A guide for social science journal editors on easing into open science.

Journal editors have a large amount of power to advance open science in their respective fields by incentivising and mandating open policies and practices at their journals. The Data PASS Journal Editors Discussion Interface (JEDI, an online community for social science journal editors: www.dpjedi.org ) has collated several resources on embedding open science in journal editing ( www.dpjedi.org/resources ). However, it can be overwhelming as an editor new to open science practices to know where to start. For this reason, we created a guide for journal editors on how to get started with open science. The guide outlines steps that editors can take to implement open policies and practices within their journal, and goes through the what, why, how, and worries of each policy and practice. This manuscript introduces and summarizes the guide (full guide: https://doi.org/10.31219/osf.io/hstcx ).

The Living Machine: A Computational Approach to the Nineteenth-Century Language of Technology.

This article examines a long-standing question in the history of technology concerning the trope of the living machine. The authors do this by using a cutting-edge computational method, which they apply to large collections of digitized texts. In particular, they demonstrate the affordances of a neural language model for historical research. In a deliberate maneuver, the authors use a type of model, often portrayed as sentient today, to detect figures of speech in nineteenth-century texts that portrayed machines as self-acting, automatic, or alive. Their masked language model detects unusual or surprising turns of phrase, which could not be discovered using simple keyword search. The authors collect and close read such sentences to explore how figurative language produced a context that conceived humans and machines as interchangeable in complicated ways. They conclude that, used judiciously, language models have the potential to open up new avenues of historical research.

DUKweb, diachronic word representations from the UK Web Archive corpus.

Lexical semantic change (detecting shifts in the meaning and usage of words) is an important task for social and cultural studies as well as for Natural Language Processing applications. Diachronic word embeddings (time-sensitive vector representations of words that preserve their meaning) have become the standard resource for this task. However, given the significant computational resources needed for their generation, very few resources exist that make diachronic word embeddings available to the scientific community. In this paper we present DUKweb, a set of large-scale resources designed for the diachronic analysis of contemporary English. DUKweb was created from the JISC UK Web Domain Dataset (1996-2013), a very large archive which collects resources from the Internet Archive that were hosted on domains ending in '.uk'. DUKweb consists of a series word co-occurrence matrices and two types of word embeddings for each year in the JISC UK Web Domain dataset. We show the reuse potential of DUKweb and its quality standards via a case study on word meaning change detection.

The citation advantage of linking publications to research data.

Efforts to make research results open and reproducible are increasingly reflected by journal policies encouraging or mandating authors to provide data availability statements. As a consequence of this, there has been a strong uptake of data availability statements in recent literature. Nevertheless, it is still unclear what proportion of these statements actually contain well-formed links to data, for example via a URL or permanent identifier, and if there is an added value in providing such links. We consider 531, 889 journal articles published by PLOS and BMC, develop an automatic system for labelling their data availability statements according to four categories based on their content and the type of data availability they display, and finally analyze the citation advantage of different statement categories via regression. We find that, following mandated publisher policies, data availability statements become very common. In 2018 93.7% of 21,793 PLOS articles and 88.2% of 31,956 BMC articles had data availability statements. Data availability statements containing a link to data in a repository-rather than being available on request or included as supporting information files-are a fraction of the total. In 2017 and 2018, 20.8% of PLOS publications and 12.2% of BMC publications provided DAS containing a link to data in a repository. We also find an association between articles that include statements that link to data in a repository and up to 25.36% (± 1.07%) higher citation impact on average, using a citation prediction model. We discuss the potential implications of these results for authors (researchers) and journal publishers who make the effort of sharing their data in repositories. All our data and code are made available in order to reproduce and extend our results.

Redefining the Etiologic Landscape of Cerebellar Malformations.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

Uptake and outcome of manuscripts in Nature journals by review model and author characteristics.

BACKGROUND: Double-blind peer review has been proposed as a possible solution to avoid implicit referee bias in academic publishing. The aims of this study are to analyse the demographics of corresponding authors choosing double-blind peer review and to identify differences in the editorial outcome of manuscripts depending on their review model. METHODS: Data includes 128,454 manuscripts received between March 2015 and February 2017 by 25 Nature-branded journals. We investigated the uptake of double-blind review in relation to journal tier, as well as gender, country, and institutional prestige of the corresponding author. We then studied the manuscripts' editorial outcome in relation to review model and author's characteristics. The gender (male, female, or NA) of the corresponding authors was determined from their first name using a third-party service (Gender API). The prestige of the corresponding author's institutions was measured from the data of the Global Research Identifier Database (GRID) by dividing institutions in three prestige groups with reference to the 2016 Times Higher Education (THE) ranking. We employed descriptive statistics for data exploration, and we tested our hypotheses using Pearson's chi-square and binomial tests. We also performed logistic regression modelling with author update, out-to-review, and acceptance as response, and journal tier, author gender, author country, and institution as predictors. RESULTS: Author uptake for double-blind submissions was 12% (12,631 out of 106,373). We found a small but significant association between journal tier and review type (p value < 0.001, Cramer's V = 0.054, df = 2). We had gender information for 50,533 corresponding authors and found no statistically significant difference in the distribution of peer review model between males and females (p value = 0.6179). We had 58,920 records with normalised institutions and a THE rank, and we found that corresponding authors from the less prestigious institutions are more likely to choose double-blind review (p value < 0.001, df = 2, Cramer's V = 0.106). In the ten countries with the highest number of submissions, we found a large significant association between country and review type (p value < 0.001, df = 10, Cramer's V = 0.189). The outcome both at first decision and post review is significantly more negative (i.e. a higher likelihood for rejection) for double-blind than single-blind papers (p value < 0.001, df = 1, Cramer's V = 0.112 for first decision; p value < 0.001; df = 1, Cramer's V = 0.082 for post-review decision). CONCLUSIONS: The proportion of authors that choose double-blind review is higher when they submit to more prestigious journals, they are affiliated with less prestigious institutions, or they are from specific countries; the double-blind option is also linked to less successful editorial outcomes.

Emo, love and god: making sense of Urban Dictionary, a crowd-sourced online dictionary.

The Internet facilitates large-scale collaborative projects and the emergence of Web 2.0 platforms, where producers and consumers of content unify, has drastically changed the information market. On the one hand, the promise of the 'wisdom of the crowd' has inspired successful projects such as Wikipedia, which has become the primary source of crowd-based information in many languages. On the other hand, the decentralized and often unmonitored environment of such projects may make them susceptible to low-quality content. In this work, we focus on Urban Dictionary, a crowd-sourced online dictionary. We combine computational methods with qualitative annotation and shed light on the overall features of Urban Dictionary in terms of growth, coverage and types of content. We measure a high presence of opinion-focused entries, as opposed to the meaning-focused entries that we expect from traditional dictionaries. Furthermore, Urban Dictionary covers many informal, unfamiliar words as well as proper nouns. Urban Dictionary also contains offensive content, but highly offensive content tends to receive lower scores through the dictionary's voting system. The low threshold to include new material in Urban Dictionary enables quick recording of new words and new meanings, but the resulting heterogeneous content can pose challenges in using Urban Dictionary as a source to study language innovation.

Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability.

BACKGROUND: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. METHODS: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches. RESULTS: We verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation. CONCLUSION: This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.

Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.

Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next-generation sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin-C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the phenotype spectrum of filaminopathies.

A Clinical Classification Scheme for Tracheobronchomegaly (Mounier-Kuhn Syndrome).

INTRODUCTION: Tracheobronchomegaly (Mounier-Kuhn Syndrome) is a rare disease characterized by tracheal enlargement and associated loss of elastic fibers in the trachea and main bronchi. MATERIALS: MEDLINE, Index Medicus, and other databases were searched with pre-defined criteria to identify cases of tracheobronchomegaly (TBM). Two new cases of TBM were also identified from the Provincial Medical Genetics Program of British Columbia. RESULTS: We identified 166 publications describing 365 occurrences of TBM. We observed that affected individuals could be grouped into subgroups according to clinical features. Type 1A (105 individuals) consists of infants who developed TBM after having undergone fetoscopic tracheal occlusion, and Type 1B patients (24 individuals) are infants and children who developed TBM after prolonged intubation. Type 2 individuals developed TBM following recurrent pulmonary infections (2A) (14 individuals) or pulmonary fibrosis (2B) (10 individuals). Type 3 represents TBM with evidence of extra-pulmonary elastolysis (18 individuals), and Type 4 denotes the development of TBM with no clear predisposing factors (196 individuals). Both of our patients had TBM and evidence of extra-pulmonary elastolysis. As well, one patient had a mildly dilated aortic root, which is a previously unreported co-occurrence. CONCLUSION: We introduce a novel classification scheme, which may sort patients into etiologically distinct groups, furthering our understanding of its pathogenesis and potentially, prevention or therapy. We also hypothesize that TBM and generalized elastolysis may have etiological commonalities, suggesting a need for further study.

Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations.

BACKGROUND: The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations. METHODS: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis. RESULTS: We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm. CONCLUSIONS: Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life.

Copy number variants (CNVs) analysis in a deeply phenotyped cohort of individuals with intellectual disability (ID).

BACKGROUND: DNA copy number variants (CNVs) are found in 15% of subjects with ID but their association with phenotypic abnormalities has been predominantly studied in smaller cohorts of subjects with detailed yet non-systematically categorized phenotypes, or larger cohorts (thousands of cases) with smaller number of generalized phenotypes. METHODS: We evaluated the association of de novo, familial and common CNVs detected in 78 ID subjects with phenotypic abnormalities classified using the Winter-Baraitser Dysmorphology Database (WBDD) (formerly the London Dysmorphology Database). Terminology for 34 primary (coarse) and 169 secondary (fine) phenotype features were used to categorize the abnormal phenotypes and determine the prevalence of each phenotype in patients grouped by the type of CNV they had. RESULTS: In our cohort more than 50% of cases had abnormalities in primary categories related to head (cranium, forehead, ears, eye globes, eye associated structures, nose) as well as hands and feet. The median number of primary and secondary abnormalities was 12 and 18 per subject, respectively, indicating that the cohort consisted of subjects with a high number of phenotypic abnormalities (median De Vries score for the cohort was 5). The prevalence of each phenotypic abnormality was comparable in patients with de novo or familial CNVs in comparison to those with only common CNVs, although a trend for increased frequency of cranial and forehead abnormalities was noted in subjects with rare de novo and familial CNVs. Two clusters of subjects were identified based on the prevalence of each fine phenotypic feature, with an average of 28.3 and 13.5 abnormal phenotypes/subject in the two clusters respectively (P < 0.05). CONCLUSIONS: Our study is a rare example of using standardized, deep morphologic phenotype clustering with phenotype/CNV correlation in a cohort of subjects with ID. The composition of the cohort inevitably influences the phenotype/genotype association, and our studies show that the influence of the de novo CNVs on the phenotype is less obvious in cohorts consisting of subjects with a high number of phenotypic abnormalities. The outcome of phenotype/genotype analysis also depends on the choice of phenotypes assessed and standardized phenotyping is required to minimize variability.

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases.

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

A severe phenotype of Gitelman syndrome with increased prostaglandin excretion and favorable response to indomethacin.

Our understanding of Gitelman syndrome (GS) and Bartter syndrome has continued to evolve with the use of genetic testing to more precisely define the tubular defects responsible. GS is caused by mutations in the SLC12A3 gene encoding the Na(+)-Cl(-) co-transporter of the distal convoluted tubule (NCCT) and tends to be associated with a milder salt-losing phenotype. We describe two female siblings presenting in infancy with a severe salt-losing tubulopathy and failure to thrive due to compound heterozygous mutations in the SLC12A3 gene encoding the NCCT. Both children were treated with indomethacin resulting in improved linear growth and polyuria. Some atypical biochemical findings in our cases are discussed including raised urinary prostaglandin (PGE2) excretion that normalized with intravenous fluid repletion.

Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers.

BACKGROUND: Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting. METHODS: We constructed a Markov model of annual MRI and mammography screening for BRCA1/2 carriers, using local data and published values. We calculated cost-effectiveness as cost per quality-adjusted life-year gained (QALY), and conducted one-way and probabilistic sensitivity analysis. RESULTS: The incremental cost-effectiveness ratio (ICER) of annual mammography plus MRI screening, compared to annual mammography alone, was $50,900/QALY. After incorporating parameter uncertainty, MRI screening is expected to be a cost-effective option 86% of the time at a willingness-to-pay of $100,000/QALY, and 53% of the time at a willingness-to-pay of $50,000/QALY. The model is highly sensitive to the cost of MRI; as the cost is increased from $200 to $700 per scan, the ICER ranges from $37,100/QALY to $133,000/QALY. CONCLUSIONS: The cost-effectiveness of using MRI and mammography in combination to screen for breast cancer in BRCA1/2 mutation carriers is finely balanced. The sensitivity of the results to the cost of the MRI screen itself warrants consideration: in jurisdictions with higher MRI costs, screening may not be a cost-effective use of resources, but improving the efficiency of MRI screening will also improve cost-effectiveness.

BPES with atypical premature ovarian insufficiency, and evidence of mitotic recombination, in a woman with trisomy X and a translocation t(3;11)(q22.3;q14.1).

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder characterized by a complex dysgenesis of the eyelids and premature ovarian insufficiency. FOXL2 located at 3q22.3, encoding a forkhead transcription factor, is the only gene known to be responsible for BPES. We describe a patient diagnosed with BPES with atypical ovarian failure, characterized by normal levels of gonadotropins, who was found to have trisomy X as well as a translocation (3;11)(q22.3;q14.1). The translocation breakpoint at 3q22.3 is located upstream of the FOXL2 gene and most likely causes BPES by separating the FOXL2 transcription unit from its cis-regulatory sequences. By array analysis we detected mosaicism for the balanced and an unbalanced form of the translocation in blood cells. We propose mitotic recombination as the likely mechanism of the mosaicism formation. Mitotic recombination is a common phenomenon in human cells. Thus, we hypothesize that it may be one of the mechanisms responsible for cryptic imbalances and possible abnormal phenotypes in some carriers of balanced rearrangements.

Genotype-phenotype analysis of 4q deletion syndrome: proposal of a critical region.

Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.

Life-history chronicle for a patient with the recently described chromosome 4q21 microdeletion syndrome.

[Bonnet et al. (2010); J Med Genet 47: 377-384] recently suggested a 4q21 microdeletion syndrome with several common features, including severe intellectual disability, lack of speech, hypotonia, significant growth restriction, and distinctive facial features. Overlap of the deleted regions of 13 patients, including a patient we previously reported, delineates a critical region, with PRKG2 and RASGEF1B emerging as candidate genes. Here we provide a detailed clinical report and photographic life history of our previously reported patient. Previous case reports of this new syndrome have not described the prognosis or natural history of these patients.

Understanding the impact of 1q21.1 copy number variant.

BACKGROUND: 1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate. Here we described the consequences of the 1q21.1 CNV on genome-wide gene expression and function of selected candidate genes within 1q21.1 using cell lines from clinically well described subjects. METHODS AND RESULTS: Eight subjects from 3 families were included in the study: six with a 1q21.1 deletion and two with a 1q21.1 duplication. High resolution Affymetrix 2.7M array was used to refine the 1q21.1 CNV breakpoints and exclude the presence of secondary CNVs of pathogenic relevance. Whole genome expression profiling, studied in lymphoblast cell lines (LBCs) from 5 subjects, showed enrichment of genes from 1q21.1 in the top 100 genes ranked based on correlation of expression with 1q21.1 copy number. The function of two top genes from 1q21.1, CHD1L/ALC1 and PRKAB2, was studied in detail in LBCs from a deletion and a duplication carrier. CHD1L/ALC1 is an enzyme with a role in chromatin modification and DNA damage response while PRKAB2 is a member of the AMP kinase complex, which senses and maintains systemic and cellular energy balance. The protein levels for CHD1L/ALC1 and PRKAB2 were changed in concordance with their copy number in both LBCs. A defect in chromatin remodeling was documented based on impaired decatenation (chromatid untangling) checkpoint (DCC) in both LBCs. This defect, reproduced by CHD1L/ALC1 siRNA, identifies a new role of CHD1L/ALC1 in DCC. Both LBCs also showed elevated levels of micronuclei following treatment with a Topoisomerase II inhibitor suggesting increased DNA breaks. AMP kinase function, specifically in the deletion containing LBCs, was attenuated. CONCLUSION: Our studies are unique as they show for the first time that the 1q21.1 CNV not only causes changes in the expression of its key integral genes, associated with changes at the protein level, but also results in changes in their known function, in the case of AMPK, and newly identified function such as DCC activation in the case of CHD1L/ALC1. Our results support the use of patient lymphoblasts for dissecting the functional sequelae of genes integral to CNVs in carrier cell lines, ultimately enhancing understanding of biological processes which may contribute to the clinical phenotype.

Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.

RATIONALE: Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner. OBJECTIVE: To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants. METHODS AND RESULTS: A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers. CONCLUSIONS: SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.