Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.

Complex genomic rearrangements (CGRs) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here, we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated, we observed localization and multiple copy number changes including deletions, duplications, and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism's life cycle.

Improving access to exome sequencing in a medically underserved population through the Texome Project.

PURPOSE: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing. METHODS: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project. RESULTS: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return of results at no cost. We summarize the psychosocial or medical implications of these genetic diagnoses. Thus far, ES provided molecular diagnoses for 18 out of 60 (30%) of Texome participants. Plus, in 11 out of 60 (18%) participants, a partial or probable diagnosis was identified. Overall, 5 participants had a change in medical management. CONCLUSION: To date, the Texome Project has recruited a racially, ethnically, and socioeconomically diverse cohort. The diagnostic rate and medical impact in this cohort support the need for expanded access to genetic testing and services. The Texome Project will continue reducing barriers to genomic care throughout the future study years.

DISP1 deficiency: Monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations.

PURPOSE: DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with division transporter dispatched-1 (DISP1) variants. METHODS: This study was based on the identification of at least 1 pathogenic variant of the DISP1 gene in individuals for whom detailed clinical data were available. RESULTS: A total of 23 DISP1 variants were identified in heterozygous, compound heterozygous or homozygous states in 25 individuals with midline craniofacial defects. Most cases were minor forms of HPE, with craniofacial features such as orofacial cleft, solitary median maxillary central incisor, and congenital nasal pyriform aperture stenosis. These individuals had either monoallelic loss-of-function variants or biallelic missense variants in DISP1. In individuals with severe HPE, the DISP1 variants were commonly found associated with a variant in another HPE-linked gene (ie, oligogenic inheritance). CONCLUSION: The genetic findings we have acquired demonstrate a significant involvement of DISP1 variants in the phenotypic spectrum of midline defects. This underlines its importance as a crucial element in the efficient secretion of Sonic hedgehog. We also demonstrated that the very rare solitary median maxillary central incisor and congenital nasal pyriform aperture stenosis combination is part of the DISP1-related phenotype. The present study highlights the clinical risks to be flagged up during genetic counseling after the discovery of a pathogenic DISP1 variant.

Where do we intervene to optimize sports systems? Leverage Points the way.

Sport and sports research are inherently complex systems. This appears to be somewhat at odds with the current research paradigm in sport in which interventions are aimed are fixing or solving singular broken components within the system. In any complex system, such as sport, there are places where we can intervene to change behaviour and, ideally, system outcomes. Meadows influential work describes 12 different points with which to intervene in complex systems (termed "Leverage Points"), which are ordered from shallow to deeper based on their potential effectiveness to influence transformational change. Whether research in sport is aimed at shallow or deeper Leverage Points is unknown. This study aimed to assess highly impactful research in sports science, sports nutrition/metabolism, sports medicine, sport and exercise psychology, sports management, motor control, sports biomechanics and sports policy/law through a Leverage Points lens. The 10 most highly cited original-research manuscripts from each journal representing these fields were analysed for the Leverage Point with which the intervention described in the manuscript was focused. The results indicate that highly impactful research in sports science, sports nutrition/metabolism, sports biomechanics and sports medicine is predominantly focused at the shallow end of the Leverage Points hierarchy. Conversely, the interventions drawn from journals representing sports management and sports policy/law were focused on the deeper end. Other journals analysed had a mixed profile. Explanations for these findings include the dual practitioner/academic needing to "think fast" to solve immediate questions in sports science/medicine/nutrition, limited engagement with "working slow" systems and method experts and differences in incremental vs. non-incremental research strategies.

Applying a systems thinking lens to anti-doping: A systematic review identifying the contributory factors to doping in sport.

The use of performance enhancing substances and methods (known as "doping") in sport is an intractable issue, with current anti-doping strategies predominantly focused on the personal responsibility and strict liability of individual athletes. This is despite an emerging understanding that athletes exist as part of a broader complex sports system that includes governance, policymakers, media, sponsors, clubs, team members, and athlete support staff, to name a few. As such, there is a need to examine the broader systemic factors that influence doping in sport. The aim of this systematic review was to identify and synthesise the factors contributing to doping and doping behaviours, attitudes, and beliefs and the extent to which this knowledge extends beyond the athlete to consider broader sports systems. The review followed PRISMA guidelines with risk of bias and study quality assessed by the Mixed Methods Appraisal Tool, and identified contributory factors synthesised and mapped onto a systems thinking-based framework. Overall, the included studies were determined to be of high quality. Support personnel, the coach, and the coach-athlete relationship represent key influences on the athletes' decisions to dope. From the evidence presented, doping is an emergent property of sport systems and represents a complex systemic problem that will require whole-of-system interventions. The implications for this and the focus of future research are discussed.

Patterns of co-occurring birth defects in children with anotia and microtia.

Many infants with anotia or microtia (A/M) have co-occurring birth defects, although few receive syndromic diagnoses in the perinatal period. Evaluation of co-occurring birth defects in children with A/M could identify patterns indicative of undiagnosed/unrecognized syndromes. We obtained information on co-occurring birth defects among infants with A/M for delivery years 1999-2014 from the Texas Birth Defects Registry. We calculated observed-to-expected ratios (OER) to identify birth defect combinations that occurred more often than expected by chance. We excluded children diagnosed with genetic or chromosomal syndromes from analyses. Birth defects and syndromes/associations diagnosed ≤1 year of age were considered. We identified 1310 infants with non-syndromic A/M, of whom 38% (N = 492) were diagnosed with co-occurring major defects. Top combinations included: hydrocephalus, ventricular septal defect, and spinal anomalies (OER 58.4); microphthalmia and anomalies of the aorta (OER 55.4); and cleft lip with or without cleft palate and rib or sternum anomalies (OER 32.8). Some combinations observed in our study may represent undiagnosed/atypical presentations of known A/M associations or syndromes, or novel syndromes yet to be described in the literature. Careful evaluation of infants with multiple birth defects including A/M is warranted to identify individuals with potential genetic or chromosomal syndromes.

Use of neuromuscular blockade for neck dissection and association with iatrogenic nerve injury.

BACKGROUND: Cranial nerve injury is an uncommon but significant complication of neck dissection. We examined the association between the use of intraoperative neuromuscular blockade and iatrogenic cranial nerve injury during neck dissection. METHODS: This was a single-center, retrospective, electronic health record review. Study inclusion criteria stipulated patients > 18 years who had ≥ 2 neck lymphatic levels dissected for malignancy under general anesthesia with a surgery date between 2008 - 2018. Use of neuromuscular blockade during neck dissection was the primary independent variable. This was defined as any use of rocuronium, cisatracurium, or vecuronium upon anesthesia induction without reversal with sugammadex prior to surgical incision. Univariate tests were used to compare variables between those patients with, and those without, iatrogenic cranial nerve injury. Multivariable logistic regression determined predictors of cranial nerve injury and was performed incorporating Firth's estimation given low prevalence of the primary outcome. RESULTS: Our cohort consisted of 925 distinct neck dissections performed in 897 patients. Neuromuscular blockade was used during 285 (30.8%) neck dissections. Fourteen instances (1.5% of surgical cases) of nerve injury were identified. On univariate logistic regression, use of neuromuscular blockade was not associated with iatrogenic cranial nerve injury (OR: 1.73, 95% CI: 0.62 - 4.86, p = 0.30). There remained no significant association on multivariable logistic regression controlling for patient age, sex, weight, ASA class, paralytic dose, history of diabetes, stroke, coronary artery disease, carotid atherosclerosis, myocardial infarction, and cardiac arrythmia (OR: 1.87, 95% CI: 0.63 - 5.51, p = 0.26). CONCLUSIONS: In this study, use of neuromuscular blockade intraoperatively during neck dissection was not associated with increased rates of iatrogenic cranial nerve injury. While this investigation provides early support for safe use of neuromuscular blockade during neck dissection, future investigation with greater power remains necessary.

Neoadjuvant Immune Checkpoint Inhibition in Metastatic Conjunctival Melanoma.

The development of immune checkpoint inhibitors (ICI) has transformed the treatment of advanced-stage cutaneous melanoma; however, most trials did not include patients with conjunctival melanoma. Herein the authors describe a patient with recurrent conjunctival melanoma who developed locally advanced, b-raf and v-raf murine sarcoma viral oncogene homolog B1-negative melanoma in her nasal cavity and extensive, metabolically active, bilateral lymphadenopathy in her thorax. Her nasal mass measured 4.3 × 1.7 cm and was determined to be unresectable. She was treated with 4 cycles of combination ipilimumab and nivolumab therapy followed by maintenance nivolumab. She experienced a dramatic treatment response with a reduction in the size of her nasal mass to 3.0 × 1.1 cm and a complete resolution of her adenopathy. She then underwent complete surgical resection of her residual mass (approximately 75% of her original tumor size) and remains melanoma-free at 1 year of follow-up. Given the underlying genetic similarities of conjunctival melanoma to cutaneous melanoma, providers should consider the use of neoadjuvant immune checkpoint inhibitors for patients with locally advanced or limited metastatic disease.

Using systems thinking-based risk assessment methods to assess hazardous manual tasks: a comparison of Net-HARMS, EAST-BL, FRAM and STPA.

Formal risk assessment is a component of safety management relating to hazardous manual tasks (HMT). Systems thinking approaches are currently gaining interest for supporting safety management. Existing HMT risk assessment methods have been found to be limited in their ability to identify risks across the whole work system; however, systems thinking-based risk assessment (STBRA) methods were not designed for the HMT context and have not been tested in this area. The aim of this study was to compare the performance of four state-of-the-art STBRA methods: Net-HARMS, EAST-BL, FRAM and STPA to determine which would be most useful for identifying HMT risks. Each method was independently applied by one of four analysts to assess the risks associated with a hypothetical HMT system. The outcomes were assessed for alignment with a benchmark analysis. Using signal detection theory (SDT), overall STPA was found to be the best performing method having the highest hit rate, second lowest false alarm rate and highest Matthews Correlation Coefficient of the four methods.Practitioner summary: A comparison of four systems thinking risk assessment methods found that STPA had the highest level of agreement with the benchmark analysis and is the most suitable for practitioners to use to identify the risks associated with HMT systems.

Birth defect co-occurrence patterns in the Texas Birth Defects Registry.

BACKGROUND: The population-level landscape of co-occurring birth defects among infants without a syndromic diagnosis is not well understood. METHODS: We analyzed data from 40,771 infants with two or more major birth defects in the Texas Birth Defects Registry (TBDR; 1999-2014). We calculated adjusted observed-to-expected (O/E) ratios for all two, three, four, and five-way combinations of 138 major defects. RESULTS: Among 530 patterns with the highest adjusted O/E ratios (top 5% of 10,595 patterns), 66% included only defects co-occurring within one organ system and 28% were suggestive of known patterns (e.g., midline developmental defects). Of the remaining patterns, the combination of defects with the highest O/E ratio (193.8) encompassed the diaphragm, spine, spleen, and heart defects. Fourteen patterns involved heart and spine defects with or without rib defects. Ten additional patterns primarily involved two hallmark components of VACTERL association (specifically, vertebral defects, anal atresia, cardiac defects, renal, or limb defects, but not tracheoesophageal fistula). CONCLUSIONS: Our analyses provide a description of the birth defect co-occurrence patterns in a multi-ethnic, population-based sample, and revealed several patterns of interest. This work complements prior work that has suggested etiologic connections between select defects (e.g., diaphragmatic hernia and heart and spleen anomalies; heart and spine defects). IMPACT: In this large-scale, population-based study of birth defect co-occurrence patterns, we found several birth defect combinations of potential interest that warrant further investigation: congenital diaphragmatic hernia, heart, spine, and spleen defects and scimitar syndrome with vertebral defects. The majority of patterns of co-occurring defects observed more frequently than expected involved multiple defects within the same system and combinations suggestive of known associations. Nearly all of the top patterns (beyond the same system and those suggestive of known associations) involved organ systems that are components of the VACTERL association, with heart, spine, and rib defect patterns being the most common.

Patient Perceptions of Wearable and Smartphone Technologies for Remote Outcome Monitoring in Patients Who Have Hip Osteoarthritis or Arthroplasties.

BACKGROUND: Although there is interest in wearables and smartphone technologies for remote outcome monitoring, little is known regarding the willingness of hip osteoarthritis (OA) and/or total hip arthroplasty (THA) patients to authorize and adhere to such treatment. METHODS: We developed an Institutional Review Board-approved questionnaire to evaluate patient perceptions of remote monitoring technologies in a high-volume orthopedic center. Forty-seven THA patients (60% female; mean age: 66 years) and 50 nonoperative OA hip patients (52% female; mean age: 63 years) participated. Patient perceptions were compared using Pearson's chi-squared analyses. RESULTS: THA patients were similarly interested in the use of smartphone apps (91% vs 94%, P = .695) in comparison to nonoperative hip OA patients. THA patients were more receptive to using wearable sensors (94% vs 44%, P < .001) relative to their nonoperative counterparts. THA patients also expressed stronger interest in learning to use custom wearables (87% vs 32%, P < .001) vs nonoperative patients. Likewise, the majority of THA patients were willing to use Global Positioning System technology (74% vs 26%, P < .001). THA patients also expressed willingness to have their body movement (89%), balance (89%), sleep (87%), and cardiac output (91%) tracked using remote technology. CONCLUSION: Overall, we found that THA patients were highly receptive to using wearable technology in their treatments. Nonoperative OA hip patients were generally unreceptive to using smart technologies, with the exception of smartphone applications. This information may be useful as utilization of these technologies for patient care continues to evolve.

Birth Defect Co-Occurrence Patterns Among Infants With Cleft Lip and/or Palate.

OBJECTIVE: To investigate 2- to 5-way patterns of defects co-occurring with orofacial clefts using data from a population-based registry. DESIGN: We used data from the Texas Birth Defects Registry for deliveries between 1999 and 2014 to Texas residents, including 1884 cases with cleft palate (CP) and 5289 cases with cleft lip with or without cleft palate (CL±P) without a known syndrome. We identified patterns of defects co-occurring with CP and with CL±P observed more frequently than would be expected if these defects occurred independently. We calculated adjusted observed-to-expected (O/E) ratios to account for the known tendency of birth defects to cluster nonspecifically. RESULTS: Among infants without a syndrome, 23% with CP and 21% with CL±P had at least 1 additional congenital anomaly. Several combinations of defects were observed much more often than expected. For example, the combination of CL±P, congenital hydrocephaly, anophthalmia, and other nose anomalies had an O/E ratio of 605. For both CP and CL±P, co-occurrence patterns with the highest O/E ratios involved craniofacial and brain abnormalities, and many included the skeletal, cardiovascular, and renal systems. CONCLUSIONS: The patterns of defects we observed co-occurring with clefts more often than expected may help improve our understanding of the relationships between multiple defects. Further work to better understand some of the top defect combinations could reveal new phenotypic subgroups and increase our knowledge of the developmental mechanisms that underlie the respective defects.

Incident reporting in the outdoors: a systems-based analysis of injury, illness, and psychosocial incidents in led outdoor activities in Australia.

Incident reporting systems are a fundamental component of safety management, however, most systems used in practice are not aligned with contemporary accident causation models. This article presents an analysis of a National Incident Dataset (NID) for adverse incidents occurring in the Australian Led Outdoor Activity (LOA) sector. The aim was to investigate the adverse Injury, Illness, and Psychosocial incidents reported to the NID. In total, 1657 injuries, 532 illnesses, and 146 psychosocial incidents were analysed from 357,691 program participation days. The findings show that the rate of incidents per 1000 program participant days in LOAs was 4.6 for injury, 1.5 for illness, and 0.04 for psychosocial incidents, and incident severity was predominately minor. The analysis of systemic contributory factors demonstrates that incidents in LOA are systemic in nature, with multiple levels of the LOA system identified as contributing to adverse incidents. For example, contributory factors were identified across local government (facilities), schools (communication), parents (communication), LOA management (policies and procedures), people involved in the incidents (mental and physical condition), and the environment (terrain) and equipment (clothing). This study presents an assessment of the current state of safety in the Australian LOA sector and demonstrates the utility of applying systems ergonomics methods in practice. Practitioner summary: This article presents an analysis of 1657 injury, 532 illness, and 146 psychosocial incidents occurring in the Australian Led Outdoor Activity (LOA) sector, using a systems ergonomics method. The findings demonstrate the incident charactersitics and how decisions and actions from across the system contribute to adverse incidents in LOAs.

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

PURPOSE: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. METHODS: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. RESULTS: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. CONCLUSION: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.

Patterns of congenital anomalies among individuals with trisomy 13 in Texas.

Few population-based studies have analyzed patterns of co-occurring birth defects among those with trisomy 13. We evaluated the frequency of all possible combinations of any one, two, three, or four additional co-occurring birth defects among 736 individuals with trisomy 13 using data from the Texas Birth Defects Registry for deliveries during 1999-2014. We calculated the observed-to-expected ratio for each combination, adjusting for the known tendency for birth defects to cluster non-specifically. To address potential ascertainment differences among live births and non-live births, we repeated analyses specifically among live births. The combination of defects with the largest observed-to-expected ratio was microcephalus, reduction deformities of brain (e.g., holoprosencephaly), anomalies of nose, and polydactyly. As expected, most of the highest 30 observed-to-expected ratios involved combinations with documented features of trisomy 13, including defects of the scalp (e.g., aplasia cutis) and heart. Results were similar among sensitivity analyses restricted to live births. Our findings may help further delineate the phenotypic spectrum for trisomy 13 and may inform future research related to improving screening and counseling for the condition.

Applying a systems thinking lens to injury causation in the outdoors: Evidence collected during 3 years of the Understanding and Preventing Led Outdoor Accidents Data System.

INTRODUCTION: This article presents a detailed systems analysis of injury incidents from 35 Australian led outdoor activity organisations between 2014 to 2017. METHOD: Injury incident reports were collected using a specific led outdoor activity incident reporting system known as UPLOADS (Understanding and Preventing Led Outdoor Accidents Data System). RESULTS: In total, 1367 people sustained injuries from across 20 different activities, with an injury rate of 1.9 injured people per 1000 participants over the three-year period. A total of 2234 contributory factors from multiple levels of the led outdoor activity system were identified from the incident reports, and 361 relationships were identified between contributory factors. DISCUSSION: This systems analysis of injury incidents demonstrates that it is not only factors within the immediate context of the incident (Participants, Environment, Equipment) but factors from across multiple systemic levels that contributes to injury incidents (Schools, Parents, Activity centre management). Prevention efforts should focus on addressing the whole network of contributing factors and not only the prominent factors at the lower system levels within the immediate context of the injury incident occurrences.

Sex associations and computed tomography coronary angiography-guided management in patients with stable chest pain.

AIMS: The relative benefits of computed tomography coronary angiography (CTCA)-guided management in women and men with suspected angina due to coronary heart disease (CHD) are uncertain. METHODS AND RESULTS: In this post hoc analysis of an open-label parallel-group multicentre trial, we recruited 4146 patients referred for assessment of suspected angina from 12 cardiology clinics across the UK. We randomly assigned (1:1) participants to standard care alone or standard care plus CTCA. Fewer women had typical chest pain symptoms (n = 582, 32.0%) when compared with men (n = 880, 37.9%; P < 0.001). Amongst the CTCA-guided group, more women had normal coronary arteries [386 (49.6%) vs. 263 (26.2%)] and less obstructive CHD [105 (11.5%) vs. 347 (29.8%)]. A CTCA-guided strategy resulted in more women than men being reclassified as not having CHD {19.2% vs. 13.1%; absolute risk difference, 5.7 [95% confidence interval (CI): 2.7-8.7, P < 0.001]} or having angina due to CHD [15.0% vs. 9.0%; absolute risk difference, 5.6 (2.3-8.9, P = 0.001)]. After a median of 4.8 years follow-up, CTCA-guided management was associated with similar reductions in the risk of CHD death or non-fatal myocardial infarction in women [hazard ratio (HR) 0.50, 95% CI 0.24-1.04], and men (HR 0.63, 95% CI 0.42-0.95; Pinteraction = 0.572). CONCLUSION: Following the addition of CTCA, women were more likely to be found to have normal coronary arteries than men. This led to more women being reclassified as not having CHD, resulting in more downstream tests and treatments being cancelled. There were similar prognostic benefits of CTCA for women and men.

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.

BACKGROUND: Mutations in the ARV1 Homolog, Fatty Acid Homeostasis Modulator (ARV1), have recently been described in association with early infantile epileptic encephalopathy 38. Affected individuals presented with epilepsy, ataxia, profound intellectual disability, visual impairment, and central hypotonia. In S. cerevisiae, Arv1 is thought to be involved in sphingolipid metabolism and glycophosphatidylinositol (GPI)-anchor synthesis. The function of ARV1 in human cells, however, has not been elucidated. METHODS: Mutations were discovered through whole exome sequencing and alternate splicing was validated on the cDNA level. Expression of the variants was determined by qPCR and Western blot. Expression of GPI-anchored proteins on neutrophils and fibroblasts was analyzed by FACS and immunofluorescence microscopy, respectively. RESULTS: Here we describe seven patients from two unrelated families with biallelic splice mutations in ARV1. The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy. The splice variants resulted in decreased ARV1 expression and significant decreases in GPI-anchored protein on the membranes of neutrophils and fibroblasts, indicating that the loss of ARV1 results in impaired GPI-anchor synthesis. CONCLUSION: Loss of GPI-anchored proteins on our patients' cells confirms that the yeast Arv1 function of GPI-anchor synthesis is conserved in humans. Overlap between the phenotypes in our patients and those reported for other GPI-anchor disorders suggests that ARV1-deficiency is a GPI-anchor synthesis disorder.