punctures of small lesions involving upper lobes due to the possibility of delayed development of pneumothorax and higher requirement for chest tube drainage

The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability

Background: 1q21 microdeletion syndrome is a rare contiguous gene deletion disorder with de novo or autosomal dominant inheritance patterns and its phenotypic features include intellectual disability, distinctive facial dysmorphism, microcephaly, cardiac abnormalities, and cataracts. MECP2 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by intellectual disability, global developmental delay, and other neurological complications including late-onset seizures. Previously, these two different genetic syndromes have not been reported segregating independently in a same family. Case presentation: Here we describe two siblings carrying either a chromosome 1q21 microdeletion or a chromosome Xq28 duplication. Using a comparative genomic hybridization (CGH) array, we identified a 1.24 Mb heterozygous deletion at 1q21 resulting in the loss of 9 genes in a girl with learning disability, hypothyroidism, short stature, sensory integration disorder, and soft dysmorphic features including cupped ears and a unilateral ear pit. We also characterized a 508 kb Xq28 duplication encompassing MECP2 in her younger brother with hypotonia, poor speech, cognitive and motor impairment. The parental CGH and quantitative PCR (qPCR) analyses revealed that the 1q21 deletion in the elder sister is de novo, but the Xq28 duplication in the younger brother was originally inherited from the maternal grandmother through the mother, both of whom are asymptomatic carriers. RT-qPCR assays revealed that the affected brother has almost double the amount of MECP2 mRNA expression compared to other family members of both genders including maternal grandmother and mother who have the same Xq28 duplication with no phenotype. This suggests the X chromosome with an Xq28 duplication in the carrier females is preferentially silenced. Conclusion: From our understanding, this would be the first report showing the independent segregation of two genetically unrelated syndromes, 1q21 microdeletion and Xq28 duplication, in a same family, especially in siblings. Although these two chromosomal abnormalities share some similar phenotypes such as intellectual disability, mild dysmorphic features, and cardiac abnormalities, the presence of two unrelated and rare syndromes in siblings is very unusual. Therefore, further comprehensive investigations in similar cases are required for future studies