Benchmarking highly entangled states on a 60-atom analogue quantum simulator.

Quantum systems have entered a competitive regime in which classical computers must make approximations to represent highly entangled quantum states1,2. However, in this beyond-classically-exact regime, fidelity comparisons between quantum and classical systems have so far been limited to digital quantum devices2-5, and it remains unsolved how to estimate the actual entanglement content of experiments6. Here, we perform fidelity benchmarking and mixed-state entanglement estimation with a 60-atom analogue Rydberg quantum simulator, reaching a high-entanglement entropy regime in which exact classical simulation becomes impractical. Our benchmarking protocol involves extrapolation from comparisons against an approximate classical algorithm, introduced here, with varying entanglement limits. We then develop and demonstrate an estimator of the experimental mixed-state entanglement6, finding our experiment is competitive with state-of-the-art digital quantum devices performing random circuit evolution2-5. Finally, we compare the experimental fidelity against that achieved by various approximate classical algorithms, and find that only the algorithm we introduce is able to keep pace with the experiment on the classical hardware we use. Our results enable a new model for evaluating the ability of both analogue and digital quantum devices to generate entanglement in the beyond-classically-exact regime, and highlight the evolving divide between quantum and classical systems.

Erasure conversion in a high-fidelity Rydberg quantum simulator.

Minimizing and understanding errors is critical for quantum science, both in noisy intermediate scale quantum (NISQ) devices1 and for the quest towards fault-tolerant quantum computation2,3. Rydberg arrays have emerged as a prominent platform in this context4 with impressive system sizes5,6 and proposals suggesting how error-correction thresholds could be significantly improved by detecting leakage errors with single-atom resolution7,8, a form of erasure error conversion9-12. However, two-qubit entanglement fidelities in Rydberg atom arrays13,14 have lagged behind competitors15,16 and this type of erasure conversion is yet to be realized for matter-based qubits in general. Here we demonstrate both erasure conversion and high-fidelity Bell state generation using a Rydberg quantum simulator5,6,17,18. When excising data with erasure errors observed via fast imaging of alkaline-earth atoms19-22, we achieve a Bell state fidelity of [Formula: see text], which improves to [Formula: see text] when correcting for remaining state-preparation errors. We further apply erasure conversion in a quantum simulation experiment for quasi-adiabatic preparation of long-range order across a quantum phase transition, and reveal the otherwise hidden impact of these errors on the simulation outcome. Our work demonstrates the capability for Rydberg-based entanglement to reach fidelities in the 0.999 regime, with higher fidelities a question of technical improvements, and shows how erasure conversion can be utilized in NISQ devices. These techniques could be translated directly to quantum-error-correction codes with the addition of long-lived qubits7,22-24.

Preparing random states and benchmarking with many-body quantum chaos.

Producing quantum states at random has become increasingly important in modern quantum science, with applications being both theoretical and practical. In particular, ensembles of such randomly distributed, but pure, quantum states underlie our understanding of complexity in quantum circuits1 and black holes2, and have been used for benchmarking quantum devices3,4 in tests of quantum advantage5,6. However, creating random ensembles has necessitated a high degree of spatio-temporal control7-12 placing such studies out of reach for a wide class of quantum systems. Here we solve this problem by predicting and experimentally observing the emergence of random state ensembles naturally under time-independent Hamiltonian dynamics, which we use to implement an efficient, widely applicable benchmarking protocol. The observed random ensembles emerge from projective measurements and are intimately linked to universal correlations built up between subsystems of a larger quantum system, offering new insights into quantum thermalization13. Predicated on this discovery, we develop a fidelity estimation scheme, which we demonstrate for a Rydberg quantum simulator with up to 25 atoms using fewer than 104 experimental samples. This method has broad applicability, as we demonstrate for Hamiltonian parameter estimation, target-state generation benchmarking, and comparison of analogue and digital quantum devices. Our work has implications for understanding randomness in quantum dynamics14 and enables applications of this concept in a much wider context4,5,9,10,15-20.

Benchmarking Quantum Simulators Using Ergodic Quantum Dynamics.

We propose and analyze a sample-efficient protocol to estimate the fidelity between an experimentally prepared state and an ideal target state, applicable to a wide class of analog quantum simulators without advanced spatiotemporal control. Our protocol relies on universal fluctuations emerging from generic Hamiltonian dynamics, which we discover in the present work. It does not require fine-tuned control over state preparation, quantum evolution, or readout capability, while achieving near optimal sample complexity: a percent-level precision is obtained with ∼10^{3} measurements, independent of system size. Furthermore, the accuracy of our fidelity estimation improves exponentially with increasing system size. We numerically demonstrate our protocol in a variety of quantum simulator platforms, including quantum gas microscopes, trapped ions, and Rydberg atom arrays. We discuss applications of our method for tasks such as multiparameter estimation of quantum states and processes.

Dark-State Enhanced Loading of an Optical Tweezer Array.

Neutral atoms and molecules trapped in optical tweezers have become a prevalent resource for quantum simulation, computation, and metrology. However, the maximum achievable system sizes of such arrays are often limited by the stochastic nature of loading into optical tweezers, with a typical loading probability of only 50%. Here we present a species-agnostic method for dark-state enhanced loading (DSEL) based on real-time feedback, long-lived shelving states, and iterated array reloading. We demonstrate this technique with a 95-tweezer array of ^{88}Sr atoms, achieving a maximum loading probability of 84.02(4)% and a maximum array size of 91 atoms in one dimension. Our protocol is complementary to, and compatible with, existing schemes for enhanced loading based on direct control over light-assisted collisions, and we predict it can enable close-to-unity filling for arrays of atoms or molecules.

Sporadic vestibular schwannoma: a molecular testing summary.

OBJECTIVES: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis. METHODS: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups. RESULTS: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants. CONCLUSIONS: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

Serial Clinical Scoring to Assess Transported Pediatric Patients.

OBJECTIVES: The objective of this study was to evaluate serial Transport Risk Assessment in Pediatrics (TRAP) scoring during pediatric critical care transport as a potential measure for specialized pediatric transport teams (PTTs). METHODS: This was a retrospective study with a provincial PTT from a tertiary hospital pediatric intensive care unit. All acutely ill children who were transported by the PTT between 2018 and 2019 were included in the study. The TRAP scores were measured at time of transport team arrival (TRAP1), time at arrival to tertiary center (TRAP2), and 4 hours postarrival to tertiary center (TRAP3). RESULTS: A total of 300 transports were included. Patients' mean age was 54 months, with lower respiratory tract infection (40.7%) as the most common diagnosis. There were significant differences between TRAP1-TRAP2 (P < 0.01) and TRAP1-TRAP3 (P < 0.01), but not between TRAP2-TRAP3 (P = 0.67). The most significant improvements of ΔTRAP1-TRAP2 scores were seen in septic shock (mean, 2.0; SD, 1.7). CONCLUSIONS: The TRAP scores improved following the PTTs' arrival to acutely ill children, particularly with sepsis. Serial TRAP scoring may present a system for evaluation of team performance and/or characterize disease states that are positively impacted by PTTs. Future prospective evaluation is needed to validate TRAP for this purpose.

Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.

Diagnosis and Management of Hereditary Meningioma and Vestibular Schwannoma.

Bilateral vestibular schwannomata and meningiomata are the tumours most commonly associated with neurofibromatosis type II (NF2). These tumours may also be seen in patients with schwannomatosis and familial meningioma, but these phenotypes are usually easy to distinguish. The main diagnostic challenge when managing these tumours is distinguishing between sporadic disease which carries low risk of subsequent tumours or NF2 with its associated morbidities and reduced life expectancy. This chapter outlines some of the diagnostic and management considerations along with associated evidence.

Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients.

BACKGROUND: Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype-phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown. METHODS: We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan-Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2. RESULTS: The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6-15 had lower mortality than patients with splice-site mutations in exons 1-5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier. CONCLUSIONS: Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.

Towards a dosimetric framework for therapeutic ultrasound.

There is a need for a coherent set of exposure and dose quantities to describe ultrasound fields in media other than water (including tissue and tissue-simulating materials). This paper proposes an outline dosimetry scheme, with quantities for free field exposure, in situ exposure, dose (both instantaneous and cumulative) and effect, to act as a structure for organising a more complete set of definitions. It also presents findings from a survey of the views of the therapeutic ultrasound community which generally supports the principle of using modified free field quantities to describe the in situ field, and the prioritising of dose quantities which are related to heating and thermal mechanisms. Although there is no one-to-one relationship between any known ultrasound dose quantity and a specific biological effect, this can also be said of radiotherapy and other modalities where weighting factors have been developed to calculate the degree of equivalence between different tissues and radiation types. This same separation is recommended for ultrasound, provided that an appropriate set of recognised 'engineering' quantities can be established for exposure and dose quantities.

Deletions in the 3' part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome.

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.

The comprehensive English National Lynch Syndrome Registry: development and description of a new genomics data resource.

Background: Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of clinical and genomic data has restricted understanding of national LS ascertainment and outcomes, and precluded evaluation of NICE guidance on testing and management. To address this, via collaboration between researchers, the National Disease Registration Service (NDRS), NHS Genomic Medicine Service Alliances (GMSAs), and NHS Regional Clinical Genetics Services, a comprehensive registry of LS carriers in England has been established. Methods: For comprehensive ascertainment of retrospectively identified MMR pathogenic variant (PV) carriers (diagnosed prior to January 1, 2023), information was retrieved from all clinical genetics services across England, then restructured, amalgamated, and validated via a team of trained experts in NDRS. An online submission portal was established for prospective ascertainment from January 1, 2023. The resulting data, stored in a secure database in NDRS, were used to investigate the demographic and genetic characteristics of the cohort, censored at July 25, 2023. Cancer outcomes were investigated via linkage to the National Cancer Registration Dataset (NCRD). Findings: A total of 11,722 retrospective and 570 prospective data submissions were received, resulting in a comprehensive English National Lynch Syndrome Registry (ENLSR) comprising 9030 unique individuals. The most frequently identified pathogenic MMR genes were MSH2 and MLH1 at 37.2% (n = 3362) and 29.1% (n = 2624), respectively. 35.9% (n = 3239) of the ENLSR cohort received their LS diagnosis before their first cancer diagnosis (presumptive predictive germline test). Of these, 6.3% (n = 204) developed colorectal cancer, at a median age of initial diagnosis of 51 (IQR 40-62), compared to 73 years (IQR 64-80) in the general population (p < 0.0001). Interpretation: The ENLSR represents the first comprehensive national registry of PV carriers in England and one of the largest cohorts of MMR PV carriers worldwide. The establishment of a secure, centralised infrastructure and mechanism for routine registration of newly identified carriers ensures sustainability of the data resource. Funding: This work was funded by the Wellcome Trust, Cancer Research UK and Bowel Cancer UK. The funder of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Identification of people with Lynch syndrome from those presenting with colorectal cancer in England: baseline analysis of the diagnostic pathway.

It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017 state that all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation of the agreed diagnostic pathway at a baseline point 2 years post-publication of official guidelines. Using real-world data collected and curated by the National Cancer Registration and Analysis Service (NCRAS), we retrospectively followed up all people diagnosed with CRC in England in 2019. Nationwide laboratory diagnostic data incorporated somatic (tumour) testing for dMMR (via immunohistochemistry or microsatellite instability), somatic testing for MLH1 promoter methylation and BRAF status, and constitutional (germline) testing of MMR genes. Only 44% of CRCs were screened for dMMR; these figures varied over four-fold with respect to geography. Of those CRCs identified as dMMR, only 51% underwent subsequent diagnostic testing. Overall, only 1.3% of patients with colorectal cancer had a germline MMR genetic test performed; up to 37% of these tests occurred outside of NICE guidelines. The low rates of molecular diagnostic testing in CRC support the premise that Lynch syndrome is underdiagnosed, with significant attrition at all stages of the testing pathway. Applying our methodology to subsequent years' data will allow ongoing monitoring and analysis of the impact of recent investment. If the diagnostic guidelines were fully implemented, we estimate that up to 700 additional people with LS could be identified each year.

Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome.

By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, Nfix-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider NFIX as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice NFIX mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that NFIX is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on NMD.

Infrared mapping of ultrasound fields generated by medical transducers: feasibility of determining absolute intensity levels.

Considerable progress has been achieved in the use of infrared (IR) techniques for qualitative mapping of acoustic fields of high intensity focused ultrasound (HIFU) transducers. The authors have previously developed and demonstrated a method based on IR camera measurement of the temperature rise induced in an absorber less than 2 mm thick by ultrasonic bursts of less than 1 s duration. The goal of this paper was to make the method more quantitative and estimate the absolute intensity distributions by determining an overall calibration factor for the absorber and camera system. The implemented approach involved correlating the temperature rise measured in an absorber using an IR camera with the pressure distribution measured in water using a hydrophone. The measurements were conducted for two HIFU transducers and a flat physiotherapy transducer of 1 MHz frequency. Corresponding correction factors between the free field intensity and temperature were obtained and allowed the conversion of temperature images to intensity distributions. The system described here was able to map in good detail focused and unfocused ultrasound fields with sub-millimeter structure and with local time average intensity from below 0.1 W/cm(2) to at least 50 W/cm(2). Significantly higher intensities could be measured simply by reducing the duty cycle.

The face in congenital melanocytic nevus syndrome.

Congenital melanocytic nevi (CMN) are known to be associated with neurological abnormalities and melanoma, but have not been considered to be part of a developmental syndrome. The objective of this study was to test our clinical observation that children with CMN show more facial similarities than might be expected by coincidence. We selected facial photographs of 95 white Caucasian children with CMN from our database only on the basis of good neutral views, allowing careful evaluation of facial morphology. These were scored independently by two clinical geneticists using standardized categories and definitions for facial morphology. Prevalence of age-independent features was compared to established norms in a large population, and associations with cutaneous phenotype were investigated. CMN were found to be associated with characteristic facies, and 74% of children in this series had at least three typical features. The characteristic features were: wide or prominent forehead, apparent hypertelorism, eyebrow variants, periorbital fullness, small/short nose, narrow nasal ridge, broad nasal tip, broad or round face, full cheeks, prominent pre-maxilla, prominent/long philtrum, and everted lower lip. No association was found with the severity of cutaneous phenotype. We conclude that children with CMN often have a characteristic face. We propose the term "congenital melanocytic nevus syndrome" to describe this association.

A comparative evaluation of three hydrophones and a numerical model in high intensity focused ultrasound fields.

The pressure fields of two different high intensity focused ultrasound (HIFU) transducers operated in burst mode were measured at acoustical power levels of 25 and 50 W (continuous wave equivalent) with three different hydrophones: A fiber-optic displacement sensor, a commercial HIFU needle hydrophone, and a prototype of a membrane hydrophone with a protective coating against cavitation effects. Additionally, the fields were modeled using a freely available simulations software package. The measured waveforms, the peak pressure profiles, as well as the spatial-peak temporal-average intensities from the different devices and from the modeling are compared and possible reasons for differences are discussed. The results clearly show that reliable pressure measurements in HIFU fields remain a difficult task concerning both the reliability of the measured values and the robustness of the sensors used: Only the fiber-optic hydrophone survived all four exposure regimes and the measured spatial-peak temporal-average intensities varied by a factor of up to 1.5 between the measurements and the modeling and between the measurements among themselves.

Detection of Microsatellite Instability in Colonoscopic Biopsies and Postal Urine Samples from Lynch Syndrome Cancer Patients Using a Multiplex PCR Assay.

Identification of mismatch repair (MMR)-deficient colorectal cancers (CRCs) is recommended for Lynch syndrome (LS) screening, and supports targeting of immune checkpoint inhibitors. Microsatellite instability (MSI) analysis is commonly used to test for MMR deficiency. Testing biopsies prior to tumour resection can inform surgical and therapeutic decisions, but can be limited by DNA quantity. MSI analysis of voided urine could also provide much needed surveillance for genitourinary tract cancers in LS. Here, we reconfigure an existing molecular inversion probe-based MSI and BRAF c.1799T > A assay to a multiplex PCR (mPCR) format, and demonstrate that it can sample >140 unique molecules per marker from <1 ng of DNA and classify CRCs with 96−100% sensitivity and specificity. We also show that it can detect increased MSI within individual and composite CRC biopsies from LS patients, and within preoperative urine cell free DNA (cfDNA) from two LS patients, one with an upper tract urothelial cancer, the other an undiagnosed endometrial cancer. Approximately 60−70% of the urine cfDNAs were tumour-derived. Our results suggest that mPCR sequence-based analysis of MSI and mutation hotspots in CRC biopsies could facilitate presurgery decision making, and could enable postal-based screening for urinary tract and endometrial tumours in LS patients.

The importance of neurology and genetic testing in the patient with non-cleft velopharyngeal dysfunction.

OBJECTIVE: A significant proportion of the referrals made to a speech investigation clinic in a cleft unit include patients with non-cleft velopharyngeal dysfunction (VPD). This study aims to quantify the underlying diagnoses of these patients and describe the investigative pathway and diagnostic information subsequent to presentation in our clinic. MATERIALS AND METHODS: The case notes of 136 consecutive patients with non-cleft VPD who attended our Velopharyngeal Investigation (VPI) clinic from July 2014-December 2019 were reviewed. RESULTS: In the paediatric group (n = 118) the most common cause was 22q11 chromosomal anomalies (n = 46), while post palatal tumour resection was the commonest cause of acquired non-cleft VPD in adults (n = 8). Fifty-nine patients were referred to the clinic with a known underlying pathology such as a syndromic diagnosis. Of those presenting without a known aetiology, fifty-eight were referred onto our genetics and/or neurology colleagues. Although a genetic or neurological cause could not be identified in some of those patients, thirty-one patients received a new diagnosis, with subsequent implications for ongoing care. CONCLUSION: There are a wide range of diagnoses resulting in non-cleft VPD, but there are very few large-scale studies focusing on investigating these patients for an underlying aetiology. This study highlights the role of genetics and neurology in the diagnosis and management plan for this cohort of patients.