Socialist Dandies International: East Europe, 1946-1959

This article maps the looks and lifestyle choices of small groups of young, like-minded people who emerged in the postwar Soviet Union and East Europe in the background of huge political, social, and cultural changes. With their androgynous bodies wrapped in drape jackets and narrow trousers, and their love of jazz and swing, these young men stood in a sharp contrast to the official ideology that promoted socialism as a new, pure, and highly rationalized project, its ideal robust and strong man, and its mass culture that insisted on educational and restrained forms of entertainment. Through the categories of dress, body, and big city, the article investigates the clashes, and the eventual truce, between the socialist streamlined and rationalized master narrative and the young dandies' fragmented and disordered narrative. The article argues that the socialist dandies were not politically minded, and that their challenge to the officially proclaimed values was informed by their adolescent recklessness and a general postwar desolation. They were declared state enemies because the socialist regimes did not allow for alternative types of modernity. Consequently, the authorities condemned the young dandies' looks and interests as cosmopolitan, because they originated in the West, and as artificial, since they belonged to the culture that had preceded a new socialist world

Organic Compounds in a Sub-Antarctic Ice Core: A Potential Suite of Sea Ice Markers.

Investigation of organic compounds in ice cores can potentially unlock a wealth of new information in these climate archives. We present results from the first ever ice core drilled on sub-Antarctic island Bouvet, representing a climatologically important but understudied region. We analyze a suite of novel and more familiar organic compounds in the ice core, alongside commonly measured ions. Methanesulfonic acid shows a significant, positive correlation to winter sea ice concentration, as does a fatty acid compound, oleic acid. Both may be sourced from spring phytoplankton blooms, which are larger following greater sea ice extent in the preceding winter. Oxalate, formate, and acetate are positively correlated to sea ice concentration in summer, but sources of these require further investigation. This study demonstrates the potential application of organic compounds from the marine biosphere in generating multiproxy sea ice records, which is critical in improving our understanding of past sea ice changes

GARS- related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA- like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl- tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile- onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease- associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss- of- function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients’ clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot- Marie- Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS- associated disease and support that severe early- onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154914/1/ajmga61544_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154914/2/ajmga61544.pd

Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation

Isolated hypocortisolism due to ACTH deficiency is a rare condition that can be caused by homozygous or compound heterozygous mutations in the gene encoding proopiomelanocortin (POMC). Loss of function mutations of POMC gene typically results in adrenal insufficiency, obesity and red hair. We describe an 18 month old Hispanic female with congenital adrenal insufficiency, a novel POMC mutation and atypical clinical features. The patient presented at the age of 9 months with hypoglycemia and the endocrine evaluation resulted in a diagnosis of ACTH deficiency. She developed extreme weight gain prompting sequence analysis of POMC, which revealed a homozygous c.231C > A change which is predicted to result in a premature termination codon. The case we report had obesity, hypocortisolism but lacked red hair which is typical for subjects with POMC mutations. Mutations of POMC should be considered in individuals with severe early onset obesity and adrenal insufficiency even when they lack the typical pigmentary phenotype

Phenotypic Consequences of Copy Number Variation: Insights from Smith-Magenis and Potocki-Lupski Syndrome Mouse Models

The characterization of mice with different number of copies of the same genomic segment shows that structural changes influence the phenotypic outcome independently of gene dosage

"Don't try to teach me, I got nothing to learn": Management students' perceptions of business ethics teaching

[EN] Interest is growing towards including business ethics in university curricula, aiming at improving ethical behaviour of future managers. Extant literature has investigated the impact of ethics education on different ethics-related students' cognitive and/or behavioural outcomes, considering variables related to training programmes and students' demographic aspects. Accordingly, we aim at assessing students' understanding of business ethics issues, by focusing on the differences in students' perceptions depending on gender, age, work experience, and ethics courses taken. Testing our hypotheses on a sample of 307 management students at a Polish university, and controlling for social desirability bias, we obtained mixed and partially surprising results. We found significant differences in students' understanding of business ethics depending on their gender and age (female and older students showed more ethical inclinations), but not depending on having taken ethics courses-actually perceptions of such courses worsened after taking them. Besides, work experience was not a significant variable. Moreover, course exposure intensiveness (i.e., number of ethics courses completed), and time passed since completion of the latest course, did not confirm hypothesized effects on most of the dependent (sub)variables. These findings stimulate further questions and challenges for future research (e.g., around course design and methodology, and social/cultural/contextual issues).Tormo-Carbó, G.; Oltra, V.; Klimkiewicz, K.; Seguí-Mas, E. (2019). "Don't try to teach me, I got nothing to learn": Management students' perceptions of business ethics teaching. Business Ethics: A European Review. 28(4):506-528. https://doi.org/10.1111/beer.12236S506528284Adkins, N., & Radtke, R. R. (2004). Students’ and Faculty Members’ Perceptions of the Importance of Business Ethics and Accounting Ethics Education: Is There an Expectations Gap? Journal of Business Ethics, 51(3), 279-300. doi:10.1023/b:busi.0000032700.07607.02Allen, W. R., Bacdayan, P., Berube Kowalski, K., & Roy, M. H. (2005). Examining the impact of ethics training on business student values. Education + Training, 47(3), 170-182. doi:10.1108/00400910510592220Auger, P., & Devinney, T. M. (2007). Do What Consumers Say Matter? The Misalignment of Preferences with Unconstrained Ethical Intentions. Journal of Business Ethics, 76(4), 361-383. doi:10.1007/s10551-006-9287-yBampton, R., & Cowton, C. J. (2012). Taking Stock of Accounting Ethics Scholarship: A Review of the Journal Literature. Journal of Business Ethics, 114(3), 549-563. doi:10.1007/s10551-012-1341-3Bampton, R., & Maclagan, P. (2005). Why teach ethics to accounting students? A response to the sceptics. Business Ethics: A European Review, 14(3), 290-300. doi:10.1111/j.1467-8608.2005.00410.xBates, A., & Godoń, R. (2016). Tackling knowledge ‘like a business’? Rethinking the modernisation of higher education in Poland. Compare: A Journal of Comparative and International Education, 47(4), 454-467. doi:10.1080/03057925.2016.1234931Beggs, J. M., & Dean, K. L. (2006). Legislated Ethics or Ethics Education?: Faculty Views in the Post-Enron Era. Journal of Business Ethics, 71(1), 15-37. doi:10.1007/s10551-006-9123-4Bernardi, R. A., & Bean, D. F. (2010). Ranking North American accounting scholars publishing ethics research: 1986 through 2008. Research on Professional Responsibility and Ethics in Accounting, 139-174. doi:10.1108/s1574-0765(2010)0000014010Blanthorne, C., Kovar, S. E., & Fisher, D. G. (2007). Accounting Educators’ Opinions about Ethics in the Curriculum: An Extensive View. 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(1984). Gender stereotypes stem from the distribution of women and men into social roles. Journal of Personality and Social Psychology, 46(4), 735-754. doi:10.1037/0022-3514.46.4.735Ede, F. O., Panigrahi, B., Stuart, J., & Calcich, S. (2000). Journal of Business Ethics, 26(2), 133-146. doi:10.1023/a:1006309212031Eweje, G., & Brunton, M. (2010). Ethical perceptions of business students in a New Zealand university: do gender, age and work experience matter? Business Ethics: A European Review, 19(1), 95-111. doi:10.1111/j.1467-8608.2009.01581.xFerguson, J., Collison, D., Power, D., & Stevenson, L. (2011). Accounting education, socialisation and the ethics of business. Business Ethics: A European Review, 20(1), 12-29. doi:10.1111/j.1467-8608.2010.01607.xFestinger, L. (1957). A Study of Thinking.J. S. Bruner , J. J. Goodnow , G. A. Austin. American Journal of Sociology, 63(2), 231-232. doi:10.1086/222197FOB and GoodBrand and Company Polska. (2010). CSR w Polsce – Menedżerowie/Menedżerki 500 Lider/Liderka CSR. [CSR in Poland ‐ Managers 500 Leaders CSR].Warszawa. Retrieved fromhttp://odpowiedzialnybiznes.pl/public/files/raport_menedzerowie500_lidercsr_2010.pdfFord, R. C., & Richardson, W. D. (1994). Ethical decision making: A review of the empirical literature. Journal of Business Ethics, 13(3), 205-221. doi:10.1007/bf02074820Geary, W. T., & Sims, R. R. (1994). Can ethics be learned? Accounting Education, 3(1), 3-18. doi:10.1080/09639289400000002Ghaffari, F., Kyriacou, O., & Brennan, R. (2008). Exploring the Implementation of Ethics in U.K. Accounting Programs. Issues in Accounting Education, 23(2), 183-198. doi:10.2308/iace.2008.23.2.183Graham, A. (2012). The Teaching of Ethics in Undergraduate Accounting Programmes: The Students’ Perspective. Accounting Education, 21(6), 599-613. doi:10.1080/09639284.2012.725638Halbesleben, J. R. B., Wheeler, A. R., & Buckley, M. R. (2005). Everybody Else is Doing it, So Why Can?t We? Pluralistic Ignorance and Business Ethics Education. Journal of Business Ethics, 56(4), 385-398. doi:10.1007/s10551-004-3897-zHarris, H. (2008). Promoting ethical reflection in the teaching of business ethics. Business Ethics: A European Review, 17(4), 379-390. doi:10.1111/j.1467-8608.2008.00541.xHaski-Leventhal, D., Pournader, M., & McKinnon, A. (2015). The Role of Gender and Age in Business Students’ Values, CSR Attitudes, and Responsible Management Education: Learnings from the PRME International Survey. Journal of Business Ethics, 146(1), 219-239. doi:10.1007/s10551-015-2936-2Hunt, S. D., & Vitell, S. (1986). A General Theory of Marketing Ethics. Journal of Macromarketing, 6(1), 5-16. doi:10.1177/027614678600600103Hurtt, R. K., & Thomas, C. W. (2008). Implementing a Required Ethics Class for Students in Accounting: The Texas Experience. Issues in Accounting Education, 23(1), 31-51. doi:10.2308/iace.2008.23.1.31Jones, G. E., & Kavanagh, M. J. (1996). An experimental examination of the effects of individual and situational factors on unethical behavioral intentions in the workplace. Journal of Business Ethics, 15(5), 511-523. doi:10.1007/bf00381927Jones, T. M. (1991). Ethical Decision Making by Individuals in Organizations: An Issue-Contingent Model. The Academy of Management Review, 16(2), 366. doi:10.2307/258867Kaynama, S. A., King, A., & Smith, L. W. (1996). The impact of a shift in organizational role on ethical perceptions: A comparative study. Journal of Business Ethics, 15(5), 581-590. doi:10.1007/bf00381933Kish-Gephart, J. J., Harrison, D. A., & Treviño, L. K. (2010). Bad apples, bad cases, and bad barrels: Meta-analytic evidence about sources of unethical decisions at work. Journal of Applied Psychology, 95(1), 1-31. doi:10.1037/a0017103Kinach-Brzozowska, K. (1995). Window on Eastern Europe: Teaching Ethics in Gda?sk. Business Ethics: A European Review, 4(4), 233-235. doi:10.1111/j.1467-8608.1995.tb00121.xLarkin, J. M. (2000). Journal of Business Ethics, 23(4), 401-409. doi:10.1023/a:1006150718834Lau, C. L. L. (2009). A Step Forward: Ethics Education Matters! Journal of Business Ethics, 92(4), 565-584. doi:10.1007/s10551-009-0173-2Lehnert, K., Park, Y., & Singh, N. (2014). Research Note and Review of the Empirical Ethical Decision-Making Literature: Boundary Conditions and Extensions. Journal of Business Ethics, 129(1), 195-219. doi:10.1007/s10551-014-2147-2Lewicka‐Strzalecka, A. (2006). Opportunities and limitations of CSR in the postcommunist countries: Polish case. Corporate Governance: The international journal of business in society, 6(4), 440-448. doi:10.1108/14720700610689559Loe, T. W., Ferrell, L., & Mansfield, P. (2000). Journal of Business Ethics, 25(3), 185-204. doi:10.1023/a:1006083612239Low, M., Davey, H., & Hooper, K. (2008). Accounting scandals, ethical dilemmas and educational challenges. Critical Perspectives on Accounting, 19(2), 222-254. doi:10.1016/j.cpa.2006.05.010Luthar, H. K., & Karri, R. (2005). Exposure to Ethics Education and the Perception of Linkage between Organizational Ethical Behavior and Business Outcomes. Journal of Business Ethics, 61(4), 353-368. doi:10.1007/s10551-005-1548-7Macfarlane, B., & Ottewill, R. (2004). Business Ethics in the Curriculum: Assessing the Evidence from U.K. Subject Review. Journal of Business Ethics, 54(4), 339-347. doi:10.1007/s10551-004-1823-zMaclagan, P., & Campbell, T. (2011). Focusing on individuals’ ethical judgement in corporate social responsibility curricula. Business Ethics: A European Review, 20(4), 392-404. doi:10.1111/j.1467-8608.2011.01634.xMadison, R. L., & Schmidt, J. J. (2006). Survey of Time Devoted to Ethics in Accountancy Programs in North American Colleges and Universities. Issues in Accounting Education, 21(2), 99-109. doi:10.2308/iace.2006.21.2.99Malinowski, C., & Berger, K. A. (1996). Undergraduate student attitudes about hypothetical marketing dilemmas. Journal of Business Ethics, 15(5), 525-535. doi:10.1007/bf00381928Marnburg, E. (2001). Journal of Business Ethics, 32(4), 275-283. doi:10.1023/a:1010643309056Marnburg, E. (2003). Educational impacts on academic business practitioner’s moral reasoning and behaviour: effects of short courses in ethics or philosophy. Business Ethics: A European Review, 12(4), 403-413. doi:10.1111/1467-8608.00341May, D. R., Luth, M. T., & Schwoerer, C. E. (2013). The Influence of Business Ethics Education on Moral Efficacy, Moral Meaningfulness, and Moral Courage: A Quasi-experimental Study. Journal of Business Ethics, 124(1), 67-80. doi:10.1007/s10551-013-1860-6Mayhew, B. W., & Murphy, P. R. (2008). The Impact of Ethics Education on Reporting Behavior. Journal of Business Ethics, 86(3), 397-416. doi:10.1007/s10551-008-9854-5McCabe, A. C., Ingram, R., & Dato-on, M. C. (2006). ‘The Business of Ethics and Gender’. Journal of Business Ethics, 64(2), 101-116. doi:10.1007/s10551-005-3327-xMedeiros, K. E., Watts, L. L., Mulhearn, T. J., Steele, L. M., Mumford, M. D., & Connelly, S. (2017). What is Working, What is Not, and What We Need to Know: a Meta-Analytic Review of Business Ethics Instruction. Journal of Academic Ethics, 15(3), 245-275. doi:10.1007/s10805-017-9281-2Nguyen, N. T., & Biderman, M. D. (2008). Studying Ethical Judgments and Behavioral Intentions Using Structural Equations: Evidence from the Multidimensional Ethics Scale*. Journal of Business Ethics, 83(4), 627-640. doi:10.1007/s10551-007-9644-5O’Fallon, M. J., & Butterfield, K. D. (2005). A Review of The Empirical Ethical Decision-Making Literature: 1996–2003. Journal of Business Ethics, 59(4), 375-413. doi:10.1007/s10551-005-2929-7Pan, Y., & Sparks, J. R. (2012). Predictors, consequence, and measurement of ethical judgments: Review and meta-analysis. Journal of Business Research, 65(1), 84-91. doi:10.1016/j.jbusres.2011.02.002Peppas, S. C., & Diskin, B. A. (2001). College courses in ethics: do they really make a difference? International Journal of Educational Management, 15(7), 347-353. doi:10.1108/09513540110407947Peterson, D., Rhoads, A., & Vaught, B. C. (2001). Journal of Business Ethics, 31(3), 225-232. doi:10.1023/a:1010744927551Rentsch, J. R., & Klimoski, R. J. (2001). Why do ?great minds? think alike?: antecedents of team member schema agreement. Journal of Organizational Behavior, 22(2), 107-120. doi:10.1002/job.81Popowska, M. (2016). Shaping New Generations of Managers and Consumers: CSR Implementation and Higher Education System in Poland. Social Responsibility Education Across Europe, 115-138. doi:10.1007/978-3-319-26716-6_6Rajah, R., Reifferscheid, G., & Borgmann, E.-L. (2016). Social Responsibility Education in Germany. Social Responsibility Education Across Europe, 29-48. doi:10.1007/978-3-319-26716-6_2Randall, D. M., & Fernandes, M. F. (1991). The social desirability response bias in ethics research. Journal of Business Ethics, 10(11), 805-817. doi:10.1007/bf00383696Rest, J. R. (1980). Development in moral judgment research. Developmental Psychology, 16(4), 251-256. doi:10.1037/0012-1649.16.4.251Ritter, B. A. (2006). Can Business Ethics be Trained? A Study of the Ethical Decision-making Process in Business Students. Journal of Business Ethics, 68(2), 153-164. doi:10.1007/s10551-006-9062-0Roozen, I., De Pelsmacker, P., & Bostyn, F. (2001). Journal of Business Ethics, 33(2), 87-99. doi:10.1023/a:1017536222355Ruegger, D., & King, E. W. (1992). A study of the effect of age and gender upon student business ethics. Journal of Business Ethics, 11(3), 179-186. doi:10.1007/bf00871965Ryan, L. V. (1995). WINDOW ON EASTERN EUROPE: Ethical Perceptions of Polish Business Students. Business Ethics: A European Review, 4(1), 36-42. doi:10.1111/j.1467-8608.1995.tb00108.xSleeper, B. J., Schneider, K. C., Weber, P. S., & Weber, J. E. (2006). Scale and Study of Student Attitudes Toward Business Education’s Role in Addressing Social Issues. Journal of Business Ethics, 68(4), 381-391. doi:10.1007/s10551-006-9000-1Sojkin, B., Bartkowiak, P., & Skuza, A. (2014). Changes in students’ choice determinants in Poland: a comparative study of tertiary business education between 2008 and 2013. Higher Education, 69(2), 209-224. doi:10.1007/s10734-014-9770-9Stachowicz-Stanusch, A. (2011). The Impact of Business Education on Students’ Moral Competency. Vision: The Journal of Business Perspective, 15(2), 163-176. doi:10.1177/097226291101500207Stedham, Y., Yamamura, J. H., & Beekun, R. I. (2007). Gender differences in business ethics: justice and relativist perspectives. Business Ethics: A European Review, 16(2), 163-174. doi:10.1111/j.1467-8608.2007.00486.xStrahan, R., & Gerbasi, K. C. (1972). Short, homogeneous versions of the Marlow-Crowne Social Desirability Scale. Journal of Clinical Psychology, 28(2), 191-193. doi:10.1002/1097-4679(197204)28:23.0.co;2-gTenbrunsel, A. E., & Smith‐Crowe, K. (2008). 13 Ethical Decision Making: Where We’ve Been and Where We’re Going. The Academy of Management Annals, 2(1), 545-607. doi:10.1080/19416520802211677Thorne, L. (1999). An analysis of the association of demographic variables with the cognitive moral development of Canadian accounting students: an examination of the applicability of American-based findings to the Canadian context. Journal of Accounting Education, 17(2-3), 157-174. doi:10.1016/s0748-5751(99)00019-6Tormo-Carbó, G., Seguí-Mas, E., & Oltra, V. (2014). Accounting Ethics in Unfriendly Environments: The Educational Challenge. Journal of Business Ethics, 135(1), 161-175. doi:10.1007/s10551-014-2455-6Trevino, L. K. (1986). Ethical Decision Making in Organizations: A Person-Situation Interactionist Model. The Academy of Management Review, 11(3), 601. doi:10.2307/258313Trevino, L. K. (1992). 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Journal of Business Ethics, 87(1), 133-151. doi:10.1007/s10551-008-9875-0Zerbe, W. J., & Paulhus, D. L. (1987). Socially Desirable Responding in Organizational Behavior: A Reconception. The Academy of Management Review, 12(2), 250. doi:10.2307/25853

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models

Lessons learned from additional research analyses of unsolved clinical exome cases

BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious