22q11 Deletion Research Articles

Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs

BackgroundPopulation-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS).PurposeTo investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS.MethodsSubjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed.ResultsAt follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells.ConclusionsThis long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring.Clinical ImplicationsThis study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.

Prenatal detection of chromosomal abnormalities and copy number variants in fetuses with congenital gastrointestinal obstruction

BackgroundCongenital gastrointestinal obstruction (CGIO) mainly refers to the stenosis or atresia of any part from the esophagus to the anus and is one of the most common surgical causes in the neonatal period. The concept of genetic factors as an etiology of CGIO has been accepted, but investigations about CGIO have mainly focused on aneuploidy, and the focus has been on duodenal obstruction. The objective of this study was to evaluate the risk of chromosome aberrations (including numeric and structural aberrations) in different types of CGIO. A second objective was to assess the risk of abnormal CNVs detected by copy number variation sequencing (CNV-seq) in fetuses with different types of CGIO.MethodsData from pregnancies referred for invasive testing and CNV-seq due to sonographic diagnosis of fetal CGIO from 2015 to 2020 were obtained retrospectively from the computerized database. The rates of chromosome aberrations and abnormal CNV-seq findings for isolated CGIOs and complicated CGIOs and different types of CGIOs were calculated.ResultsOf the 240 fetuses with CGIO that underwent karyotyping, the detection rate of karyotype abnormalities in complicated CGIO was significantly higher than that of the isolated group (33.8% vs. 10.8%, p < 0.01). Ninety-three cases with normal karyotypes further underwent CNV-seq, and CNV-seq revealed an incremental diagnostic value of 9.7% over conventional karyotyping. In addition, the incremental diagnostic yield of CNV-seq analysis in complicated CGIOs (20%) was higher than that in isolated CGIOs (4.8%), and the highest prevalence of pathogenic CNVs/likely pathogenic CNVs was found in the duodenal stenosis/atresia group (17.5%), followed by the anorectal malformation group (15.4%). The 13q deletion, 10q26 deletion, 4q24 deletion, and 2p24 might be additional genetic etiologies of duodenal stenosis/atresia.ConclusionsThe risk of pathogenic chromosomal abnormalities and CNVs increased in the complicated CGIO group compared to that in the isolated CGIO group, especially when fetuses presented duodenal obstruction (DO) and anorectal malformation. CNV-seq was recommended to detect submicroscopic chromosomal aberrations for DO and anorectal malformation when the karyotype was normal. The relationship between genotypes and phenotypes needs to be explored in the future to facilitate prenatal diagnosis of fetal CGIO and yield new clues into their etiologies.

RPP25 as a Prognostic-Related Biomarker That Correlates With Tumor Metabolism in Glioblastoma.

RPP25, a 25 kDa protein subunit of ribonuclease P (RNase P), is a protein-coding gene. Disorders associated with RPP25 include chromosome 15Q24 deletion syndrome and diffuse scleroderma, while systemic sclerosis can be complicated by malignancy. However, the functional role of RPP25 expression in glioblastoma multiforme (GBM) is unclear. In this study, comprehensive bioinformatics analysis was used to evaluate the impact of RPP25 on GBM occurrence and prognosis. Differential analysis of multiple databases showed that RPP25 was commonly highly expressed in multiple cancers but lowly expressed in GBM. Survival prognostic results showed that RPP25 was prognostically relevant in six tumors (CESC, GBM, LAML, LUAD, SKCM, and UVM), but high RPP25 expression was significantly associated with poor patient prognosis except for CESC. Analysis of RPP25 expression in GBM alone revealed that RPP25 was significantly downregulated in GBM compared with normal tissue. Receiver operating characteristic (ROC) combined with Kaplan-Meier (KM) analysis and Cox regression analysis showed that high RPP25 expression was a prognostic risk factor for GBM and had a predictive value for the 1-year, 2-year, and 3-year survival of GBM patients. In addition, the expression of RPP25 was correlated with the level of immune cell infiltration. The gene set enrichment analysis (GSEA) results showed that RPP25 was mainly associated with signalling pathways related to tumor progression and tumor metabolism.

2q37.3 Deletion with Complex Heart Defects Suggesting Interruption of Early Ventricular Looping

A maternally inherited 828 kb microdeletion of 2q37.3 manifested in a 3-week-old premature boy as left juxtaposition of the atrial appendages associated with tricuspid atresia, double outlet infundibulum, subvalvar pulmonary atresia, large secundum atrial septal defect, and right aortic arch with mirror-image branching, consistent with developmental arrest early in heart looping. To the best of our knowledge, no previous 2q37 deletion syndrome has been reported with such a severe cardiac dysmorphology. Hence, this case adds to the cardiac phenotypes identified in 2q37 deletion syndrome.

14. Deletions resulting in Brachydactyly Mental Retardation Syndrome (BDMR): Multiple contributing regions in distal 2q37

Brachydactyly mental retardation syndrome (BDMR), due to distal 2q37 deletions, is characterized by a variable phenotype that most often includes DD/ID, autism, behavioral issues, brachydactyly type E, obesity, microcephaly and other dysmorphic craniofacial features. Affected individuals typically have large deletions (>2 to 9 Mb) that include the HDAC4 gene. Haploinsufficiency of HDAC4 is proposed as the primary genetic cause of BDMR-associated phenotypes, with potential incomplete penetrance (Williams et al., 2010; Le et al., 2019; Wheeler et al., 2014).

Neural substrates of psychosis revealed by altered dependencies between brain activity and white-matter architecture in individuals with 22q11 deletion syndrome

BackgroundDysconnectivity has been consistently proposed as a major key mechanism in psychosis. Indeed, disruptions in large-scale structural and functional brain networks have been associated with psychotic symptoms. However, brain activity is largely constrained by underlying white matter pathways and the study of function-structure dependency, compared to conventional unimodal analysis, allows a biologically relevant assessment of neural mechanisms. The 22q11.2 deletion syndrome (22q11DS) constitutes a remarkable opportunity to study the pathophysiological processes of psychosis. Methods58 healthy controls and 57 deletion carriers, aged from 16 to 32 years old,underwent resting-state functional and diffusion-weighted magnetic resonance imaging. Deletion carriers were additionally fully assessed for psychotic symptoms. Firstly, we used a graph signal processing method to combine brain activity and structural connectivity measures to obtain regional structural decoupling indexes (SDIs). We use SDI to assess the differences of functional structural dependency (FSD) across the groups. Subsequently we investigated how alterations in FSDs are associated with the severity of positive psychotic symptoms in participants with 22q11DS. ResultsIn line with previous findings, participants in both groups showed a spatial gradient of FSD ranging from sensory-motor regions (stronger FSD) to regions involved in higher-order function (weaker FSD). Compared to controls, in participants with 22q11DS, and further in deletion carriers with more severe positive psychotic symptoms, the functional activity was more strongly dependent on the structure in parahippocampal gyrus and subcortical dopaminergic regions, while it was less dependent within the cingulate cortex. This analysis revealed group differences not otherwise detected when assessing the structural and functional nodal measures separately. ConclusionsOur findings point toward a disrupted modulation of functional activity on the underlying structure, which was further associated to psychopathology for candidate critical regions in 22q11DS. This study provides the first evidence for the clinical relevance of function-structure dependency and its contribution to the emergence of psychosis.

Neural Substrates of Psychosis Revealed by Altered Dependencies between Brain Activity and White-Matter Architecture in Individuals with 22q11 Deletion Syndrome

Neural Substrates of Psychosis Revealed by Altered Dependencies between Brain Activity and White-Matter Architecture in Individuals with 22q11 Deletion Syndrome

Prenatal ultrasound features and genetic analysis for 17q12 microdeletion syndrome.

The 17q12 microdeletion syndrome is a type of syndrome caused by a deletion of 1.4 to 1.8 Mb in the 17q12 region of the chromosome. The main clinical features of the syndrome are structural or functional abnormalities in the kidney and urethra, type 5 diabetes, and neurodevelopmental or neuropsychiatric disorders. The diverse range of phenotypes associated with 17q12 microdeletion limited clinical recognition and diagnosis. In addition, the phenotypic description of this microdeletion is mainly about postpartum. Due to the rarity of the 17q12 microdeletion itself, studies on the prenatal phenotype of the 17q12 microdeletion are limited. This study aims to analyze the prenatal ultrasound features of 17q12 microdeletion, and to investigate the possibility of genotype-phenotype relationship for providing evidence for genetic counseling in such pregnancies. A total of 3 320 pregnant women and their fetuses were collected for the detection of chromosome copy number variation sequencing (CNV-Seq) due to different ultrasound anomalies in Xiangya Hospital of Central South University. The clinical data of pregnant women and their fetuses who were found to harbor 17q12 microdeletion were reviewed, including maternal age, fetus ultrasound findings, gestational week of the invasive procedure, CNV-Seq results, and the pregnancy outcome. CNV-Seq was tested in the parents to verify whether the abnormality was de novo or inherited. The prenatal ultrasound features and CNV-Seq test results of these 12 fetuses were analyzed and their pregnancy outcomes were followed up. Approximately 0.36% (12/3 320) of fetuses were detected to have 17q12 microdeletion, all characterized as renal abnormalities, accounting for 4.2% (12/288) of all prenatal ultrasound with renal abnormalities, accounting for 48% (12/25) of prenatal ultrasound with renal abnormalities and pathogenic chromosomal abnormalities. The sizes of 17q12 deletion ranged from 1.4 to 1.7 Mb, and all of them included the HNF1B gene. Nine cases were de novo, 2 inherited from the mother, and 1 inherited from father. Among 12 fetuses with 17q12 deletion, 11 cases of prenatal ultrasound suggested bilateral hyperechogenic kidneys and 1 case only showed renal cyst, in which 3 fetuses with enlarged kidneys, 1 with clubfeet, and 1 with subependymal cyst. Pregnancy outcomes were available for 11 of the 12 fetuses. Of them, the parents of 9 fetuses with de novo deletion chose to terminate the pregnancy, and 2 live birth babies inherited from their mother with normal renal function had persistent renal echogenicity enhancement after birth. Bilateral hyperechogenic kidneys show strikingly correlation with 17q12 microdeletion, suggesting the necessity of chromosome copy numbers detection for fetuses with hyperechogenic kidneys.

Agency Deficits in a Human Genetic Model of Schizophrenia: Insights From 22q11DS Patients.

Schizophrenia is a chronic and disabling mental illness characterized by a disordered sense of self. Current theories suggest that deficiencies in the sense of control over one’s actions (Sense of Agency, SoA) may underlie some of the symptoms of schizophrenia. However, it is not clear if agency deficits are a precursor or a result of psychosis. Here, we investigated full body agency using virtual reality in a cohort of 22q11 deletion syndrome participants with a genetic propensity for schizophrenia. In two experiments employing virtual reality, full body motion tracking, and online feedback, we investigated SoA in two separate domains. Our results show that participants with 22q11DS had a considerable deficit in monitoring their actions, compared to age-matched controls in both the temporal and spatial domain. This was coupled with a bias toward erroneous attribution of actions to the self. These results indicate that nonpsychotic 22q11DS participants have a domain general deficit in the conscious sensorimotor mechanisms underlying the bodily self. Our data reveal an abnormality in the SoA in a cohort with a genetic predisposition for schizophrenia, but without psychosis, providing evidence that deficits in delineation of the self may be a precursor rather than a result of the psychotic state.

Improving renal phenotype and evolving extra-renal features of 17q12 deletion encompassing the HNF1B gene.

BackgroundHNF1B deletion/intragenic mutations are the most commonly identified genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT) suggested by fetal ultrasound findings such as: parenchymal hyperechogenicity, overt cystic changes or gross morphological urinary system (UT) abnormalities. The postnatal evolution of these 17q12 deletions encompassing the HNF1B gene-associated findings has not been assessed in depth.MethodsIn this observational study, we present postnatal follow-up findings in 5 of 6 cases (one pregnancy was terminated on parental request) of fetal-onset cystic/hyperechogenic kidneys eventually diagnosed with 17q12 microdeletion encompassing the HNF1B gene between 2009 and 2017.ResultsComplete normalization of kidney parenchymal abnormalities and of depressed neonatal renal function was observed in 4/5 and 5/5 patients within 2–4.9 years and 1.5–8 months, respectively. All 5 patients had preserved normal renal function at 3–11 years of follow-up. The evolving later-onset renal features included: hypomagnesemia, hyperuricemia, urinary tract infection (UTI), and bilateral grade 3–4 vesicoureteral reflux and bladder diverticula in 3, 3, 2, and 1 patient, respectively. HNF1B gene deletion-associated extra-renal manifestations with delayed presentation were global developmental delay/autistic spectrum disorder (ASD), rolandic-type seizures, overweight, and borderline fasting hyperglycemia observed in 1–2 patients each. Family history was positive for small-size or asymptomatic cystic kidneys with normal function, diabetes mellitus, seizures, and mental/psychiatric problems in 3/6 cases.ConclusionsFetal-onset HNF1B deletion-associated kidneys’ parenchymal abnormalities confirmed postnatally with initially depressed renal function might undergo complete resolution within several years and few months, respectively. However, later-onset urinary tract, metabolic, and neurodevelopmental features of this mutation might appear over years. Therefore, genetic molecular evaluation/diagnosis and continuous follow-up for evolving features are mandatory in affected children.

Expanding the Neuroradiological Phenotype of 18q Deletion Syndrome

Expanding the Neuroradiological Phenotype of 18q Deletion Syndrome

Immune Dysregulation in Patients With Chromosome 18q Deletions-Searching for Putative Loci for Autoimmunity and Immunodeficiency.

IntroductionAutoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions.Material and MethodsMedical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG1-4 serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR—a free web resource for gene prioritization.Results18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min–max: 4.0–33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG1-4) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls.ConclusionsPatients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.

Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience.

Constitutional LZTR1 or SMARCB1 pathogenic variants (PVs) have been found in ∼86% of familial and ∼40% of sporadic schwannomatosis cases. Hence, we performed massively parallel sequencing of the entire LZTR1, SMARCB1, and NF2 genomic loci in 35 individuals with schwannomas negative for constitutional first-hit PVs in the LZTR1/SMARCB1/NF2 coding sequences; however, with 22q deletion and/or a different NF2 PV in each tumor, including six cases with only one tumor available. Furthermore, we verified whether any other LZTR1/SMARCB1/NF2 (likely) PVscould be found in 16 cases carrying a SMARCB1 constitutional variant in the 3'-untranslated region (3'-UTR) c.*17C>T, c.*70C>T, or c.*82C>T. As no additional variants were found, functional studies were performed to clarify the effect of these 3'-UTR variants on the transcript. The 3'-UTR variants c.*17C>T and c.*82C>T showed pathogenicity by negatively affecting theSMARCB1 transcript level. Two novel deep intronic SMARCB1 variants, c.500+883T>G and c.500+887G>A, resulting in out-of-frame missplicing of intron 4, were identified in two unrelated individuals. Further resequencing of the entire repeat-masked genomics sequences of chromosome 22q in individuals negative for PVs in the SMARCB1/LZTR1/NF2 coding- and noncoding regions revealed five potential schwannomatosis-predisposing candidate genes, that is,MYO18B, NEFH, SGSM1, SGSM3, and SBF1, pending further verification.

Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice

Copy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which the CNVs contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in mice with a heterozygous deletion of Tbx1, one of the 22q11.2-encoded genes. Ex vivo whole-brain diffusion-tensor imaging (DTI)–magnetic resonance imaging (MRI) in Tbx1 heterozygous mice indicated that the fimbria was the only region with significant myelin alteration. Electron microscopic and histological analyses showed that Tbx1 heterozygous mice exhibited an apparent absence of large myelinated axons and thicker myelin in medium axons in the fimbria, resulting in an overall decrease in myelin. The fimbria of Tbx1 heterozygous mice showed reduced mRNA levels of Ng2, a gene required to produce oligodendrocyte precursor cells. Moreover, postnatal progenitor cells derived from the subventricular zone, a source of oligodendrocytes in the fimbria, produced fewer oligodendrocytes in vitro. Behavioral analyses of these mice showed selectively slower acquisition of spatial memory and cognitive flexibility with no effects on their accuracy or sensory or motor capacities. Our findings provide a genetic and cellular basis for the compromised cognitive speed in patients with 22q11.2 hemizygous deletion.

Abnormal nodal and global network organization in resting state functional MRI from subjects with the 22q11 deletion syndrome

The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis.

A Novel 4q32.3 Deletion in a Child: Additional Signs and the Role of MARCH1.

The 4q deletion syndrome is an uncommon condition manifesting with broad clinical expression and phenotypic variability. We report a 5-year-old boy affected by 4q deletion syndrome who showed minor craniofacial features, growth failure, mild developmental delay, severe speech delay, and marked irascibility and aggressivity. Moreover, he showed precocious and crowded primary dentition, digital hyperlaxity, and congenital bilateral adducted thumbs, signs which were previously unreported in the syndrome. The array comparative genomic hybridization analysis revealed a 4q partial terminal deletion of ∼329.6 kb extending from 164.703.186 to 165.032.803 nt, which includes part of MARCH1 (membrane associated ring-CH-type finger 1) gene (OMIM#613331). Same rearrangement was found in his healthy mother. Clinical phenotype of the child and its relationship to the deleted region is presented with a revision of the cases having the same copy number losses from the literature and genomic variant databases.

M149 PARTIAL DIGEORGE SYNDROME WITH PROLONGED T-CELL LYMPHOPENIA

The clinical presentation of DiGeorge Syndrome (22q deletion) is highly variable, particularly with respect to the immunologic manifestations. The length of time required for recovery of immune system abnormalities is not well-defined in current literature. This case demonstrates spontaneous immune reconstitution in a patient with partial DiGeorge syndrome following a prolonged period of T-cell lymphopenia.

M208 A RARE CONDITION IN A RARE DISEASE: A CHALLENGING CASE OF ATYPICAL COMPLETE DIGEORGE

DiGeorge Syndrome (DGS) is a congenital defect affecting the heart, thymus and parathyroid glands due to deletion of 22q11.2. This case describes an infant with Complete DiGeorge Syndrome who developed Atypical DiGeorge.

Translational pediatrics: clinical perspective for Phelan-McDermid syndrome and autism research.

Phelan-McDermid syndrome (PMS) is a rare genetic disorder presenting with developmental delay, epilepsy, and autism spectrum disorder (ASD). The segmental deletion of chromosome 22q13.3 affects the copy number of SHANK3, the gene encoding a scaffolding protein at the postsynaptic density. Biological studies indicate that SHANK3 plays crucial roles in the development of synaptic functions in the postnatal brain. Notably, induced pluripotent stem (iPS) cells have enabled researchers to develop brain organoids and microglia from patients and to explore the pathophysiology of neurodevelopmental disorders in human cells. Single-cell RNA sequencing of these cells revealed that human-specific genes are uniquely expressed during cortical development. Thus, patient-derived disease models are expected to identify as-yet-unidentified functions of SHANK3 in the development of human brain. These efforts may help establish a new style of translational research in pediatrics, which is expected to provide therapeutic insight for children with PMS and broader categories of disease. IMPACT: Phelan-McDermid syndrome is a prototypic model for molecular studies of autism spectrum disorder. Brain organoids are expected to provide therapeutic insight. Single-cell RNA sequencing of microglia may uncover the functional roles of human-specific genes.

Surgical Considerations for an Osseointegrated Steady State Implant (OSIA2®) in Children.

Surgical Considerations for an Osseointegrated Steady State Implant (OSIA2®) in Children.