Positive Deviance and Exploring the Role of Mental Health on Early Postoperative Recovery After Total Hip Arthroplasty: A Retrospective Analysis Using the PROMIS-10 Global Health.

INTRODUCTION: Mental illnesses are well-known factors that contribute to poor outcomes among total hip arthroplasty (THA) patients. However, a dichotomized mental illness diagnosis may not reflect the complex biopsychosocial factors contributing to a patient's health. Investigating patients who achieve positive outcomes despite having risk factors, known as positive deviants, may help identify protective characteristics and decrease health disparities among this growing population of patients. Using preoperative Mental Health T-scores (MHT) from the PROMIS-10 Global Health questionnaire among patients with a mental illness diagnosis, the purpose of this study was to explore whether patients with above-average MHT, or positive deviants, experienced a different immediate postoperative recovery path compared with patients with below-average MHT. METHODS: This was a retrospective chart review of patients undergoing elective primary THA. Patients with a formal diagnosis of a mental health condition were divided based on their MHT (above average [AA] >50, average [A] 40 to 50, below average [BA] <40). Postsurgical parameters included total opioid consumption, self-reported pain scores, and discharge disposition. RESULTS: A total of 299 patients were analyzed. After controlling for length of stay and type of mental illness, patients in the AA-MHT and A-MHT groups used 33.8 and 29.8 morphine milligram equivalents less than patients in the BA-MHT group during the inpatient stay, respectively. Patients in the AA-MHT group reported a 1.0 lower pain with activity score at discharge compared with patients in the BA-MHT group. DISCUSSION: The intersection between patients with a mental illness in need of a THA is becoming more commonplace. Data suggest that patients with a mental illness who report AA-MHT on the PROMIS-10 Global Health questionnaire may represent positive deviants or those with a more positive in-hospital recovery path compared with those patients with BA-MHT. LEVEL OF EVIDENCE: Diagnostic study-retrospective cohort study.

Further delineation of dosage-sensitive K/L mediated Xq28 duplication syndrome includes incomplete penetrance.

The low copy tandem repeat area at Xq28 is prone to recurrent copy number gains, including the K/L mediated duplications of 300 kb size (herein described as the K/L mediated Xq28 duplication syndrome). We describe five families, including nine males with K/L mediated Xq28 duplications, some with regions of greater copy number variation (CNV). We summarise findings in 25 affected males reported to date. Within the five families, males were variably affected by seizures, intellectual disability, and neurological features; however, one male with a familial K/L mediated Xq28 duplication has normal intelligence, suggesting that this CNV is not 100% penetrant. Including our five families, 13 carrier females have been identified, with nine presenting phenotypically normal. Three carrier females reported mild learning difficulties, and all of them had duplications containing regions with at least four copies. Delineation of the spectrum of K/L mediated Xq28 duplication syndrome highlights GDI1 as the most likely candidate gene contributing to the phenotype. For patients identified with CNVs in this region, high-resolution microarray is required to define copy number gains and provide families with accurate information.

Expanding access to difficult urinary catheter insertion services through a novel nurse practitioner-led team.

BACKGROUND: Within the United States health care system, one of the most common procedures performed daily is urinary catheterization. Oftentimes, the urinary catheter is placed by nursing personnel without any difficulty. Although the procedure is usually simple and routine, there are instances in which placement can be problematic. LOCAL PROBLEM: Urology is one of the smallest surgical subspecialties, with intermittent availability given active commitments in the operating room and clinic. This opened an opportunity for nurse practitioners (NPs) at an urban quaternary care hospital to further enhance their skill set in the care of these patients. METHODS: Fifteen Rapid Response Team NPs were selected based on specific criteria. Their roles expanded to include consults for difficult urinary catheter insertions. INTERVENTION: A 2-step training program was implemented for NPs to develop proficiency in inserting urinary catheters in patients with new or known urologic conditions. RESULTS: Of the 391 catheter consults made to the NP group, 73 (18.7%) of them required urology follow-up. CONCLUSION: This program can benefit patients by potentially reducing catheter-related complications and associated length of stay.

Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability.

We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva samples. Our cohort comprised 370 individuals who had testing of both, 224 with syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 individuals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in individuals with syndromic ID, we recommend it as a first-tier testing in this group.

Sociodemographic Factors Associated with Do-Not-Resuscitate Order Utilization in the Surgical Intensive Care Unit: An Observational Study.

The use of a do-not-resuscitate (DNR) order is a powerful tool in outlining end-of-life care. This study explores sociodemographic factors associated with selection of a DNR order and assigning a healthcare proxy in the Surgical Intensive Care Unit (SICU). A retrospective chart review of 312 patients who expired in the SICU over a 7-year period was conducted. We analyzed the association of sociodemographic factors to selection of a DNR order and assignment of a healthcare proxy. Year of admission, age, religion, and proxy were independently associated with selection of DNR. In particular, the relative chance of a DNR selection in 2019 compared to 2012 was 3.538 (95% CL = 2.001-6.255, P < .01). There are significant sociodemographic factors that influence DNR utilization, highlighting the need to consider the social and religious backgrounds when engaging patients and their families in end-of-life care. Future studies will need to be conducted on whether these sociodemographic factors influence surviving patients as this study's findings can only be applied to those who have expired.

The fourth wave: vaccination status and intensive care unit mortality at a large hospital system in New York City.

BACKGROUND: We aim to describe the demographics and outcomes of patients with severe disease with the Omicron variant. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to mutate, and the availability of vaccines and boosters continue to rise, it is important to understand the health care burden of new variants. We analyze patients admitted to intensive care units (ICUs) in a large Academic Health System during New York City's fourth surge beginning on November 27, 2021. METHODS: All patients admitted to an ICU were included in the primary analysis. Key demographics and outcomes were retrospectively compared between patients stratified by vaccination status. Univariate and multivariate logistic regression was used to identify risk factors for in-hospital mortality. RESULTS: In-hospital mortality for all admitted patients during the fourth wave was significantly lower than in previous waves. However, among patients requiring intensive care, in-hospital mortality was high across all levels of vaccination status. In a multivariate model older age was associated with increased in-hospital mortality, vaccination status of overdue for booster was associated with decreased in hospital mortality, and vaccination status of up-to-date with vaccination showed a trend to reduced mortality. CONCLUSIONS: In-hospital mortality of patients with severe respiratory failure from coronavirus disease 2019 (COVID-19) remains high despite decreasing overall mortality. Vaccination against SARS-CoV-2 was protective against mortality. Vaccination remains the best and safest way to protect against serious illness and death from COVID-19. It remains unclear that any other treatment will have success in changing the natural history of the disease.

Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis.

Whole genome sequencing (WGS) improves Mendelian disorder diagnosis over whole exome sequencing (WES); however, additional diagnostic yields and costs remain undefined. We investigated differences between diagnostic and cost outcomes of WGS and WES in a cohort with suspected Mendelian disorders. WGS was performed in 38 WES-negative families derived from a 64 family Mendelian cohort that previously underwent WES. For new WGS diagnoses, contemporary WES reanalysis determined whether variants were diagnosable by original WES or unique to WGS. Diagnostic rates were estimated for WES and WGS to simulate outcomes if both had been applied to the 64 families. Diagnostic costs were calculated for various genomic testing scenarios. WGS diagnosed 34% (13/38) of WES-negative families. However, contemporary WES reanalysis on average 2 years later would have diagnosed 18% (7/38 families) resulting in a WGS-specific diagnostic yield of 19% (6/31 remaining families). In WES-negative families, the incremental cost per additional diagnosis using WGS following WES reanalysis was AU$36,710 (£19,407;US$23,727) and WGS alone was AU$41,916 (£22,159;US$27,093) compared to WES-reanalysis. When we simulated the use of WGS alone as an initial genomic test, the incremental cost for each additional diagnosis was AU$29,708 (£15,705;US$19,201) whereas contemporary WES followed by WGS was AU$36,710 (£19,407;US$23,727) compared to contemporary WES. Our findings confirm that WGS is the optimal genomic test choice for maximal diagnosis in Mendelian disorders. However, accepting a small reduction in diagnostic yield, WES with subsequent reanalysis confers the lowest costs. Whether WES or WGS is utilised will depend on clinical scenario and local resourcing and availability.

Adaptations in vascular access procedures as an initiative to protect healthcare workers throughout the COVID-19 pandemic.

COVID-19 has led to procedural changes in vascular access services to protect healthcare workers and patients from further spread of the virus. Operational changes made by the vascular access service at a healthcare system in New York City during the first wave of the COVID-19 (SARS-CoV-2) pandemic included a team-based approach as well as consideration for types of lines placed to address the increase in patient volume while providing safety to healthcare workers and conserving personal protective equipment. The study consists of two samples of adult inpatients admitted to Mount Sinai Hospital in New York City in need of vascular access. Chi-square tests of independence were used to analyze trends in data. By the fourth wave, usage of shorter lifespan ultrasound-guided peripheral intravenous lines increased significantly and the use of longer lasting intravenous catheters decreased significantly between the first and fourth waves of COVID-19. This paper aims to show that with greater knowledge about proper personal protective equipment and mindful resource use, hospitals are able to become more comfortable and efficient while providing increasingly frequent vascular access services in the current and future pandemics.

Postoperative Nursing Care of a Deceased Donor Tracheal Transplant Recipient.

INTRODUCTION: Certain airway disorders, such as tracheal stenosis, can severely affect the ability to breathe, reduce quality of life, and increase morbidity and mortality. Treatment options for long-segment tracheal stenosis include multistage tracheal replacement with biosynthetic material, autotransplantation, and allotransplantation. These interventions have not demonstrated long-term dependable results because of lack of adequate blood supply to the organ and ciliated epithelium. A new transplant program featuring single-stage long-segment tracheal transplant addresses this concern. CLINICAL FINDINGS: The patient was a 56-year-old woman with a history of obesity, type 2 diabetes, hypertension, hyperlipidemia, liver sarcoidosis, 105-pack-year smoking history, and asthma. A severe asthma exacerbation in 2014 required prolonged intubation, and she subsequently developed long-segment cricotracheal stenosis. In 2015 she underwent an unsuccessful tracheal resection followed by failed attempts at tracheal stenting and dilation procedures. These attempts at stenting resulted in a permanent extended-length tracheostomy and ultimately ventilator dependency. INTERVENTIONS: The patient underwent a single-stage long-segment deceased donor tracheal transplant. Important nursing considerations included hemodynamic monitoring, airway management and securement, graft assessment, stoma and wound care, nutrition, medication administration, and patient education. CONCLUSION: High-quality nursing care postoperatively in the intensive care unit is critical to safe and effective treatment of the tracheal transplant recipient and success of the graft. To effectively treat these patients, nurses need relevant education and training. This article is the first documentation of postoperative nursing care following single-stage long-segment tracheal transplant.

Novel Multidisciplinary Vascular Access Team Helps to Improve ICU Workflow Amidst Covid-19 Pandemic.

OBJECTIVE: The surge in critically ill patients has pressured hospitals to expand their intensive care unit capacities and critical care staff. This was difficult given the country's shortage of intensivists. This paper describes the implementation of a multidisciplinary central line placement team and its impact in reducing the vascular access workload of ICU physicians during the height of the COVID-19 pandemic. METHODS: Vascular surgeons, interventionalists, and anesthesiologists, were redeployed to the ICU Access team to place central and arterial lines. Nurses with expertise in vascular access were recruited to the team to streamline consultation and assist with line placement. RESULTS: While 51 central and arterial lines were placed per 100 ICU patients in 2019, there were 87 central and arterial lines placed per 100 COVID-19 ICU patients in the sole month of April, 2020. The ICU Access Team placed 107 of the 226 vascular access devices in April 2020, reducing the procedure-related workload of ICU treating teams by 46%. CONCLUSIONS: The ICU Access Team was able to complete a large proportion of vascular access insertions without reported complications. Given another mass casualty event, this ICU Access Team could be reassembled to rapidly meet the increased vascular access needs of patients.

The Third Wave: Comparing Seasonal Trends in COVID-19 Patient Data at a Large Hospital System in New York City.

The third wave of COVID-19 is unique in that vaccines have been widely available; however, the highly transmissible Delta variant has been the predominant strain. Temporal changes of hospitalized patient characteristics should continue to be analyzed as COVID-19 progresses. OBJECTIVES: Compare the demographics and outcomes of hospitalized patients during New York City's third wave of COVID-19 to the first two waves. DESIGN SETTING AND PARTICIPANTS: Retrospective cohort study across five hospitals within Mount Sinai Health System, a quaternary academic medical system in New York City. Participants were adult inpatients admitted with COVID-19 identified by positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction at admission or clinical documentation of infection during the three waves of COVID-19. MAIN OUTCOMES AND MEASURES: Patient demographics, comorbidities, vaccination status, and outcomes of COVID-19 patients hospitalized at Mount Sinai Health System were examined. Patients admitted during the third wave were notably younger than the first two, were mostly unvaccinated against COVID-19, and there was a higher rate of patients who self-report as Black or African American as compared with the first two waves. The rate of patients requiring ICU level of care remained consistent throughout all three periods; however, the rate of patients requiring invasive mechanical ventilation decreased and inhospital mortality has trended down. Unvaccinated patients in the third wave are significantly younger with lower comorbidity burden than fully vaccinated patients. RESULTS: A total of 13,036 patients were included between the 3 waves. In the 3rd wave patients were notably younger, with a lower intubation rate and lower inhospital death rate. In the 3rd wave, 400 (62.9%) were unvaccinated, 236 (37.1%) were fully vaccinated, and 34 (4.8%) were partially vaccinated. Unvaccinated patients had similar rates of intubation and invasive mechanical ventilation compared with vaccinated patients, though inhospital mortality was lower in unvaccinated patients compared with vaccinated patients which may be expected given their lower age and burden of comorbidities. CONCLUSIONS AND RELEVANCE: We continue to see improved outcomes in hospitalized COVID-19 patients. Patients that are unvaccinated against COVID-19 are younger and have less reported comorbidities.

Development of a Peripheral Intravenous Access Training Program for Nurses in the Pediatric Intensive Care Units.

PURPOSE: Obtaining vascular access in the pediatric population can be challenging, with insertion success rates varying widely based on patient and practitioner associated factors. Difficulty establishing peripheral intravenous access can delay treatment, which can be detrimental in emergent situations. Nurses who are trained in vascular access yield a much higher first attempt success rate, which decreases resource utilization, time to intervention, and complication rate. Fewer insertion attempts can also result in improved outcomes including decreased length of stay and better patient and family perception of pain. DESIGN AND METHODS: The Vascular Access Service at our institution developed an extensive training program, which included three stages: didactic learning, simulation training, and insertion validation. RESULTS: During the first three months of 2020, there were 54 ultrasound-guided peripheral IVs placed in the pediatric intensive care units, 100% of which were placed by the vascular access service. In the first three months of 2021, 63 ultrasound-guided peripheral IVs were placed, 100% of which were placed by pediatric intensive care unit nurses. Of those placed by pediatric intensive care unit nurses, 52 (82.5%) were placed following their ultrasound-guided peripheral IV training. First time insertion success rates were 86.5% with competency in a diverse patient population of widely varying ages. CONCLUSIONS: Programs that include repeated simulation experiences may facilitate greater learning and thus increase the confidence of the nurses trained. Improving staff skills for vascular access has promoted independent bedside practice and contributed to a culture of quality and safety for the pediatric patient population.

Different types of disease-causing noncoding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability.

The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide; however, approximately 30% of XLID families still remain unresolved. We postulated that noncoding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different noncoding variants. We used comprehensive structural, single-nucleotide, and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, reverse-transcription polymerase chain reactions, Western blots, and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic noncoding variants: a retrotransposon insertion, a novel intronic splice donor, and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favor of a regulatory noncoding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic noncoding variant discovery.

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Management of stroke in the Australian Indigenous population: from hospitals to communities.

BACKGROUND: Ischaemic strokes lead to significant morbidity and mortality within the Australian Indigenous population, with known variances in the management of strokes between indigenous and non-indigenous populations. AIMS: To compare investigations and management of indigenous and non-indigenous patients presenting to a New South Wales rural referral hospital with an ischaemic stroke to the national stroke standards across inpatient and outpatient settings. METHODS: Historical cohort study of 43 indigenous and 167 non-indigenous patients admitted to Tamworth Rural Referral Hospital with an ischaemic cerebrovascular accident. RESULTS: Indigenous patients were significantly less likely to have investigations completed, including carotid imaging (93.8% vs 100%, P = 0.012) and echocardiography (73.3% vs 97.7%, P = 0.004). Discharge follow up was significantly lower for the indigenous population (74.4% vs 87.4%, P = 0.034). Indigenous stroke patients were 15.8 years younger than non-indigenous subjects (56.8 vs 72.6 years old; P < 0.001). Indigenous patients were more likely to have stroke risk factors, including smoking (51.2% vs 15.0%; P < 0.001), diabetes mellitus (37.2% vs 16.8%, P = 0.003) and past history of cerebrovascular accident or transient ischaemic attack (50.2% vs 31.1%, P = 0.032). CONCLUSIONS: The investigation and post-discharge care of indigenous ischaemic stroke patients is inferior to non-indigenous patients. Indigenous patients within rural NSW have a higher prevalence of preventable disease, including those that confer a higher stroke risk. Further research is needed to investigate the cause of these discrepancies and to improving indigenous stroke care between hospitals and primary care providers.

Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders.

BACKGROUND: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. METHODS: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. RESULTS: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. CONCLUSIONS: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.

A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation.

We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles. In transfected Chinese hamster ovary AP-1 cells, the Leu515Phe mutant protein was correctly targeted to the TGN/post-Golgi vesicles, but its N-linked oligosaccharide maturation as well as that of a co-transfected secretory membrane glycoprotein, vesicular stomatitis virus G (VSVG) glycoprotein, was reduced compared to cells co-expressing SLC9A7 wild-type and VSVG. This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function. Membrane trafficking of glycosylation-deficient Leu515Phe and co-transfected VSVG to the cell surface, however, was relatively unaffected. Mass spectrometry analysis of patient sera also revealed an abnormal N-glycosylation profile for transferrin, a clinical diagnostic marker for congenital disorders of glycosylation. These data implicate a crucial role for SLC9A7 in the regulation of TGN/post-Golgi pH homeostasis and glycosylation of exported cargo, which may underlie the cellular pathophysiology and neurodevelopmental deficits associated with this particular nonsyndromic form of X-linked ID.

A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.

Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype.Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome.

Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability.

BACKGROUND: Massively parallel genetic sequencing allows rapid testing of known intellectual disability (ID) genes. However, the discovery of novel syndromic ID genes requires molecular confirmation in at least a second or a cluster of individuals with an overlapping phenotype or similar facial gestalt. Using computer face-matching technology we report an automated approach to matching the faces of non-identical individuals with the same genetic syndrome within a database of 3681 images [1600 images of one of 10 genetic syndrome subgroups together with 2081 control images]. Using the leave-one-out method, two research questions were specified: 1) Using two-dimensional (2D) photographs of individuals with one of 10 genetic syndromes within a database of images, did the technology correctly identify more than expected by chance: i) a top match? ii) at least one match within the top five matches? or iii) at least one in the top 10 with an individual from the same syndrome subgroup? 2) Was there concordance between correct technology-based matches and whether two out of three clinical geneticists would have considered the diagnosis based on the image alone? RESULTS: The computer face-matching technology correctly identifies a top match, at least one correct match in the top five and at least one in the top 10 more than expected by chance (P < 0.00001). There was low agreement between the technology and clinicians, with higher accuracy of the technology when results were discordant (P < 0.01) for all syndromes except Kabuki syndrome. CONCLUSIONS: Although the accuracy of the computer face-matching technology was tested on images of individuals with known syndromic forms of intellectual disability, the results of this pilot study illustrate the potential utility of face-matching technology within deep phenotyping platforms to facilitate the interpretation of DNA sequencing data for individuals who remain undiagnosed despite testing the known developmental disorder genes.

MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.

Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery but little is known regarding the role of each Mediator subunits. Mutations in MED12 are linked with a broad spectrum of genetic disorders with X-linked intellectual disability that are difficult to range as Lujan, Opitz-Kaveggia or Ohdo syndromes. Here, we investigated several MED12 patients mutations (p.R206Q, p.N898D, p.R961W, p.N1007S, p.R1148H, p.S1165P and p.R1295H) and show that each MED12 mutations cause specific expression patterns of JUN, FOS and EGR1 immediate early genes (IEGs), reflected by the presence or absence of MED12 containing complex at their respective promoters. Moreover, the effect of MED12 mutations has cell-type specificity on IEG expression. As a consequence, the expression of late responsive genes such as the matrix metalloproteinase-3 and the RE1 silencing transcription factor implicated respectively in neural plasticity and the specific expression of neuronal genes is disturbed as documented for MED12/p.R1295H mutation. In such case, JUN and FOS failed to be properly recruited at their AP1-binding site. Our results suggest that the differences between MED12-related phenotypes are essentially the result of distinct IEGs expression patterns, the later ones depending on the accurate formation of the transcription initiation complex. This might challenge clinicians to rethink the traditional syndromes boundaries and to include genetic criterion in patients' diagnostic.