CHD7 and SOX2 act in a common gene regulatory network during mammalian semicircular canal and cochlear development.

Inner ear morphogenesis requires tightly regulated epigenetic and transcriptional control of gene expression. CHD7, an ATP-dependent chromodomain helicase DNA-binding protein, and SOX2, an SRY-related HMG box pioneer transcription factor, are known to contribute to vestibular and auditory system development, but their genetic interactions in the ear have not been explored. Here, we analyzed inner ear development and the transcriptional regulatory landscapes in mice with variable dosages of Chd7 and/or Sox2. We show that combined haploinsufficiency for Chd7 and Sox2 results in reduced otic cell proliferation, severe malformations of semicircular canals, and shortened cochleae with ectopic hair cells. Examination of mice with conditional, inducible Chd7 loss by Sox2CreER reveals a critical period (~E9.5) of susceptibility in the inner ear to combined Chd7 and Sox2 loss. Data from genome-wide RNA-sequencing and CUT&Tag studies in the otocyst show that CHD7 regulates Sox2 expression and acts early in a gene regulatory network to control expression of key otic patterning genes, including Pax2 and Otx2. CHD7 and SOX2 directly bind independently and cooperatively at transcription start sites and enhancers to regulate otic progenitor cell gene expression. Together, our findings reveal essential roles for Chd7 and Sox2 in early inner ear development and may be applicable for syndromic and other forms of hearing or balance disorders.

CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct.

Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants in SLC26A4. However, in European-Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein structure. Consistent with a role of CHD7 in this tissue, Chd7 transcript and protein were detected in all epithelial cells of the endolymphatic duct and sac of the developing mouse inner ear. These results suggest that some CHD7 variants can cause nonsyndromic hearing loss and EVA. CHD7 should be included in DNA sequence analyses to detect pathogenic variants in EVA patients. Chd7 expression and mutant phenotype data in mice suggest that CHD7 contributes to the formation or function of the endolymphatic sac and duct.

Chromatin remodeler Chd7 regulates photoreceptor development and outer segment length.

Mutations in the chromatin remodeling factor CHD7 are the predominant cause of CHARGE syndrome, a congenital disorder that frequently includes ocular coloboma. Although CHD7 is known to be required for proper ocular morphogenesis, its role in retinal development has not been thoroughly investigated. Given that individuals with CHARGE syndrome can experience visual impairment even in the absence of coloboma, a better understanding of CHD7 function in the retina is needed. In this study, we characterized the expression pattern of Chd7 in the developing zebrafish and mouse retina and documented ocular and retinal phenotypes in Chd7 loss-of-function mutants. Zebrafish Chd7 was expressed throughout the retinal neuroepithelium when retinal progenitor cells were actively proliferating, and later in subsets of newly post-mitotic retinal cells. At stages of retinal development when most retinal cell types had terminally differentiated, Chd7 expression remained strong in the ganglion cell layer and in some cells in the inner nuclear layer. Intriguingly, strong expression of Chd7 was also observed in the outer nuclear layer where it was co-expressed with markers of post-mitotic cone and rod photoreceptors. Expression of mouse CHD7 displayed a similar pattern, including expression in the ganglion cells, subsets of inner nuclear layer cells, and in the distal outer nuclear layer as late as P15. Two different mutant chd7 zebrafish lines were characterized for ocular and retinal defects. These mutants displayed microphthalmia, reduced numbers of cone photoreceptors, and truncated rod and cone photoreceptor outer segments. Reduced cone photoreceptor number and abnormal outer segments were also observed in heterozygous Chd7 mutant mice. Taken together, our results in zebrafish and mouse reveal a conserved, previously undescribed role for Chd7 in retinal development and photoreceptor outer segment morphogenesis. Moreover, our work suggests an avenue of future investigation into the pathogenesis of visual system defects in CHARGE syndrome.

Chromatin remodeler CHD7 is critical for cochlear morphogenesis and neurosensory patterning.

Epigenetic regulation of gene transcription by chromatin remodeling proteins has recently emerged as an important contributing factor in inner ear development. Pathogenic variants in CHD7, the gene encoding Chromodomain Helicase DNA binding protein 7, cause CHARGE syndrome, which presents with malformations in the developing ear. Chd7 is broadly expressed in the developing mouse otocyst and mature auditory epithelium, yet the pathogenic effects of Chd7 loss in the cochlea are not well understood. Here we characterized cochlear epithelial phenotypes in mice with deletion of Chd7 throughout the otocyst (using Foxg1Cre/+ and Pax2Cre), in the otic mesenchyme (using TCre), in hair cells (using Atoh1Cre), in developing neuroblasts (using NgnCre), or in spiral ganglion neurons (using ShhCre/+). Pan-otic deletion of Chd7 resulted in shortened cochleae with aberrant projections and axonal looping, disorganized, supernumerary hair cells at the apical turn and a narrowed epithelium with missing hair cells in the middle region. Deletion of Chd7 in the otic mesenchyme had no effect on overall cochlear morphology. Loss of Chd7 in hair cells did not disrupt their formation or organization of the auditory epithelium. Similarly, absence of Chd7 in spiral ganglion neurons had no effect on axonal projections. In contrast, deletion of Chd7 in developing neuroblasts led to smaller spiral ganglia and disorganized cochlear neurites. Together, these observations reveal dosage-, tissue-, and time-sensitive cell autonomous roles for Chd7 in cochlear elongation and cochlear neuron organization, with minimal functions for Chd7 in hair cells. These studies provide novel information about roles for Chd7 in development of auditory neurons.

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.

The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

Challenges of variant reinterpretation: Opinions of stakeholders and need for guidelines.

PURPOSE: The knowledge used to classify genetic variants is continually evolving, and the classification can change on the basis of newly available data. Although up-to-date variant classification is essential for clinical management, reproductive planning, and identifying at-risk family members, there is no consistent practice across laboratories or clinicians on how or under what circumstances to perform variant reinterpretation. METHODS: We conducted exploratory focus groups (N = 142) and surveys (N = 1753) with stakeholders involved in the process of variant reinterpretation (laboratory directors, clinical geneticists, genetic counselors, nongenetic providers, and patients/parents) to assess opinions on key issues, including initiation of reinterpretation, variants to report, termination of the responsibility to reinterpret, and concerns about consent, cost, and liability. RESULTS: Stakeholders widely agreed that there should be no fixed termination point to the responsibility to reinterpret a previously reported genetic variant. There were significant concerns about liability and lack of agreement about many logistical aspects of variant reinterpretation. CONCLUSION: Our findings suggest a need to (1) develop consensus and (2) create transparency and awareness about the roles and responsibilities of parties involved in variant reinterpretation. These data provide a foundation for developing guidelines on variant reinterpretation that can aid in the development of a low-cost, scalable, and accessible approach.

A critical exploration of nurses' perceptions of access to oncology care among Indigenous peoples: Results of a national survey.

Inequities in access to oncology care among Indigenous peoples in Canada are well documented. Access to oncology care is mediated by a range of factors; however, emerging evidence suggests that healthcare providers, including nurses, play a significant role in shaping healthcare access. The purpose of this study was to critically examine access to oncology care among Indigenous peoples in Canada from the perspective of oncology nurses. Guided by postcolonial theoretical perspectives, interpretive descriptive and critical discourse analysis methodologies informed study design and data analysis. Oncology nurses were recruited from across Canada to complete an online survey (n = 78). Nurses identified a range of barriers experienced by Indigenous peoples when accessing oncology care, yet located these barriers primarily at the individual and systems levels. Nurses perceived themselves as mediators of access to oncology care; however, their efforts to facilitate access to care were constrained by the dominance of biomedicine within healthcare. Nurses' constructions of access to oncology care highlight the embedded narrative of individualism within nursing practice and the relative invisibility of racism as a determinant of equitable access to care among Indigenous peoples. This suggests a need for oncology nurses to better understand and incorporate structural determinants of health perspectives.

Incorporation of exome-based CNV analysis makes trio-WES a more powerful tool for clinical diagnosis in neurodevelopmental disorders: A retrospective study.

Neurodevelopmental disorders (NDDs) are a genetically heterogeneous group of diseases, affecting 1%-3% of children. Whole-exome sequencing (WES) has been widely used as a first-tier tool for identifying genetic causes of rare diseases. Trio-WES was performed in a cohort of 74 pedigrees with NDDs. Exome-based copy number variant (CNV) calling was incorporated into the traditional single-nucleotide variant (SNV) and small insertion/deletion (Indel) analysis pipeline for WES data. An overall positive diagnostic yield of 54.05% (40/74) was obtained in the pipeline of combinational SNV/Indel and CNV analysis, including 35.13% (26/74) from SNV/Indel analysis and 18.92% (14/74) from exome-based CNV analysis, respectively. In total, SNV/Indel analysis identified 38 variants in 28 different genes, of which 24 variants were novel; exome-based CNV analysis identified 14 CNVs, including 2 duplications and 12 deletions, which ranged from 440 bp (single exon) to 16.86 Mb (large fragment) in size. In particular, a hemizygous deletion of exon 1 in the SLC16A2 gene was detected. Based on the diagnostic results, two families underwent prenatal diagnosis and had unaffected babies. The incorporation of exome-based CNV detection into conventional SNV/Indel analysis for a single trio-WES test significantly improved the diagnostic rate, making WES a more powerful, practical, and cost-effective tool in the clinical diagnosis of NDDs.

Development and implementation of an electronic medical record module to track genetic testing results.

PURPOSE: Genetic testing and results return pose many challenges, even in the era of electronic medical records. Whether results are positive or negative, genetic testing and return of results necessitate patient follow-up, referrals, and coordination between providers. Genetic evaluations typically utilize a variety of testing modalities with differing timetables and/or avenues to return. Therefore, genetic information requires a secondary, unified mechanism for storing and tracking results and communication to facilitate patient care. METHODS: We developed an electronic medical record (EMR) episodes-based module called Pediatric Genetic Tracking to provide a centralized summary of patient tracking information in a single-institution pediatric genetics setting. RESULTS: We created episodes for 6,133 patients evaluated in our division over a 3-year period. They highlighted clinical information for 1,901 different diagnoses and 547 genetic tests, and the involvement of 9 providers, 7 genetic counselors, 61 trainees, and 15 students using two modes of follow-up. CONCLUSION: This Pediatric Genetic Tracking episodes system serves as a "one-stop shop" living document for updated patient genetic information and can be easily expanded to include variant content for broader population level sharing or analysis. These episodes-based modules facilitate communication to support timely and accurate return of genetic test results and follow-up.

Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome.

CHARGE syndrome-which stands for coloboma of the eye, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear anomalies-is a severe developmental disorder with wide phenotypic variability, caused mainly by mutations in CHD7 (chromodomain helicase DNA-binding protein 7), known to encode a chromatin remodeler. The genetic lesions responsible for CHD7 mutation-negative cases are unknown, at least in part because the pathogenic mechanisms underlying CHARGE syndrome remain poorly defined. Here, we report the characterization of a mouse model for CHD7 mutation-negative cases of CHARGE syndrome generated by insertional mutagenesis of Fam172a (family with sequence similarity 172, member A). We show that Fam172a plays a key role in the regulation of cotranscriptional alternative splicing, notably by interacting with Ago2 (Argonaute-2) and Chd7. Validation studies in a human cohort allow us to propose that dysregulation of cotranscriptional alternative splicing is a unifying pathogenic mechanism for both CHD7 mutation-positive and CHD7 mutation-negative cases. We also present evidence that such splicing defects can be corrected in vitro by acute rapamycin treatment.

Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8.

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.

Clinical debriefing: A concept analysis.

AIMS AND OBJECTIVES: The purpose of this paper is to enhance nursing and collaborative practice by presenting a concept analysis of clinical debriefing and introducing an operational definition. BACKGROUND: Debriefing has taken many forms, using a variety of approaches. Variations and inconsistencies in clinical debriefing, and its related terms, still exist in the clinical setting. DESIGN: Concept analysis. METHODS: Walker and Avant's eight-step approach to concept analysis. RESULTS: The defining attributes of clinical debriefing identified in this analysis are described as the five E's: educated/experienced facilitator, environment, education, evaluation and emotions. Antecedents identified in this analysis include the critical event, the desire or need to review such an event and the organizational awareness to execute clinical debriefs. The consequences of clinical debriefings are primarily advantageous and positively impact involved nurses, healthcare teams, patients and organizations. Empirical referents of clinical debriefing are complex and multifactorial. The productivity of a clinical debrief can be enhanced through a series of proposed questions. Together, the defining attributes, antecedents and consequences shape a proposed operational definition of clinical debriefing. CONCLUSION: Clinical debriefing is a valuable tool within healthcare organizations. Debriefing can be a holistic, interprofessional, collaborative experience when all five defining attributes are present. Further investigation is required to standardise debriefing practices in clinical settings. RELEVANCE TO CLINICAL PRACTICE: A concept analysis on clinical debriefing promotes uniformity of debriefing practices, reflective practice among nurses and healthcare teams, and contributes to nursing science by creating a platform for the development of practice standards, research and theory development.

Digital Storytelling as a Patient Engagement and Research Approach With First Nations Women: How the Medicine Wheel Guided Our Debwewin Journey.

When research is conducted from a Western paradigm alone, the findings and resultant policies often ignore Indigenous peoples' health practices and fail to align with their health care priorities. There is a need for decolonized approaches within qualitative health research to collaboratively identify intersecting reasons behind troubling health inequities and to integrate Indigenous knowledge into current health care services. We engaged with First Nations women to explore to what extent digital storytelling could be a feasible, acceptable, and meaningful research method to inform culturally safe health care services. This novel approach created a culturally safe and ethical space for authentic patient engagement. Our conversations were profound and provided deep insights into First Nations women's experiences with breast cancer and guidance for our future qualitative study. We found that the digital storytelling workshop facilitated a Debwewin journey, which is an ancient Anishinabe way of knowing that connects one's heart knowledge and mind knowledge.

Nurses as agents of disruption: Operationalizing a framework to redress inequities in healthcare access among Indigenous Peoples.

Health equity is a global concern. Although health equity extends far beyond the equitable distribution of healthcare, equitable access to healthcare is essential to the achievement of health equity. In Canada, Indigenous Peoples experience inequities in health and healthcare access. Cultural safety and trauma- and violence-informed care have been proposed as models of care to improve healthcare access, yet practitioners lack guidance on how to implement these models. In this paper, we build upon an existing framework of equity-oriented care for primary healthcare settings by proposing strategies to guide nurses in operationalizing cultural safety and trauma- and violence-informed care into nursing practice at the individual level. This component is one strategy to redress inequitable access to care among Indigenous Peoples in Canada. We conceptualize barriers to accessing healthcare as intrapersonal, interpersonal, and structural. We then define three domains for nursing action: practicing reflexivity, prioritizing relationships, and considering the context. We have applied this expanded framework within the context of Indigenous Peoples in Canada as a way of illustrating specific concepts and focusing our argument; however, this framework is relevant to other groups experiencing marginalizing conditions and inequitable access to healthcare, and thus is applicable to many areas of nursing practice.

Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes.

CHARGE syndrome is characterized by a pattern of congenital anomalies (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital abnormalities, and Ear abnormalities). De novo mutations of chromodomain helicase DNA binding protein 7 (CHD7) are the primary cause of CHARGE syndrome. The clinical phenotype is highly variable including a wide spectrum of congenital heart defects. Here, we review the range of congenital heart defects and the molecular effects of CHD7 on cardiovascular development that lead to an over-representation of atrioventricular septal, conotruncal, and aortic arch defects in CHARGE syndrome. Further, we review the overlap of cardiovascular and noncardiovascular comorbidities present in CHARGE and their impact on the peri-operative morbidity and mortality in individuals with CHARGE syndrome.

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

BACKGROUND: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate. METHODS: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES. RESULTS: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice. CONCLUSIONS: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.

Inappropriate p53 activation during development induces features of CHARGE syndrome.

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

Mutation update for the SATB2 gene.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Nervous system development and disease: A focus on trithorax related proteins and chromatin remodelers.

The nervous system comprises many different cell types including neurons, glia, macrophages, and immune cells, each of which is defined by specific patterns of gene expression, morphology, function, and anatomical location. Establishment of these complex and highly regulated cell fates requires spatial and temporal coordination of gene transcription. Open chromatin (euchromatin) allows transcription factors to interact with gene promoters and activate lineage specific genes, whereas closed chromatin (heterochromatin) remains inaccessible to transcriptional activation. Changes in the genome-wide distribution of euchromatin accompany transcriptional plasticity that allows the diversity of mature cell fates to be generated during development. In the past 20years, many new genes and gene families have been identified to participate in regulation of chromatin accessibility. These genes include chromatin remodelers that interact with Trithorax group (TrxG) and Polycomb group (PcG) proteins to activate or repress transcription, respectively. Here we review the role of TrxG proteins in neurodevelopment and disease.