Portuguese Cohort Research Articles

Predicting factors of neurodevelopmental performance in children with phenylketonuria.

In phenylketonuria (PKU), high phenylalanine (Phe) levels hamper neurodevelopment impairing executive function later in life. While the second has been more studied, fewer data exist on predictors of PKU patients' development in specific populations. To contribute to the field, we performed a retrospective analysis of predictors of neurodevelopment in PKU patients in a Portuguese cohort. We analyzed the retrospective data on the metabolic control of 89 patients, as their health and familial features. Griffith's Mental Development Scale performance at age 6 (GMDS6) was used to assess neurodevelopment. Our cohort included 14 GMDS6low and 75 GMDS6high patients. In a multivariate analysis, the better predictors of neurodevelopment were the metabolic control at age 3 and year of birth (n= 87, β0 = -121, β1 = -1.77, β2 = 0.06, LRchi2(2)=13.61, Prob >chi2=0.001, Pseudo R2=0.1773). With this model, it was possible to define a safety cut-off of 7.8mg/dL for the Phe level at age 3 (sensitivity=72.6%, specificity=78.6%), confirming the safety of the cut-off of 6mg/dL already used in the clinical practice. Our study supports the relevance of metabolic control to predict the neurodevelopment of PKU patients, in the historical context of the disease management.

Next-generation sequencing of 12 obesity genes in a Portuguese cohort of patients with overweight and obesity

We examined 12 monogenic obesity genes in 72 Portuguese individuals with overweight and obesity (class 1 and class 2), some of which with suspected genetic obesity, to identify known or unknown potential obesity variants. Genomic DNA was analyzed for variants in genes LEP, LEPR, MC4R, POMC, PCSK1, BDNF, NTRK2, SIM1, SH2B1, UCP3, GCG and ADCY3 through next generation sequencing (NGS). The impact of the rare variants was investigated in the ClinVar database and using in silico tools for prediction of pathogenicity. Four potential pathogenic missense variants were detected at the heterozygous state in five individuals: two in the ADCY3 gene, NM_004036.5:c.1153G > A (p.Val385Ile) (rs756783003) and NM_004036.5:c.1222G > A (p.Gly408Arg) (rs201606553), one in gene SH2B1, NM_001145795.1:c.127C > A (p.Arg43Ser) (rs547678855), and the fourth in gene POMC NM_000939.4:c.706C > G (p.Arg236Gly) (rs28932472), which was found in two individuals. Moreover, six rare variants near splicing sites were also identified, as well as eight rare synonymous variants. In summary, some potential pathogenic rare missense variants were identified, two of them in ADCY3 gene, the most recently identified gene as having a role in monogenic obesity. Further analysis should be performed to confirm the clinical relevance of these variants.

Height benefit of GnRH agonists after age 8 in a Portuguese cohort of central precocious puberty.

Idiopathic central precocious puberty (iCPP) is common in paediatric endocrinology. Gonadotropin-releasing hormone agonists (GnRHa) are safe, but the effect on final height and the ideal timing for treatment remains controversial. This study aims to assess the effectiveness of GnRHa on growth outcomes in girls with iCPP treated before and after the age of 8 years old. This retrospective longitudinal study evaluated data from Portuguese girls with iCPP who completed treatment between 2010 and 2021. Auxological and clinical characteristics were compared according to age at treatment onset. A cohort of 134 girls with iCPP, was divided into early treatment (ET) (<8 years, n = 48) and later treatment (LT) groups (≥8 years, n = 86). In both groups, most children presented with Tanner II and III. Tanner IV was more frequent in LT group (p = .003).At the end of treatment, predicted adult height increased in both groups (ET p = .032; LT p = .04) and bone age significantly slowed down in all participants (p = .008, p = .034). The height gain was greater in the ET group, but without significant differences (p = .065). Treatment with GnRHa improved final height in all girls with iCPP, even when initiated after 8 years. To achieve better outcomes, treatment should be provided promptly after diagnosis.

Characterization of a late-onset multiple sclerosis Portuguese cohort.

Late-onset multiple sclerosis (LOMS) is defined as the onset of symptoms above 50 years, corresponding to an increasingly recognized subset of MS. This study aimed at comparing demographic and clinical data of patients with LOMS to those of early-onset MS (EOMS) from a Portuguese cohort. Retrospective chart review of an MS cohort from a Portuguese tertiary center. From 746 patients with MS (61.7% female), we identified 39 cases with presentation after 50 years of age (22 males and 17 females), corresponding to 5.3%. The mean age at onset was 55.4 (±5.0) for LOMS and 29.5 (±8.9) for EOMS. There was no significant difference in disease duration. The most common type was relapsing-remitting MS, accounting for 51.5% and 83.9% of LOMS and EOMS patients, respectively. Primary-progressive MS (PPMS) was significantly more represented in the LOMS group (41.0%) (p<0.01). The median EDSS was significantly higher in the LOMS group (4.75, 0.0-7.5) when compared to the EOMS group (2.0, 0.0-9,0). The most frequent presenting feature was myelitis in both LOMS (48.7%) and EOMS patients (47.4%), resulting in significantly higher EDSS (p=0.003). LOMS is associated with higher EDSS when considering the same disease duration, translating into increased disability.

Caries Experience and Risk Indicators in a Portuguese Population: A Cross-Sectional Study.

Oral health surveys are essential for assessing the dental caries experience and to influence national policies. This retrospective cross-sectional study aims to analyze dental caries experience for which dental treatment was sought in a reference university dental hospital at the Lisbon Metropolitan Area between January 2016 and March 2020. Full-mouth examination, and sociodemographic, behavior, and medical information were included. Descriptive analyses and logistic regression analysis were applied to ascertain risk indicators associated with dental caries experience. A final sample of 9349 participants (5592 females/3757 males) were included, aged 18 to 99 years old. In this population, caries experience was 91.1%, higher in female participants. Age (OR = 1.01, 95% CI [1.00-1.02], occupation (OR = 2.94, 95% CI [2.37-3.65], OR = 3.35, 95% CI [2.40-4.67], OR = 2.55, 95% CI [1.66-3.91], for employed, unemployed, and retired, respectively), overweight (OR = 1.52, 95% CI [1.18-1.96]), reporting to have never visited a dentist (OR = 0.38, 95% CI [0.23-0.64], and self-reported week teeth status (OR = 2.14, 95% CI [1.40-3.28]) were identified as risk indicators for the presence of dental caries, according to adjusted multivariable logistic analyses. These results highlight a substantial rate of dental experience in a Portuguese cohort and will pave the way for future tailored oral public health programs in Portugal.

P208 Validation of the IBD-Disk in a Portuguese cohort of patients with inflammatory bowel disease

Abstract Background Inflammatory Bowel Disease-Disability Index (IBD-DI) is a validated tool that was developed for assessing disability and to help clinicians to guide different therapeutic decisions. However, due to its complexity, it is difficult to apply in daily practice. The IBD-Disk is a new shortened adaptation of the IBD-DI, designed to give an immediate representation of disability. However, further investigation is required to validate this tool in clinical practice. The objective of this study was to evaluate the IBD-Disk for its capacity to assess disability in a Portuguese cohort of patients with IBD. Methods In this single-center, cross-sectional observational study, patients with IBD were consecutively recruited between February 2021 to February 2022 from our outpatient department. Both IBD-Disk and IBD-DI were delivered and filled out simultaneously by all included patients. Sociodemographic and clinical data were also collected. Results A total of 258 patients were included, the majority female (51.9%), with a median age of 41 years old (IQR 32-52). There were 184 (71.3%) individuals with Crohn′s disease and 74 (28.7%) with ulcerative colitis (Table 1). The median total score of IBD-Disk was 29.6±24.4 and that of IBD-DI was 23.8±11.2. The item on the IBD-Disk with the highest score was “energy” (4.33±3.5) and the lowest scoring item was interpersonal interactions (1.98±2.8). A significant positive correlation between total scores of IBD-Disk and IBD-DI was identified (r=0.722, p&amp;lt;0.001), with a high Pearson correlation. Regarding the validity per item, there was also a good correlation between both scores. Including all 10 items in the IBD-Disk scale, a value of 0.918 was observed for Cronbach’s alpha, demonstrating a very good homogeneity of IBD-Disk items. Performing the one-at-a-time removal procedure, Cronbach’s alpha varied between 0.905 and 0.915, confirming that all items contribute to the construct. All items showed an item-total correlation coefficient &amp;gt;0.4. Table 2 shows the univariate analysis of clinical factors associated with the IBD-Disk score. Hemoglobin level (p=0.973), serum albumin (p=0.998) and fecal calprotectin (p=0.183) were not associated with the IBD-Disk score. In multivariate analysis, a significant impact of the female sex (β=11.760 [6.117; 17.404], p&amp;lt;0.001), biological therapy (β=9.042 [1.546; 16.539], p=0.018) and perianal surgery (β=12.091 [2.862; 21.320], p=0.010) on the IBD-Disk total score was observed. Conclusion IBD-Disk is a valid and reliable tool for quantifying disability for both Crohn’s disease and ulcerative colitis in clinical practice. It should allow gastroenterologists to rapidly assess a patient’s disability at a given time.

P369 Do teenager and adult onset Crohn′s disease patients have different outcomes? A Portuguese cohort study

Abstract Background Crohn’s disease (CD) is a chronic illness that, according to the age of onset, has disease heterogeneity. Comparing with CD adult-onset (AO), the teenager-onset (TO) may lead to a deeper health impact: late pubertal development and psychosocial problems. There is paucity of data comparing TO with AO in the biologics era. The aim of this single center study was to compare disease characteristics, the use rate and predictive risk factors at diagnosis for CD biologic therapy (anti-TNF) and the rate of CD related surgery Methods Observational study designed as an analysis of a historical cohort: 298 CD patients followed up to 21 years (2000-2021), 49 TO (&amp;lt;20 years-old) and 249 AO (≥20 years-old). Median follow-up was 9 years in TO and 10 years in AO cohort (p=0.792). The data collected included sex, and at diagnosis, age, smoking habits, CD location, CD behaviour, presence of perianal disease and extra intestinal manifestations. The independent effect of significant variables (p&amp;lt;0.05) was assessed using multivariate logistics regression analysis. The cumulative use rate of biologic therapy and CD related surgery were estimated using Kaplan-Meier plots. Results The TO cohort comprised 49 (16.4%) and the AO 249 (83.6%) CD patients. Upper digestive tract involvement and inflammatory behaviour at diagnosis were significantly higher in the TO cohort (p&amp;lt;0.001). Biologic therapy rate was significantly higher in TO than in AO (63.3% vs 43.8%, OR=2.21(95%CI:1.17-4.15), although the time span from diagnosis to the fist biologic use is independent of group (Log-Rank(Mantel-Cox);p=0.812). On multivariate analysis, predictive risk factors at diagnosis for biologic therapy in AO cohort were non-inflammatory phenotype, OR=2.75(95%CI:1.58-4.81), steroid therapy, OR=3.64(95%CI:2.05-6.47) and perianal disease, OR=14.49(95%CI:5.50-38.17); no significant predictive risk factors were identified in the TO cohort. Regarding CD related surgery, there was no significant different rates between the two age groups (18.4% in teens vs 26.1% in adults, OR=0.66(95%CI:0.31-1.45); p=0.300) and the time span from diagnosis to surgery was also independent of group (Log Rank(Mantel-Cox);p=0.204). Conclusion Compared with AO, TO CD has different characteristics and, «per se», is a higher risk for biologics drugs treatment. However, TO CD is not associated with higher risk of surgery.

Monitoring clusterin and fibrillar structures in aging and dementia

Clusterin is involved in a variety of physiological processes, including proteostasis. Several clusterin polymorphisms were associated with an increased risk of developing Alzheimer's disease, the world-leading cause of dementia. Herein, the effect of a clusterin polymorphism, aging and dementia in the levels of clusterin in human plasma were analysed in a primary care-based cohort, and the association of this chaperone with fibrillar structures discussed.64 individuals with dementia (CDR≥1) and 64 age- and sex-matched Controls from a Portuguese cohort were genotyped for CLU rs1136000 polymorphism, and the plasma levels of clusterin and fibrils were assessed.An increased prevalence of the CC genotype was observed for the dementia group, although no significant robustness was achieved. CLU rs11136000 SNP did not significantly change plasma clusterin levels in demented individuals. Instead, clusterin levels decreased with aging and even more in individuals with dementia. Importantly, plasma clusterin levels correlated with the presence of fibrillar structures in Control individuals, but not in those with dementia.This study reveals a significant decrease in plasma clusterin in demented individuals with aging, which related to altered clusterin-fibrils dynamics. Potentially, plasma clusterin and its association with fibrillar structures can be used to monitor dementia progression along aging.

FIB-4 index should guide the referral of patients with Metabolic Syndrome to Gastroenterology – the perspective of a Portuguese cohort

FIB-4 index should guide the referral of patients with Metabolic Syndrome to Gastroenterology – the perspective of a Portuguese cohort

Hospitalizations in Octogenarian Patients with End-Stage Renal Disease: What Changes after Beginning of Hemodialysis?

The benefits of dialysis in the octogenarian are dubious. This study aimed to investigate whether initiation of chronic hemodialysis (HD) changes the rate and duration of hospitalizations in a Portuguese cohort of octogenarian patients.

Validation of the kidney failure risk equation in a Portuguese cohort

IntroductionIn chronic kidney disease (CKD) patients, the risk of kidney replacement therapy (KRT) is highly variable. In 2011, Tangri et al. developed the kidney failure risk equations (KFRE) to predict the 2 and 5-year probability of requiring kidney replacement therapy (KRT). The KFRE is an easily calculated 4-variable equation which has been extensively validated in multiple cohorts. The aim of this study was to validate this risk score in a Portuguese cohort. MethodsWe conducted a retrospective analysis of CKD patients stage 3–5 referred for nephrology consult at Centro Hospitalar Universitário Lisboa Norte during the first 6 months of 2018. Age, gender, estimated glomerular filtration rate (eGFR) and albuminuria were assessed. The 4-variable kidney failure risk equation (KFRE) calibrated to a non-North American population was calculated. Requirement of KRT was assessed in a 2-year follow-up. We assessed the Cox logistic regression method of the KFRE to predict KRT requirement and the discriminatory ability was determined using the receiver operating characteristic (ROC) curve. A cut-off value was defined as that with the highest validity. Results360 patients were included and 54.4% were male. Mean age was 74.9±12.2 years, serum creatinine was 1.97±0.84mg/dL, eGFR was 33.4±12.13ml/min/1.73m2 and albuminuria was 571.1±848.3mg/g. Mean calculated risk score was 6.2±11.2%. Twenty-three patients required KRT (6.4%) in the two-year follow-up. The hazard ratio was 1.1 [95% CI (1.06–1.12), p<0.001] for the 2-year risk of KRT. The KFRE predicted progression to KRT requirement with an auROC of 0.903, [95% CI (0.86–0.95), p<0.001], with a sensitivity 91.3% and specificity of 71.8%. The optimal KFRE cut-off was >4.5% for 2-year nephrologist referral, with an hazard ratio of HR 26.7 [95% CI (6.15–116.3), p<0.001] for 2-year risk of KRT requirement. DiscussionWe have independently externally validated the 2-year KFRE and shown that it has excellent discrimination. The KFRE should be incorporated in clinical care of patients with CKD to improve patient-clinician dialogue and provide guidance on timing of referral for nephrology evaluation and planning for dialysis access.

Liraglutide Effectiveness in Type 2 Diabetes: Insights from a Real-World Cohort of Portuguese Patients.

Liraglutide is a long-acting glucagon-like peptide-1 receptor agonist prescribed to diabetic patients for glycaemic control. To understand the impact of liraglutide in the real-world setting, this study analysed its effects in a Portuguese cohort of Type 2 diabetes patients. This was an observational, multicentric, and retrospective study that included 191 liraglutide-treated patients with at least 12 months of treatment. Patients' data were collected and analysed during a 24-month follow-up period. Overall, liraglutide treatment effectively reduced HbA1c levels from 8.3% to around 7.5%, after 6, 12, and 24 months (p &lt; 0.001). In fact, 38.2%, 37.2%, and 44.8% of patients at 6, 12, and 24 months, respectively, experienced an HbA1c reduction of at least 1%. Moreover, a persistent reduction in anthropometric features was also observed, with 44.0%, 47.6%, and 54.4% of patients achieving a weight reduction of at least 3% at 6, 12, and 24 months, respectively. Finally, significant improvements were observed in the HDL-c and LDL-c levels. Our results demonstrate that liraglutide effectively promoted the reduction of HbA1c values during routine clinical practice, which was sustained throughout the study. In addition, there were significant improvements in anthropometric parameters and other cardiovascular risk factors.

Maturity-onset diabetes of the young in a large Portuguese cohort.

Monogenic forms of diabetes that develop with autosomal dominant inheritance are classically aggregated in the Maturity-Onset Diabetes of the Young (MODY) categories. Despite increasing awareness, its true prevalence remains largely underestimated. We describe a Portuguese cohort of individuals with suspected monogenic diabetes who were genetically evaluated for MODY-causing genes. This single-center retrospective cohort study enrolled patients with positive genetic testing for MODY between 2015 and 2021. Automatic sequencing and, in case of initial negative results, next-generation sequencing were performed. Their clinical and molecular characteristics were described. Eighty individuals were included, 55 with likely pathogenic/pathogenic variants in one of the MODY genes and 25 MODY-positive family members, identified by cascade genetic testing. The median age at diabetes diagnosis was 23years, with a median HbA1c of 6.5%. The most frequently mutated genes were identified in HNF1A (40%), GCK (34%) and HNF4A (13%), followed by PDX1, HNF1B, INS, KCNJ11 and APPL1. Thirty-six unique variants were found (29 missense and 7 frameshift variants), of which ten (28%) were novel. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of its subtypes, leading to more personalized treatment and follow-up strategies.

Brugada syndrome in Portugal: a cohort characterization

Abstract Introduction Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder that can lead to sudden death. Although SCN5A was the first pathogenic associated gene, other potential genes have been described. The relationship between SCN5A, spontaneous type 1 pattern and the predisposition to ventricular arrhythmias is not totally understood. Purpose To characterize mutations in a Portuguese cohort with BrS and explore the genotype-phenotype association in terms of electrocardiographic pattern and arrhythmic risk. Methods Prospective single-center study of patients (pts) with BrS. Genetic test included SCN5A direct sequencing from 2003 a broad panel of 120 genes associated with cardiomyopathies and arrhythmic disorders from 2018. Genetic test results were classified according to pathogenicity: mutations of unknown significance (MUS), mutations potentially pathogenic (MPP) and known pathogenic mutations (KPM). Kaplan-Meyer survival analysis was used to explore the association between genetic test results and the risk of arrhythmic events. Results A total of 94 pts [46±12 years, 67% male,64.9% with type 1 spontaneous pattern] were submitted to genetic testing. No relevant mutations were identified in 68pts and suspicious or pathogenic mutations were recognized in 26pts. The most frequent mutations occurred in SCN5A (N=20,76.9%), and included 8 KPM: 4 in exon 23 (3 of them had the same mutation,c.4018G&amp;gt;A), 2 in exon 26 (c.4534C&amp;gt;T), 1 in exon 28 and 1 in exon 16. All MPP in SCN5A occurred either in exon 23 or 28. Considering MUS, different mutations were described in 6 different exons (8,15,18,23,25 and two in 28). Additionally, 6 pts presented MUS in other genes: SCN10A (N=2), ANK2 (N=2), SFM13A, CAV2 (associated with long QT), CACNA1D and PXDNL. We found no differences in the prevalence of spontaneous type 1 pattern considering gene mutation or mutation pathogenicity. A non-significant trend to higher arrhythmic risk was observed in pts presenting genetic mutations (either KPM, MPP or MUS), Long-Rank: 1.743, p=0.187. Conclusion Gene mutations are identified in a minority of BrS pts, mostly at SCN5A gene. No association was noticed between genetic test results and the ECG pattern. However, pts with identified mutation presented a tendency to higher arrhythmic risk. At present time, genetic tests in BrS are only relevant for familial screening, but long-term collection of data is crucial to elucidate the genotype-phenotype relation and arrhythmic risk. Funding Acknowledgement Type of funding sources: None.

Utility-driven assessment of anonymized data via clustering

In this study, clustering is conceived as an auxiliary tool to identify groups of special interest. This approach was applied to a real dataset concerning an entire Portuguese cohort of higher education Law students. Several anonymized clustering scenarios were compared against the original cluster solution. The clustering techniques were explored as data utility models in the context of data anonymization, using k-anonymity and (ε, δ)-differential as privacy models. The purpose was to assess anonymized data utility by standard metrics, by the characteristics of the groups obtained, and the relative risk (a relevant metric in social sciences research). For a matter of self-containment, we present an overview of anonymization and clustering methods. We used a partitional clustering algorithm and analyzed several clustering validity indices to understand to what extent the data structure is preserved, or not, after data anonymization. The results suggest that for low dimensionality/cardinality datasets the anonymization procedure easily jeopardizes the clustering endeavor. In addition, there is evidence that relevant field-of-study estimates obtained from anonymized data are biased.

MODY probability calculator utility in individuals' selection for genetic testing: Its accuracy and performance.

IntroductionMODY probability calculator (MPC) represents an easy‐to‐use tool developed by Exeter University to help clinicians prioritize which individuals should be oriented to genetic testing. We aimed to assess the utility of MPC in a Portuguese cohort with early‐onset monogenic diabetes.MethodsThis single‐centre retrospective study enrolled 132 participants submitted to genetic testing between 2015 and 2020. Automatic sequencing and, in case of initial negative results, generation sequencing were performed. MODY probability was calculated using the probability calculator available online. Positive and negative predictive values (PPV and NPV, respectively), accuracy, sensitivity and specificity of the calculator were determined for this cohort.ResultsSeventy‐three individuals were included according to inclusion criteria: 20 glucokinase (GCK‐MODY); 16 hepatocyte nuclear factor 1A (HNF1A‐MODY); 2 hepatocyte nuclear factor 4A (HNF4A‐MODY) and 35 DM individuals with no monogenic mutations found. The median probability score of MODY was significantly higher in monogenic diabetes‐positive subgroup (75.5% vs. 24.2%, p < .001). The discriminative accuracy of the calculator, as expressed by area under the curve, was 75% (95% CI: 64%–85%). In our cohort, the best cut‐off value for the MODY calculator was found to be 36%, with a PPV of 74.4%, NPV of 73.5% and corresponding sensitivity and specificity of 76.2% and 71.4%, respectively.ConclusionsIn a highly pre‐selected group of probands qualified for genetic testing, the Exeter MODY probability calculator provided a useful tool in individuals' selection for genetic testing, with good discrimination ability under an optimal probability cut‐off of 36%. Further geographical and population adjustments are warranted for general use.

Prevalence of Adverse Childhood Experiences in the First Decade of Life: A Study in the Portuguese Cohort, Generation XXI.

Adverse childhood experiences (ACEs) are a modifiable risk factor for diseases throughout life. This study estimates the prevalence of ACEs in children, addressing associated sociodemographic characteristics and examining the relationship of ACEs with the child’s health and behaviors. We used information on 5295 participants at 10 years old, of the birth cohort Generation XXI, established in Porto, Portugal. Children answered a self-administered questionnaire on ACEs, based on the original ACEs study. Principal component analysis was used to group correlated ACEs, and a score was computed to assess their cumulative effect. Overall, 96.2% of children reported having been exposed to at least one ACE. The most prevalent ACE was a household member shouting, yelling, or screaming at the child (57.7%). Boys were more likely than girls to report “abuse”, “school problems”, and “death/severe disease”. Low parental education, income, and unemployment were associated with an increased risk of “school problems”, “death/severe disease”, and “household dysfunction”. We observed that the dimensions of ACEs could be identified at 10 years of age. A disadvantaged socioeconomic environment was associated with dimensions of ACEs. These data illustrate the natural history of dimensions of ACEs and their potential social patterning.

Exome Sequencing of a Portuguese Cohort of Frontotemporal Dementia Patients: Looking Into the ALS-FTD Continuum.

IntroductionFrontotemporal dementia (FTD) is considered to be part of a continuum with amyotrophic lateral sclerosis (ALS). Many genes are associated with both ALS and FTD. Yet, many genes associated with ALS have not been shown to cause FTD. We aimed to study a Portuguese cohort of FTD patients, searching for variants in genes associated with both FTD and/or ALS.MethodsWe included 57 thoroughly characterized index FTD patients from our memory clinic, who were not carriers of pathogenic variants in GRN, MAPT or C9orf72. We performed exome sequencing and 1) prioritized potential FTD and ALS causing variants by using Exomiser to annotate and filter results; and 2) looked specifically at rare variability in genes associated with FTD (excluding GRN, MAPT and C9ORF72) and/or ALS.ResultsWe identified 13 rare missense variants in 10 patients (three patients had two variants) in the following genes: FUS, OPTN, CCNF, DCTN1, TREM2, ERBB4, ANG, CHRNA4, CHRNB4 and SETX. We found an additional frameshift variant on GLT8D1 in one patient. One variant (ERBB4 p.Arg1112His) gathered enough evidence to be classified as likely pathogenic by the ACMG criteria.DiscussionWe report, for the first time, an expanded study of genes known to cause FTD-ALS, in the Portuguese population. Potentially pathogenic variants in ERBB4, FUS, SETX, ANG, CHRNA4 and CHRNB4 were identified in FTD patients. These findings provide additional evidence for the potential role of rare variability in ALS-associated genes in FTD, expanding the genetic spectrum between the two diseases.

Whole-Exome Sequencing Targeting a Gene Panel for Sensorineural Hearing Loss: The First Portuguese Cohort Study

Next-generation sequencing (NGS) technologies revolutionized the molecular diagnosis of sensorineural hearing loss (SNHL) and are now a standard of care. In this study, 71 Portuguese probands with hereditary SNHL were assessed by whole-exome sequencing (WES) targeting a panel of 158 genes related to SNHL, aiming to evaluate the diagnostic yield of this methodological approach and to report the spectrum of variants. Patients with either nonsyndromic or syndromic SNHL were included. Also, patients were previously screened for variants in the GJB2 gene and for duplications/deletions in the GJB6 gene. Causative variants in 11 different genes were identified in 15 (21.1%) out of 71 probands, 5 of which had associated syndromes. In 6 other patients (8.5%), presumptive causative variants were identified in MYO15A, TMIE, TBC1D24, SPMX, GJB3, PCDH15, and CDH23 genes, uncovering a potential case of digenic Usher syndrome. The study was inconclusive in 20 probands (28.2%), in 19 due to lack of segregation analysis and in one due to uncertain phenotype-genotype matching. In the remaining 30 patients (42.3%) no potentially causative variants were identified. The diagnostic yield did not significantly vary according to the age of hearing-impairment onset. As the first study on the application of NGS technologies in SNHL based on a Portuguese cohort, our results may contribute to characterize the spectrum of variants related to SNHL in the Portuguese population. Additionally, the present study provides new insights into the contribution of MYO3A, TECTA, EDNRB, TBC1D24, and GJB3 genes to SNHL. For the significant number of undiagnosed patients, reanalysis of WES data – either for a broader gene panel or in a non-targeted approach – may be considered.

Efficacy of radioactive iodine treatment in Graves Disease using a calculated 131I dose and predictive factors of success in a Portuguese cohort

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)