X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases

The Mass-Luminosity Relation in the L/T Transition:Individual Dynamical Masses for the New J-Band Flux Reversal Binary SDSSJ105213.51+442255.7AB

We have discovered that SDSSJ105213.51+442255.7 (T0.5$\pm$1.0) is a binary in Keck laser guide star adaptive optics imaging, displaying a large J-to-K-band flux reversal ($\Delta$J = -0.45$\pm$0.09 mag, $\Delta$K = 0.52$\pm$0.05 mag). We determine a total dynamical mass from Keck orbital monitoring (88$\pm$5 $M_{\rm Jup}$) and a mass ratio by measuring the photocenter orbit from CFHT/WIRCam absolute astrometry ($M_B/M_A$ = 0.78$\pm$0.07). Combining these provides the first individual dynamical masses for any field L or T dwarfs, 49$\pm$3 $M_{\rm Jup}$ for the L6.5$\pm$1.5 primary and 39$\pm$3 $M_{\rm Jup}$ for the T1.5$\pm$1.0 secondary. Such a low mass ratio for a nearly equal luminosity binary implies a shallow mass$-$luminosity relation over the L/T transition ($\Delta$log$L_{\rm bol}$/$\Delta$log$M = 0.6^{+0.6}_{-0.8}$). This provides the first observational support that cloud dispersal plays a significant role in the luminosity evolution of substellar objects. Fully cloudy models fail our coevality test for this binary, giving ages for the two components that disagree by 0.2 dex (2.0$\sigma$). In contrast, our observed masses and luminosities can be reproduced at a single age by "hybrid" evolutionary tracks where a smooth change from a cloudy to cloudless photosphere around 1300 K causes slowing of luminosity evolution. Remarkably, such models also match our observed JHK flux ratios and colors well. Overall, it seems that the distinguishing features SDSSJ1052+4422AB, like a J-band flux reversal and high-amplitude variability, are normal for a field L/T binary caught during the process of cloud dispersal, given that the age (1.11$^{+0.17}_{-0.20}$ Gyr) and surface gravity (log$g$ = 5.0$-$5.2) of SDSSJ1052+4422AB are typical for field ultracool dwarfs.Comment: Accepted to ApJ; 33 pages, 8 figures, 5 table

Individual Dynamical Masses of Ultracool Dwarfs

We present the full results of our decade-long astrometric monitoring programs targeting 31 ultracool binaries with component spectral types M7-T5. Joint analysis of resolved imaging from Keck Observatory and Hubble Space Telescope and unresolved astrometry from CFHT/WIRCam yields parallactic distances for all systems, robust orbit determinations for 23 systems, and photocenter orbits for 19 systems. As a result, we measure 38 precise individual masses spanning 30-115 $M_{\rm Jup}$. We determine a model-independent substellar boundary that is $\approx$70 $M_{\rm Jup}$ in mass ($\approx$L4 in spectral type), and we validate Baraffe et al. (2015) evolutionary model predictions for the lithium-depletion boundary (60 $M_{\rm Jup}$ at field ages). Assuming each binary is coeval, we test models of the substellar mass-luminosity relation and find that in the L/T transition, only the Saumon & Marley (2008) "hybrid" models accounting for cloud clearing match our data. We derive a precise, mass-calibrated spectral type-effective temperature relation covering 1100-2800 K. Our masses enable a novel direct determination of the age distribution of field brown dwarfs spanning L4-T5 and 30-70 $M_{\rm Jup}$. We determine a median age of 1.3 Gyr, and our population synthesis modeling indicates our sample is consistent with a constant star formation history modulated by dynamical heating in the Galactic disk. We discover two triple-brown-dwarf systems, the first with directly measured masses and eccentricities. We examine the eccentricity distribution, carefully considering biases and completeness, and find that low-eccentricity orbits are significantly more common among ultracool binaries than solar-type binaries, possibly indicating the early influence of long-lived dissipative gas disks. Overall, this work represents a major advance in the empirical view of very low-mass stars and brown dwarfs.Comment: ApJS, in press. This arxiv posting contains all figures (111 pages) and tables (107 pages). Updated version contains additional acknowledgments and references and corrects typo

Euclid: Early Release Observations -- A glance at free-floating new-born planets in the sigma Orionis cluster

We provide an early assessment of the imaging capabilities of the Euclid space mission to probe deeply into nearby star-forming regions and associated very young open clusters, and in particular to check to what extent it can shed light on the new-born free-floating planet population. This paper focuses on a low-reddening region observed in just one Euclid pointing where the dust and gas has been cleared out by the hot sigma Orionis star. One late-M and six known spectroscopically confirmed L-type substellar members in the sigma Orionis cluster are used as benchmarks to provide a high-purity procedure to select new candidate members with Euclid. The exquisite angular resolution and depth delivered by the Euclid instruments allow us to focus on bona-fide point sources. A cleaned sample of sigma Orionis cluster substellar members has been produced and the initial mass function (IMF) has been estimated by combining Euclid and Gaia data. Our sigma Orionis substellar IMF is consistent with a power-law distribution with no significant steepening at the planetary-mass end. No evidence of a low-mass cutoff is found down to about 4 Jupiter masses at the young age (3 Myr) of the sigma Orionis open cluster.Comment: 13 pages, 10 figures, submitted to the A&A special issue on "Euclid on the sky

Euclid: Early Release Observations -- Programme overview and pipeline for compact- and diffuse-emission photometry

The Euclid ERO showcase Euclid's capabilities in advance of its main mission, targeting 17 astronomical objects, from galaxy clusters, nearby galaxies, globular clusters, to star-forming regions. A total of 24 hours observing time was allocated in the early months of operation, engaging the scientific community through an early public data release. We describe the development of the ERO pipeline to create visually compelling images while simultaneously meeting the scientific demands within months of launch, leveraging a pragmatic, data-driven development strategy. The pipeline's key requirements are to preserve the image quality and to provide flux calibration and photometry for compact and extended sources. The pipeline's five pillars are: removal of instrumental signatures; astrometric calibration; photometric calibration; image stacking; and the production of science-ready catalogues for both the VIS and NISP instruments. We report a PSF with a full width at half maximum of 0.16" in the optical and 0.49" in the three NIR bands. Our VIS mean absolute flux calibration is accurate to about 1%, and 10% for NISP due to a limited calibration set; both instruments have considerable colour terms. The median depth is 25.3 and 23.2 AB mag with a SNR of 10 for galaxies, and 27.1 and 24.5 AB mag at an SNR of 5 for point sources for VIS and NISP, respectively. Euclid's ability to observe diffuse emission is exceptional due to its extended PSF nearly matching a pure diffraction halo, the best ever achieved by a wide-field, high-resolution imaging telescope. Euclid offers unparalleled capabilities for exploring the LSB Universe across all scales, also opening a new observational window in the NIR. Median surface-brightness levels of 29.9 and 28.3 AB mag per square arcsec are achieved for VIS and NISP, respectively, for detecting a 10 arcsec x 10 arcsec extended feature at the 1 sigma level.Comment: Submitted to A&A, 44 pages, 36 figures - Part of the A&A special issue `Euclid on Sky', which contains Euclid key reference papers and first results from the Euclid Early Release Observation

Euclid: Early Release Observations -- Overview of the Perseus cluster and analysis of its luminosity and stellar mass functions

The Euclid ERO programme targeted the Perseus cluster of galaxies, gathering deep data in the central region of the cluster over 0.7 square degree, corresponding to approximately 0.25 r_200. The data set reaches a point-source depth of IE=28.0 (YE, JE, HE = 25.3) AB magnitudes at 5 sigma with a 0.16" and 0.48" FWHM, and a surface brightness limit of 30.1 (29.2) mag per square arcsec. The exceptional depth and spatial resolution of this wide-field multi-band data enable the simultaneous detection and characterisation of both bright and low surface brightness galaxies, along with their globular cluster systems, from the optical to the NIR. This study advances beyond previous analyses of the cluster and enables a range of scientific investigations summarised here. We derive the luminosity and stellar mass functions (LF and SMF) of the Perseus cluster in the Euclid IE band, thanks to supplementary u,g,r,i,z and Halpha data from the CFHT. We adopt a catalogue of 1100 dwarf galaxies, detailed in the corresponding ERO paper. We identify all other sources in the Euclid images and obtain accurate photometric measurements using AutoProf or AstroPhot for 138 bright cluster galaxies, and SourceExtractor for half a million compact sources. Cluster membership for the bright sample is determined by calculating photometric redshifts with Phosphoros. Our LF and SMF are the deepest recorded for the Perseus cluster, highlighting the groundbreaking capabilities of the Euclid telescope. Both the LF and SMF fit a Schechter plus Gaussian model. The LF features a dip at M(IE)=-19 and a faint-end slope of alpha_S = -1.2 to -1.3. The SMF displays a low-mass-end slope of alpha_S = -1.2 to -1.35. These observed slopes are flatter than those predicted for dark matter halos in cosmological simulations, offering significant insights for models of galaxy formation and evolution.Comment: Submitted to A&A, 44 pages, 35 figures, Part of the A&A special issue `Euclid on Sky', which contains Euclid key reference papers and first results from the Euclid Early Release Observation

Differential diagnosis of perinatal hypophosphatasia: radiologic perspectives

Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and postnatally. Diagnosis is challenging because of the large number of skeletal dysplasias with overlapping clinical features. This review focuses on the role of fetal and neonatal imaging modalities in the differential diagnosis of perinatal HPP from other skeletal dysplasias (e.g., osteogenesis imperfecta, campomelic dysplasia, achondrogenesis subtypes, hypochondrogenesis, cleidocranial dysplasia). Perinatal HPP is associated with a broad spectrum of imaging findings that are characteristic of but do not occur in all cases of HPP and are not unique to HPP, such as shortening, bowing and angulation of the long bones, and slender, poorly ossified ribs and metaphyseal lucencies. Conversely, absent ossification of whole bones is characteristic of severe lethal HPP and is associated with very few other conditions. Certain features may help distinguish HPP from other skeletal dysplasias, such as sites of angulation of long bones, patterns of hypomineralization, and metaphyseal characteristics. In utero recognition of HPP allows for the assembly and preparation of a multidisciplinary care team before delivery and provides additional time to devise treatment strategies

<i>Euclid</i>: Early Release Observations – Programme overview and pipeline for compact- and diffuse-emission photometry

The Euclid Early Release Observations (ERO) showcase Euclid’s capabilities in advance of its main mission by targeting 17 astronomical objects, including galaxy clusters, nearby galaxies, globular clusters, and star-forming regions. A total of 24 hours of observing time was allocated in the early months of operation, and the scientific community was engaged through an early public data release. We describe the development of the ERO pipeline to create visually compelling images while simultaneously meeting the scientific demands within months of launch by leveraging a pragmatic data-driven development strategy. The pipeline’s key requirements are to preserve the image quality and to provide flux calibration and photometry for compact and extended sources. The pipeline’s five pillars are removal of instrumental signatures, astrometric calibration, photometric calibration, image stacking, and the production of science-ready catalogues for both the VIS and NISP instruments. We report a point spread function (PSF) with a full width at half maximum of 0ʺ.16 in the optical I E -band and 0ʺ.49 in the near-infrared (NIR) bands YE , JE , and HE . Our VIS mean absolute flux calibration is accurate to about 1%, and the accuracy is 10% for NISP due to a limited calibration set; both instruments have considerable colour terms for individual sources. The median depth is 25.3 and 23.2 AB mag with a signal-to-noise ratio (S/N) of ten for galaxies, while it is 27.1 and 24.5 AB mag at an S/N of five for point sources for VIS and NISP, respectively. Euclid’s ability to observe diffuse emission is exceptional due to its extended PSF nearly matching a pure diffraction halo, the best ever achieved by a wide-field high-resolution imaging telescope. Euclid offers unparalleled capabilities for exploring the low-surface brightness (LSB) Universe across all scales, providing high precision within a wide field of view (FoV), and opening a new observational window in the NIR. Median surface-brightness levels of 29.5 and 27.9, AB mag arcsec−2 are achieved for VIS and NISP, respectively, for detecting a 10ʺ × 10ʺ extended feature at the 1 σ level