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.

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.

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.

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.

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.

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.

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.

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.

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.

Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients.

De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability.

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations-four nonsense (c.1195A>T [p.Lys399(∗)], c.1333C>T [p.Arg445(∗)], c.1866C>G [p.Tyr622(∗)], and c.3001C>T [p.Arg1001(∗)]) and three frameshift (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.

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.

A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A.

BACKGROUND: Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnostic feature is sparse, brittle, sulfur deficient hair that has a 'tiger-tail' banding pattern under polarising light microscopy. PATIENTS AND METHODS: We describe two male cousins affected by TTD associated with microcephaly, profound intellectual disability, sparse brittle hair, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation. Linkage analysis and Sanger sequencing of 737 X-chromosome exons and whole exome sequencing was used to find the responsible gene and mutation. RESULTS: Linkage analysis localised the disease allele to a 7.75 Mb interval from Xq23-q25. We identified a nonsense mutation in the highly conserved RNF113A gene (c.901 C>T, p.Q301*). The mutation segregated with the disease in the family and was not observed in over 100,000 control X chromosomes. The mutation markedly reduced RNF113A protein expression in extracts from lymphoblastoid cell lines derived from the affected individuals. CONCLUSIONS: The association of RNF113A mutation with non-photosensitive TTD identifies a new locus for these disorders on the X chromosome. The extended phenotype within this family includes panhypopituitarism, cutis marmorata and congenital short oesophagus.

Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.

Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype and one with the FG phenotype. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.

Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.

Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.

A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability.

The discovery of mutations causing human disease has so far been biased toward protein-coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel resequencing of the nonrepetitive genomic linkage interval at Xq28 of family MRX3. We identified in the binding site of transcription factor YY1 a regulatory mutation that leads to overexpression of the chromatin-associated transcriptional regulator HCFC1. When tested on embryonic murine neural stem cells and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and a considerable reduction in neurite growth. Two other nonsynonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function.

Refinement of genotype-phenotype correlation in 18 patients carrying a 1q24q25 deletion.

Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.

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.

Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability.

Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes, PTCHD1, WDR13, FAAH2, and GSPT2, as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as noncoding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort, where currently disease remains unexplained in two-thirds of families.