Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently... Show moreMissense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis. Show less
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently... Show moreMissense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis. Show less
We present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets... Show moreWe present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets and Disks with Subaru, and 1.1 {$μ$}m Hubble Space Telescope/NICMOS data. While submillimeter studies suggested there is a dust-depleted cavity with r = 0.''35, we find scattered light as close as 0.''1 (20-28 AU) from the star, with no visible cavity at H, K', or K$_s$ . We find two small-scaled spiral structures that asymmetrically shadow the outer disk. We model one of the spirals using spiral density wave theory, and derive a disk aspect ratio of h ~{} 0.18, indicating a dynamically warm disk. If the spiral pattern is excited by a perturber, we estimate its mass to be 5$^{+3}$ $_{- 4}$ M$_J$ , in the range where planet filtration models predict accretion continuing onto the star. Using a combination of non-redundant aperture masking data at L' and angular differential imaging with Locally Optimized Combination of Images at K' and K$_s$ , we exclude stellar or massive brown dwarf companions within 300 mas of the Herbig Ae star, and all but planetary mass companions exterior to 0.''5. We reach 5{$σ$} contrasts limiting companions to planetary masses, 3-4 M$_J$ at 1.''0 and 2 M$_J$ at 1.''55, using the COND models. Collectively, these data strengthen the case for MWC 758 already being a young planetary system. Show less
Grady, C.; Muto, T.; Hashimoto, J.; Fukagawa, M.; Currie, T.; Biller, B.; ... ; Tamura, M. 2013
We present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets and... Show moreWe present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets and Disks with Subaru, and 1.1 {$μ$}m Hubble Space Telescope/NICMOS data. While submillimeter studies suggested there is a dust-depleted cavity with r = 0.''35, we find scattered light as close as 0.''1 (20-28 AU) from the star, with no visible cavity at H, K', or K$_s$ . We find two small-scaled spiral structures that asymmetrically shadow the outer disk. We model one of the spirals using spiral density wave theory, and derive a disk aspect ratio of h ~{} 0.18, indicating a dynamically warm disk. If the spiral pattern is excited by a perturber, we estimate its mass to be 5$^{+3}$ $_{- 4}$ M$_J$ , in the range where planet filtration models predict accretion continuing onto the star. Using a combination of non-redundant aperture masking data at L' and angular differential imaging with Locally Optimized Combination of Images at K' and K$_s$ , we exclude stellar or massive brown dwarf companions within 300 mas of the Herbig Ae star, and all but planetary mass companions exterior to 0.''5. We reach 5{$σ$} contrasts limiting companions to planetary masses, 3-4 M$_J$ at 1.''0 and 2 M$_J$ at 1.''55, using the COND models. Collectively, these data strengthen the case for MWC 758 already being a young planetary system. Show less
