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Recent (sub)millimetre polarization observations of protoplanetary discs reveal toroidally aligned, effectively prolate dust grains large enough (at least |$\sim 100$| |$\mu$| m) to efficiently scatter millimetre light. The alignment mechanism for these grains remains unclear. We explore the possibility that gas drag aligns grains through gas–dust relative motion when the grain's centre of mass is offset from its geometric centre, analogous to a badminton birdie's alignment in flight. A simple grain model of two non-identical spheres illustrates how a grain undergoes damped oscillations from flow-induced restoring torques which align its geometric centre in the flow direction relative to its centre of mass. Assuming specular reflection and subsonic flow, we derive an analytical equation of motion for spheroids where the centre of mass can be shifted away from the spheroid's geometric centre. We show that a prolate or an oblate grain can be aligned with the long axis parallel to the gas flow when the centre of mass is shifted along that axis. Both scenarios can explain the required effectively prolate grains inferred from observations. Application to a simple disc model shows that the alignment time-scales are shorter than or comparable to the orbital time. The grain alignment direction in a disc depends on the disc (sub-)structure and grain Stokes number (St) with azimuthal alignment for large St grains in sub-Keplerian smooth gas discs and for small St grains near the gas pressure extrema, such as rings and gaps. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis‐like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1. Methods: Two individuals with unsolved juvenile‐onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole‐exome sequencing (WES). Results: The two probands (MNOT002‐01 and K1440‐01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440‐01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002‐01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440‐01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002‐01 displayed rimmed vacuoles. Monoallelic stop‐loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440‐01) and c.1118A>C p.*373Serext*6 (MNOT002‐01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon. Discussion: Both stop‐loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile‐onset myopathy. [ABSTRACT FROM AUTHOR]

Background: The ITPR1 gene encodes the inositol 1,4,5‐trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. Objectives: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. Methods: Cases were identified using next‐generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. Results: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N‐terminal IP3‐binding domain, the carbonic anhydrase 8 (CA8)‐binding region, and the C‐terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. Conclusions: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development., (© 2022 Wiley Periodicals LLC.)

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants., (© 2021 Wiley Periodicals LLC.)

Pulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-beta cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age- and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the concept of a critical threshold of signaling activity below which disease may be precipitated., (2006 Wiley-Liss, Inc.)

Background: Primary pulmonary arterial hypertension (PAH) is a potentially devastating condition resulting from occlusion of the pulmonary arterioles by the formation of vascular lesions. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified in both familial (FPAH) and idiopathic PAH. Mutant alleles are typically of low penetrance, indicating that other factors are required for the onset of PAH. Previous reports have suggested that the characteristic plexiform lesions in affected lungs are akin to neoplasia, showing monoclonal expansion and microsatellite instability. We hypothesized that in patients with germline mutations, BMPR2 might behave as a classic tumor suppressor gene, with somatic loss of the wild-type allele contributing to disease progression., Methods and Results: To test this hypothesis, plexiform and concentric vascular lesions were serially microdissected from lung explant tissue derived from 7 FPAH cases. DNA was analyzed for loss of heterozygosity at BMPR2 and for microsatellite instability (MSI) at 5 loci. MSI was detected in 1 of 37 lesions at a single locus, BAT-26, whereas heterozygosity at BMPR2 was retained at all informative loci. We also describe a FPAH patient carrying biallelic constitutional missense mutations of BMPR2 who manifested disease at a stage and manner similar to heterozygous patients., Conclusions: Taken together, these data demonstrate that MSI is uncommon in FPAH and suggest that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers likely does not play a significant role in modulating the onset or progression of FPAH.