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  1. Łagowska B, Martin JH, Hodgson CJ
    Zootaxa, 2015;4006(1):128-42.
    PMID: 26623761 DOI: 10.11646/zootaxa.4006.1.6
    All life stages (adult female and male, first-instar nymph, second-instar male and female nymphs, and prepupa and pupa) of a new species of Asterolecaniidae, Bambusaspis transversa Lagowska & Martin sp. n., from bamboo in Malaysia, are described and illustrated. The adult female and first-instar nymphs are compared with those Bambusaspis species considered to be closest to the new species.
    Matched MeSH terms: Female; Male
  2. Łagowska B, Martin JH, Hodgson CJ
    Zootaxa, 2017 Nov 29;4358(2):295-310.
    PMID: 29245470 DOI: 10.11646/zootaxa.4358.2.4
    The adult female, first-instar nymph, second-instar male, third-instar female, pupa and adult male of a new species of Marsipococcus Cockerell & Bueker (Hemiptera: Coccomorpha: Coccidae) from Malaysia, M. ulubendulensis Łagowska & Martin sp. n., are described and illustrated, while the second-instar female is only described. Marsipococcus is rediagnosed and a key to the adult females of the four species now placed in this genus is included.
    Matched MeSH terms: Female; Male
  3. Özgüroğlu M, Kilickap S, Sezer A, Gümüş M, Bondarenko I, Gogishvili M, et al.
    Lancet Oncol, 2023 Sep;24(9):989-1001.
    PMID: 37591293 DOI: 10.1016/S1470-2045(23)00329-7
    BACKGROUND: Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression.

    METHODS: EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540.

    FINDINGS: Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months (10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer.

    FUNDING: Regeneron Pharmaceuticals and Sanofi.

    Matched MeSH terms: Female; Male
  4. Özbilgin A, Çavuş İ, Yıldırım A, Gündüz C
    Mikrobiyol Bul, 2016 Jul;50(3):484-90.
    PMID: 27525405
    Plasmodium knowlesi is now added to the known four Plasmodium species (P.vivax, P.falciparum, P.malariae, P.ovale) as a cause of malaria in humans because of the recent increasing rate of cases reported from countries of southeastern Asia. P.knowlesi which infects macaque monkeys (Macaca fascicularis and M.nemestrina) is transmitted to humans especially by Anopheles leucosphyrus and An.hackeri mosquitos. First human cases of P.knowlesi malaria have been detected in Malaysia which have reached high numbers in recent years and also have been reported from countries of Southeast Asia such as Thailand, Philippines, Myanmar, Singapore and Vietnam. However the number of cases reported from western countries are rare and limited only within voyagers. This report is the first presentation of an imported case of P.knowlesi malaria in Turkey and aims to draw attention to the point that it could also be detected in future. A 33-year-old male patient from Myanmar who has migrated to Turkey as a refugee, was admitted to a health center with the complaints of fever with a periodicity of 24 hours, headache, fatigue, cough, sore throat, anorexia, myalgia and arthralgia. He was prediagnosed as upper respiratory tract infection, however because of his periodical fever and background in Myanmar, thick and thin blood films were prepared and sent to our laboratory for further examinations. Microscopic examination of the thin blood films revealed erythrocytic stages compatible with P.knowlesi (three large early trophozoites in an erythrocyte, three late trophozoites with compact view, and three late band-form trophozoites). Upon this, both real-time polymerase chain reaction (Rt-PCR) targeting the small subunit ribosomal RNA (SSU-rRNA) genes of Plasmodium genus and DNA sequence analysis targeting P.knowlesi rRNA gene were performed. As a result, the suspected identification of P.knowlesi by microscopy was confirmed by Rt-PCR and DNA sequencing. The patient was treated with chloroquine and primaquine combination and in the follow-up on the seventh day after the treatment, his parasitemia and symptoms had ceased. Although there were some previous reports concerning about imported patients infected with different Plasmodium species in our country, no cases of P.knowlesi have been reported. This first case presented here emphasizes the occurence of P.knowlesi malaria in Turkey hereinafter due to the increasing number of refugees.
    Matched MeSH terms: Male
  5. Çitil M, İlbasmış M, Olanrewaju VO, Barut A, Karaoğlan S, Ali M
    Environ Sci Pollut Res Int, 2023 Apr;30(18):53962-53976.
    PMID: 36869955 DOI: 10.1007/s11356-023-26016-2
    As the negative repercussions of environmental devastation, such as global warming and climate change, become more apparent, environmental consciousness is growing across the world, forcing nations to take steps to mitigate the damage. Thus, the current study assesses the effect of green investments, institutional quality, and political stability on air quality in the G-20 countries for the period 2004-2020. The stationarity of the variables was examined with the Pesaran (J Appl Econ 22:265-312, 2007) CADF, the long-term relationship between the variables by Westerlund (Oxf Bull Econ Stat 69(6):709-748, 2007), the long-run relationship coefficients with the MMQR method proposed by Machado and Silva (Econ 213(1):145-173, 2019), and the causality relationship between the variables by Dumitrescu and Hurlin (Econ Model 29(4):1450-1460, 2012) panel causality. The study findings revealed that green finance investments, institutional quality and political stability increased the air quality, while total output and energy consumption decreased air quality. The panel causality reveals a unidirectional causality from green finance investments, total output, energy consumption and political stability to air quality, and a bidirectional causality between institutional quality and air quality. According to these findings, it has been found that in the long term, green finance investments, total output, energy consumption, political stability, and institutional quality affect air quality. Based on these results, policies implications were proposed.
    Matched MeSH terms: Male
  6. von Stumm S, Chamorro-Premuzic T, Furnham A
    Br J Psychol, 2009 May;100(Pt 2):429-42.
    PMID: 18851768 DOI: 10.1348/000712608X357876
    This study examines the structure of self-estimates of intelligence (SEI) across 12 nations (Australia, Austria, Brazil, France, Iran, Israel, Malaysia, South Africa, Spain, Turkey, UK and US). Participants rated themselves on general and specific abilities from three popular models of intelligence: Gardner's multiple intelligences, Sternberg's triarchic theory of intelligence, and Goleman's emotional intelligence. The results showed that (a) laypeople across nations have similar and invariant concepts of intelligence, (b) concepts of intelligence are cross-culturally closely related to academic notions of intellectual ability and (c) sex differences in general and specific SEI favouring men are consistent across countries. Male hubris and female humility in SEI seem independent of sex differences in actual cognitive ability and national levels of masculinity-femininity. Furthermore, international mean differences in general SEI could not be attributed to discrepancies in national intelligence quotient (IQ) levels or to cultural variations.
    Matched MeSH terms: Female; Male
  7. von Seth J, Dussex N, Díez-Del-Molino D, van der Valk T, Kutschera VE, Kierczak M, et al.
    Nat Commun, 2021 Apr 26;12(1):2393.
    PMID: 33896938 DOI: 10.1038/s41467-021-22386-8
    Small populations are often exposed to high inbreeding and mutational load that can increase the risk of extinction. The Sumatran rhinoceros was widespread in Southeast Asia, but is now restricted to small and isolated populations on Sumatra and Borneo, and most likely extinct on the Malay Peninsula. Here, we analyse 5 historical and 16 modern genomes from these populations to investigate the genomic consequences of the recent decline, such as increased inbreeding and mutational load. We find that the Malay Peninsula population experienced increased inbreeding shortly before extirpation, which possibly was accompanied by purging. The populations on Sumatra and Borneo instead show low inbreeding, but high mutational load. The currently small population sizes may thus in the near future lead to inbreeding depression. Moreover, we find little evidence for differences in local adaptation among populations, suggesting that future inbreeding depression could potentially be mitigated by assisted gene flow among populations.
    Matched MeSH terms: Female; Male
  8. van der Werf ET, Redmond NM, Turnbull S, Thornton H, Thompson M, Little P, et al.
    Br J Gen Pract, 2019 Apr;69(681):e236-e245.
    PMID: 30858333 DOI: 10.3399/bjgp19X701837
    BACKGROUND: Severity assessments of respiratory tract infection (RTI) in children are known to differ between parents and clinicians, but determinants of perceived severity are unknown.

    AIM: To investigate the (dis)agreement between, and compare the determinants of, parent and clinician severity scores.

    DESIGN AND SETTING: Secondary analysis of data from a prospective cohort study of 8394 children presenting to primary care with acute (≤28 days) cough and RTI.

    METHOD: Data on sociodemographic factors, parent-reported symptoms, clinician-reported findings, and severity assessments were used. Kappa (κ)-statistics were used to investigate (dis) agreement, whereas multivariable logistic regression was used to identify the factors associated with illness severity.

    RESULTS: Parents reported higher illness severity (mean 5.2 [standard deviation (SD) 1.8], median 5 [interquartile range (IQR) 4-7]), than clinicians (mean 3.1 [SD 1.7], median 3 [IQR 2-4], P<0.0001). There was low positive correlation between these scores (+0.43) and poor inter-rater agreement between parents and clinicians (κ 0.049). The number of clinical signs was highly correlated with clinician scores (+0.71). Parent-reported symptoms (in the previous 24 hours) that were independently associated with higher illness severity scores, in order of importance, were: severe fever, severe cough, rapid breathing, severe reduced eating, moderate-to-severe reduced fluid intake, severe disturbed sleep, and change in cry. Three of these symptoms (severe fever, rapid breathing, and change in cry) along with inter/subcostal recession, crackles/crepitations, nasal flaring, wheeze, and drowsiness/irritability were associated with higher clinician scores.

    CONCLUSION: Clinicians and parents use different factors and make different judgements about the severity of children's RTI. Improved understanding of the factors that concern parents could improve parent-clinician communication and consultation outcomes.

    Matched MeSH terms: Female; Male
  9. van der Meij SE
    Zookeys, 2015.
    PMID: 25987871 DOI: 10.3897/zookeys.500.9244
    A new species of gall crab is described from the free-living stony coral Trachyphylliageoffroyi. Specimens were collected during field work in Lembeh Strait (Indonesia) and off Kudat (Malaysian Borneo). This new species, here named Lithoscaptussemperi sp. n., is the ninth species assigned to the genus. It can be separated from its congeners by not having the internal orbital angle extending beyond the external orbital angle, and by the stout female P2 merus with prominent distomesial projection. In addition, the carapace surface appears smooth, despite having small tubercles on the anterior half, and is without noticeable spines, other than those on the frontal margin. The distinctive carapace pattern in life is a diagnostic character in male specimens.
    Matched MeSH terms: Female; Male
  10. van Rostenberghe H, Yong A, Mohd Zin F, Fuad MDF, Idris B, Tahir NA, et al.
    MyJurnal
    Autonomy is widely accepted to be the third pillar of medical ethics. However, if it comes to refusal of life saving treatments, some extra considerations are necessary, especially if decisions are made by surrogate decision makers. Four cases of problematic decision making are presented here, followed by a discussion about the cultural and religious misconceptions about the rights of surrogate decision makers.
    Matched MeSH terms: Female; Male
  11. van Roekel EH, Trijsburg L, Assi N, Carayol M, Achaintre D, Murphy N, et al.
    Nutrients, 2018 May 22;10(5).
    PMID: 29789452 DOI: 10.3390/nu10050654
    Identifying the metabolites associated with alcohol consumption may provide insights into the metabolic pathways through which alcohol may affect human health. We studied associations of alcohol consumption with circulating concentrations of 123 metabolites among 2974 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Alcohol consumption at recruitment was self-reported through dietary questionnaires. Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQTM p180 kit). Data were randomly divided into discovery (2/3) and replication (1/3) sets. Multivariable linear regression models were used to evaluate confounder-adjusted associations of alcohol consumption with metabolite concentrations. Metabolites significantly related to alcohol intake in the discovery set (FDR q-value < 0.05) were further tested in the replication set (Bonferroni-corrected p-value < 0.05). Of the 72 metabolites significantly related to alcohol intake in the discovery set, 34 were also significant in the replication analysis, including three acylcarnitines, the amino acid citrulline, four lysophosphatidylcholines, 13 diacylphosphatidylcholines, seven acyl-alkylphosphatidylcholines, and six sphingomyelins. Our results confirmed earlier findings that alcohol consumption was associated with several lipid metabolites, and possibly also with specific acylcarnitines and amino acids. This provides further leads for future research studies aiming at elucidating the mechanisms underlying the effects of alcohol in relation to morbid conditions.
    Matched MeSH terms: Female; Male
  12. van Noordwijk MA, Utami Atmoko SS, Knott CD, Kuze N, Morrogh-Bernard HC, Oram F, et al.
    J Hum Evol, 2018 12;125:38-49.
    PMID: 30502896 DOI: 10.1016/j.jhevol.2018.09.004
    Orangutans (Pongo spp.) are reported to have extremely slow life histories, including the longest average interbirth intervals of all mammals. Such slow life history can be viable only when unavoidable mortality is kept low. Thus, orangutans' survivorship under natural conditions is expected to be extremely high. Previous estimates of orangutan life history were based on captive individuals living under very different circumstances or on small samples from wild populations. Here, we combine birth data from seven field sites, each with demographic data collection for at least 10 years (range 12-43 years) on wild orangutans to better document their life history. Using strict criteria for data inclusion, we calculated infant survival, interbirth intervals and female age at first reproduction, across species, subspecies and islands. We found an average closed interbirth interval of 7.6 years, as well as consistently very high pre-weaning survival for males and females. Female survival of 94% until age at first birth (at around age 15 years) was higher than reported for any other mammal species under natural conditions. Similarly, annual survival among parous females is very high, but longevity remains to be estimated. Current data suggest no major life history differences between Sumatran and Bornean orangutans. The high offspring survival is remarkable, noting that modern human populations seem to have reached the same level of survival only in the 20th century. The orangutans' slow life history illustrates what can be achieved if a hominoid bauplan is exposed to low unavoidable mortality. Their high survival is likely due to their arboreal and non-gregarious lifestyle, and has allowed them to maintain viable populations, despite living in low-productivity habitats. However, their slow life history also implies that orangutans are highly vulnerable to a catastrophic population crash in the face of drastic habitat change.
    Matched MeSH terms: Female; Male
  13. van Langeveld AWB, Teo PS, Mars M, Feskens EJM, de Graaf C, de Vries JHM
    Eur J Clin Nutr, 2019 01;73(1):132-140.
    PMID: 30254242 DOI: 10.1038/s41430-018-0300-1
    BACKGROUND/OBJECTIVE: Taste is of key importance in food choice and dietary patterns, but studies on taste profiles are limited. We previously assessed dietary taste patterns by 24 h recalls (24hR), but for epidemiological studies food frequency questionnaires (FFQ) may also be suitable. This study compared dietary taste patterns based on FFQ against 24hR and biomarkers of exposure.

    SUBJECTS/METHODS: A taste database including 467 foods' sweet, sour, bitter, salt, umami and fat sensation values was combined with food intake data to assess dietary taste patterns: the contribution to energy intake of 6 taste clusters. The FFQ's reliability was assessed against 3-d 24hR and urinary biomarkers for sodium (Na) and protein intake (N) in Dutch men (n = 449) and women (n = 397) from the NQplus validation study (mean age 53 ± 11 y, BMI 26 ± 4 kg/m2).

    RESULTS: Correlations of dietary taste patterns ranged from 0.39-0.68 between FFQ and 24hR (p 

    Matched MeSH terms: Female; Male
  14. van Hellemond JJ, van Genderen PJ
    Ned Tijdschr Geneeskd, 2010;154:A1353.
    PMID: 20456798
    Matched MeSH terms: Male
  15. van Eekelen A, Stokvis-Brantsma H, Frölich M, Smelt AH, Stokvis H
    Diabetes Care, 2000 Sep;23(9):1435-6.
    PMID: 10977050
    Matched MeSH terms: Female; Male
  16. van Duijnhoven FJB, Jenab M, Hveem K, Siersema PD, Fedirko V, Duell EJ, et al.
    Int J Cancer, 2018 Mar 15;142(6):1189-1201.
    PMID: 29114875 DOI: 10.1002/ijc.31146
    Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.
    Matched MeSH terms: Female; Male
  17. van Dongen MC, Wijckmans-Duysens NEG, den Biggelaar LJ, Ocké MC, Meijboom S, Brants HA, et al.
    Nutrition, 2019 06;62:39-46.
    PMID: 30826598 DOI: 10.1016/j.nut.2018.10.015
    OBJECTIVE: The aim of this study was to develop and validate a comprehensive food frequency questionnaire (FFQ) for The Maastricht Study, a population-based prospective cohort study in Maastricht, The Netherlands.

    METHODS: Item selection for the FFQ was based on explained variation and contribution to intake of energy and 24 nutrients. For validation, the FFQ was completed by 135 participants (25-70 y of age) of the Nutrition Questionnaires plus study. Per person, on average 2.8 (range 1-5) telephone-based 24-h dietary recalls (24HRs), two 24-h urinary samples, and one blood sample were available. Validity of 54 nutrients and 22 food groups was assessed by ranking agreement, correlation coefficients, attenuation factors, and ultimately deattenuated correlation coefficients (validity coefficients).

    RESULTS: Median correlation coefficients for energy and macronutrients, micronutrients, and food groups were 0.45, 0.36, and 0.38, respectively. Median deattenuated correlation coefficients were 0.53 for energy and macronutrients, 0.45 for micronutrients, and 0.64 for food groups, being >0.50 for 18 of 22 macronutrients, 16 of 30 micronutrients and >0.50 for 17 of 22 food groups. The FFQ underestimated protein and potassium intake compared with 24-h urinary nitrogen and potassium excretion by -18% and -2%, respectively. Correlation coefficients ranged from 0.50 and 0.55 for (fatty) fish intake and plasma eicosapentaenoic acid and docosahexaenoic acid, and from 0.26 to 0.42 between fruit and vegetable intake and plasma carotenoids.

    CONCLUSION: Overall, the validity of the 253-item Maastricht FFQ was satisfactory. The comprehensiveness of this FFQ make it well suited for use in The Maastricht Study and similar populations.

    Matched MeSH terms: Female; Male
  18. ul Haq N, Hassali MA, Shafie AA, Saleem F, Farooqui M, Haseeb A, et al.
    BMC Public Health, 2013;13:448.
    PMID: 23641704 DOI: 10.1186/1471-2458-13-448
    Hepatitis-B is a life threatening infection resulting in 0.6 million deaths annually. The prevalence of Hepatitis-B is rising in Pakistan and furthermore, there is paucity of information about Knowledge, Attitude and Practice among Hepatitis-B patients. Better disease related knowledge is important to have positive attitude and that will bring the good practices which will prevent the further spread of infection. This study aimed to evaluate knowledge, attitude and practice of Hepatitis-B Patients in Quetta city, Pakistan.
    Matched MeSH terms: Female; Male
  19. ul Haq N, Hassali MA, Shafie AA, Saleem F, Aljadhey H
    PMID: 22866752 DOI: 10.1186/1477-7525-10-91
    The study aims to assess Health Related Quality of Life (HRQoL) among Hepatitis B (HB) patients and to identify significant predictors of the HRQoL in HB patients of Quetta, Pakistan.
    Matched MeSH terms: Female; Male
  20. den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, et al.
    Am J Hum Genet, 2021 02 04;108(2):346-356.
    PMID: 33513338 DOI: 10.1016/j.ajhg.2021.01.007
    Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
    Matched MeSH terms: Female; Male
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