Phenotypic Characteristics Of Patients Research Articles

Phenotypic/Genotypic Profile of Children with Neuronal Ceroid Lipofuscinosis in Southern Brazil

Abstract Introduction Neuronal ceroid lipofuscinoses (CLNs) are a group of lysosomal storage disorders of genetic origin, characterized by progressive neurodegeneration and intracellular accumulation of autofluorescent lipopigment. Thirteen genes related to CLNs are currently described, showing genetic and allelic heterogeneity, most of them with an autosomal recessive pattern. Due to the few descriptions of cases related to CLNs in Brazil, it is necessary to describe the phenotypic and genotypic characteristics of these patients. This study aims to evaluate the genotypic profile and correlate it with the phenotypic characteristics of patients with CLN in a children's hospital. Methods This study was performed as a descriptive cross-sectional study with analysis of medical records, imaging, and laboratory tests of patients who had a confirmed molecular diagnosis of CLN. Results The sample consisted of 11 patients from nine families with different subtypes of CLNs (CLN2, 5, 6, 7, and 8), with CLN2 being the most prevalent in the study. A total of 16 mutation variants were identified in genes associated with the five CLNs described in this study, with typical and atypical clinical phenotypes depending on the subtype and its variants. Conclusion Novel mutations identified in the patients in this study showed phenotypes of rapid and severe progression in the CLN2 patient and similar characteristics in CLN6 and CLN7 patients, as previously described in the literature.

P031 Determining the genotypic and phenotypic characteristics of patients in the Turkish National Cystic Fibrosis Registry System

P031 Determining the genotypic and phenotypic characteristics of patients in the Turkish National Cystic Fibrosis Registry System

GENETIC ETIOLOGY AND CLINICAL FEATURES OF ACHROMATOPSIA IN JAPAN.

To ascertain the characteristics of achromatopsia (ACHM) in Japan by analyzing the genetic and phenotypic features of patients with ACHM. The medical records of 52 patients from 47 Japanese families who were clinically diagnosed with ACHM were reviewed in this retrospective observational study. Thirty-six causative variants of ACHM were identified in 26 families via whole-exome sequencing: PDE6C (12 families), CNGA3 (10 families), CNGB3 (two families), and GNAT2 (two families). However, none of the 6 causative variants that are known to cause ACHM, or the 275 other genes listed in RetNet, were observed in 19 families. A significant trend toward older age and worsening of ellipsoid zone disruption on optical coherence tomography images was observed (P < 0.01). Progressive ellipsoid zone disruptions were observed in 13 eyes of seven patients during the follow-up visits. These patients harbored one or more variants in PDE6C. The ACHM phenotype observed in this study was similar to those observed in previous reports; however, the causative gene variants differed from those in Europe. The low identification ratio of causative genes in whole-exome sequencing suggests the presence of unique hotspots in Japanese patients with ACHM that were not detectable via ordinal whole-exome sequencing.

СВЯЗЬ ЦИРКУЛИРУЮЩИХ УРОВНЕЙ АМИНОКИСЛОТ С РАЗВЕТВЛЕННОЙ ЦЕПЬЮ У ПАЦИЕНТОВ С ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ С НАЛИЧИЕМ НАРУШЕНИЙ УГЛЕВОДНОГО ОБМЕНА

The importance of the problem of chronic heart failure (CHF) is hard to overestimate: this syndrome is diagnosed in millions of patients around the world and its prevalence continues to grow. The proportion of patients suffering from carbohydrate metabolism disorders (CMD) is also steadily increasing. The close connection between carbohydrate metabolism disorders and the progression of CHF allowed such patients to be classified into a separate phenotype cluster - the “metabolic phenotype of CHF”. The pathophysiology of the “metabolic phenotype of CHF” is based on significant metabolic disorders, which determines the characteristic features of the metabolome of this cohort of patients. Therefore, the purpose of this work is to compare and evaluate the relationship between metabolites that occupy one of the most important places in the metabolic processes of the body - the levels of branched chain amino acids (BCAA) and the phenotypic characteristics of patients with CHF. The study included 218 patients: 133 patients of the main group suffering from CHF and having CMD; comparison group - 85 patients with CHF without CMD. The groups were comparable by gender (p=0,324) and age (p=0,936). The levels of BCAAs - leucine, isoleucine, valine - in the blood plasma of patients were assessed by high-performance liquid chromatography combined with mass spectrometry (HPLC-MS). Based on the results of the analysis, the following data were obtained: plasma levels of valine and leucine in patients with CHF and CMD were higher (p=0,022 and p&lt;0,001, respectively) than in patients with CHF and normal carbohydrate metabolism. A direct relationship between the level of leucine + isoleucine and the concentration of glucose (r=0,3, p&lt;0,001) and an inverse relationship between the plasma concentration of valine and the level of N-terminal propeptide of natriuretic hormone (NTproBNP) (r=-0,388, p&lt;0,001) were found. It has been established that a high level of tissue insulin resistance in patients is associated with increased concentrations of BCAA. The results indicate the important role of BCAA in the pathogenesis of the “metabolic phenotype of CHF,” which requires further research in this direction.

Comprehensive analyses of phenylalanine hydroxylase variants and phenotypic characteristics of patients in the eastern region of Türkiye.

Phenylalanine hydroxylase (PAH) is predominantly a hepatic enzyme that catalyzes phenylalanine (Phe) into tyrosine, which is the rate-limiting step in Phe catabolism. Biallelic variants in the PAH gene cause PAH enzyme deficiency. Phenylketonuria (PKU) is an autosomal recessive disorder that causes neurologic, behavioral, and dermatological findings. PKU could be divided clinically into three types based on the blood Phe levels: classic phenylketonuria (cPKU), mild-moderate phenylketonuria (mPKU), and mild hyperphenylalaninemia (MHP). This study aimed to determine the phenotypic and genotypic characteristics of Turkish PKU patients in the eastern region of Türkiye. Demographic characteristics, serum Phe levels, treatments, and PAH variants of 163 patients with PKU and hyperphenylalaninemia (HPA) were retrospectively evaluated. Blood Phe levels of the patients were analyzed with the high-performance liquid chromatography method. For PAH gene analysis, next-generation sequencing was performed. Of the 163 patients included in the study, 38 (23.3 %) had cPKU, 16 (9.8 %) had mPKU, and 109 (66.9 %) had MHP. Homozygous variants in the PAH gene were detected in 66 (40.5 %) of the patients, while compound heterozygous variants were detected in 97 (59.5 %) patients. Two novel and 35 recurrent variants in the PAH gene were detected. Of the twonovel variants, one was missense (p.Phe351Leu) and the other was frameshift (p.Met276Cysfs*65). The most frequently detected variants were p.Thr380Met (18 %), p.Arg261Gln (16.8 %), and p.Ala300Ser (12.8 %). All patients with the homozygous c.1066-11G>A variant exhibited cPKU phenotype. The c.898G>T (p.Ala300Ser), c.1139C>T (p.Thr380Met), and c.1208C>T (p.Ala403Val) variants were statistically related to mild phenotype. On the other hand, c.592_613del (p.Tyr198Serfs*136), c.1028A>G (p.Tyr343Cys), and c.782G>A (p.Arg261Gln) variants were more frequently detected in the cPKU group. Our study, conducted with patients from the eastern region of Türkiye, demonstrates the genetic heterogeneity in the Turkish population. Simultaneously, our research contributes to genotype-phenotype correlation and expands the genotypic spectrum by identifying novel variants.

Phenotypic characteristics of patients with chronic widespread pain and fibromyalgia: a cross-sectional cluster analysis

Objective This study aimed to explore whether phenotypic characteristics of patients with chronic widespread pain (CWP) and fibromyalgia (FM) can be aggregated into definable clusters that may help to tailor treatments. Method Baseline variables (sex, age, education, marital/employment status, pain duration, prior CWP/FM diagnosis, concomitant rheumatic disease, analgesics, tender point count, and disease variables derived from standardized questionnaires) collected from 1099 patients (93.4% females, mean age 44.6 years) with a confirmed CWP or FM diagnosis were evaluated by hierarchical cluster analysis. The number of clusters was based on coefficients in the agglomeration schedule, supported by dendrograms and silhouette plots. Simple and multiple regression analyses using all variables as independent predictors were used to assess the likelihood of cluster assignment, reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results Only one cluster emerged (Cluster 1: 455 patients). Participants in this cluster were characterized as working (OR 66.67, 95% CI 7.14 to 500.00), with a medium-term/higher education (OR 16.80, 95% CI 1.94 to 145.41), married/cohabiting (OR 14.29, 95% CI 1.26 to 166.67), and using mild analgesics (OR 25.64, 95% CI 0.58 to > 999.99). The odds of being an individual in Cluster 1 were lower when having a worse score on the PDQ (score ≥ 18) (OR < 0.001, 95% CI < 0.001 to 0.02). Conclusion We identified one cluster, where participants were characterized by a potentially favourable clinical profile. More studies are needed to evaluate whether these characteristics could be used to guide the management of patients with CWP and FM.

Frailty in rheumatoid arthritis: prevalence, fenotype signs and associated factors

The aim – to establish the frequency of frailty and the ratio of its main phenotypic features in patients with rheumatoid arthritis (RA), as well as to identify associated factors. Material and methods. The study included 101 patients (86 women and 15 men) with RA at the age of 60 [52; 66] years; the average duration of the disease – 8 [3; 15] years. Frailty syndrome was diagnosed by the phenotypic model of L.P. Fried et al. In addition, the strength of the quadriceps femoris muscle was assessed using the test of getting up from a chair, functional status according to HAQ-DI (Health Assessment Questionnaire – Disability Index); Charlson comorbidity index, presence of cardiovascular disease (CVD); dementia severity and nutritional status. Factors associated with frailty were identified by the principal component method with the rotation of the correlation matrix using the Varimax raw method. Results. Frailty syndrome was detected in 40.6%, prefrailty in 55.4% of patients with RA, robust patients were 4.0%. The dominant signs of frailty in RA patients are reduced hand strength, fatigue, and weight loss. Four clusters of factors associated with frailty syndrome in RA have been identified: reduced hand strength, HAQ-DI impairment, and RA activity; reduced survival, comorbid cardiovascular disease and age; the total dose of glucocorticoids (GC) taken, an increase in walking time by 4 m and hypodynamia; eating disorders. Conclusion. Frailty and prefrailty dominate in patients with RA and have certain phenotypic features. Factors associated with frailty and it’s diagnostic features include impairment of vital activity, RA activity; premature mortality, CVD comorbidity, older age; taking GCS and malnutrition.

Genotypic And Phenotypic Features of Patients with GJB1 Mutations: Single Center Experience (P11-8.003)

<h3>Objective:</h3> To describe the clinical and genetic characteristics of patients with <i>GJB1</i> mutations in Turkey. <h3>Background:</h3> <i>GJB1</i> mutations are the most common cause of X-linked Charcot-Marie-Tooth (CMT) disease. Typical manifestation includes distal muscle weakness and atrophy in the lower limbs. On the other hand, additional clinical features, such as stroke-like episodes, vocal cord paralysis, and hearing loss, can be observed. <h3>Design/Methods:</h3> Herein, we evaluated the clinical and genetic features of 29 patients from 23 unrelated families with <i>GJB1</i> mutation at the Neuromuscular Unit of the Istanbul Faculty of Medicine, Istanbul University. <h3>Results:</h3> Eight patients were female. The mean age of onset was 19.0 ± 12.0 (between 3 and 53 years). Females (27.3 ± 13.2) had later disease onset than males (15.4 ± 11.4). The most common presenting symptom was distal muscle weakness and foot deformities (21 patients), followed by foot pain (4 patients) and hand tremor (3 patients). Family history was absent in six patients. Two patients had immunosuppressive treatment for a misdiagnosis of inflammatory neuropathy. In neurological examination, all but two female patients had distal weakness in the lower extremities, and 24 had upper extremity weakness. The most frequent skeletal deformity was pes cavus (25 patients), followed by hammer toes (16 patients). Nine patients had hand tremor, and one had vocal cord paralysis. One patient had a history of stroke-like episodes, and one had multiple-sclerosis like cranial and spinal cord MRI lesions. In a mean disease duration of 22.5 ± 14.6 years all patients were ambulatory. The mean median motor nerve conduction velocity was 36.5 ± 8.2, consistent with intermediate-type CMT disease. Eighteen different mutations were identified in the <i>GJB1</i> gene. <h3>Conclusions:</h3> Our patients exhibited diverse phenotypic features regarding the disease onset and additional symptoms. Moreover, genotypic features were also heterogeneous, considering the identified mutations were scattered throughout the gene. <b>Disclosure:</b> Dr. Parman has nothing to disclose. Arman Cakar has nothing to disclose. Ayse Candayan has nothing to disclose. Dr. Durmus has nothing to disclose. Esra Battaloglu has nothing to disclose.

A Retrospective Analysis of Clinically Focused Exome Sequencing Results of 372 Infants with Suspected Monogenic Disorders in China.

The context was designed to optimize the diagnostic utility of clinically focused exome sequencing (CFES) and shorten the diagnostic odyssey among pediatric patients suspected of monogenic disorders (MDs). Here, we retrospectively analyzed the clinical notes of 372 patients from different areas in the Jiangxi province that were referred for a diagnostic CFES and analysis from June 2018 to March 2022 with symptoms suggestive of MDs. In our study, preliminary tests using the proband-only clinical exome sequencing as a cost-effective first-tier diagnostic test for pediatric patients with unidentified MDs, supplemented by family segregation studies for targeted variants when indicated. Probands with confirmed diagnostic (CD) or likely diagnostic (LD) genetic influences accounted for 12% of all cases, whereas those with an uncertain diagnosis accounted for 48%. We also found that systemic primary carnitine deficiency (CDSP) (SLC22A5 gene) and phenylketonuria (PAH gene) were relatively more prevalent, and these patients with CDSP had the most frequent c.1400C > G variant (p.S467C) and c.51C > G variant (p. F17L) in this study. In addition, statistical analysis revealed that the estimates of diagnostic yields varied across certain phenotypic features of patients, and patients with specific phenotypic traits tended to benefit more from CFES. The CFES may be a first-line genetic test for diagnosing young children with suspected genetic conditions, as it validates the identification of molecular genetics alterations and facilitates comprehensive medical management. Moreover, we found that infants exhibiting metabolism/homeostasis abnormalities, craniofacial /otolaryngology/ ophthalmologic abnormalities, and/or the integument were significantly more likely to receive a genetic diagnosis via CFES than infants without such features. However, due to the current study's low diagnostic yield and inherent limitations, high-quality clinical studies with larger sample sizes are still needed to provide more likely results and confirm our findings.

Coexistent diabetes is associated with the presence of adverse phenotypic features in patients with hypertrophic cardiomyopathy

Abstract Background Type 2 diabetes mellitus (DM) is associated with worsened clinical outcomes in hypertrophic cardiomyopathy (HCM) patients. The reasons for this adverse prognostic association are incompletely understood. Although distinct entities both HCM and DM share common features of impaired myocardial energetics and coronary microvascular function. Purpose We sought to test the hypothesis that co-existent diabetes is associated with greater reductions in myocardial energetics and perfusion, and higher scar burden in HCM. Research design and methods Seventy-five age- and sex-matched participants with concomitant HCM and DM (HCM-DM, n=20), isolated HCM (n=20), isolated DM (n=20) and healthy volunteers (HV, n=15) underwent 31phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance imaging. The HCM groups were matched for HCM phenotype. The DM groups were matched for diabetes treatment, duration, HbA1c, body mass index and hypertension comorbidity. Results ESC sudden cardiac death risk scores were comparable between the HCM groups (HCM: 2.2±1.5%, HCM-DM: 1.9±1.2%; p=NS) and sarcomeric mutations were equally common. HCM-DM had the highest NT-proBNP levels (HV: 42 ng/L [IQR: 35–66], DM: 118 ng/L [IQR: 53–187], HCM: 298 ng/L [IQR: 157–837], HCM-DM: 726 ng/L [IQR: 213–8695]; p&amp;lt;0.0001). Left-ventricular ejection fraction, mass and wall thickness were similar between the HCM groups. HCM-DM displayed a greater degree of fibrosis burden with higher scar percentage, and lower global longitudinal strain compared to the isolated HCM. PCr/ATP was similarly decreased in the HCM-DM and DM (HV: 2.17±0.49, DM: 1.61±0.23, HCM: 1.93±0.38, HCM-DM: 1.54±0.27; p=0.0003). HCM-DM had the lowest stress myocardial blood flow (HV: 2.06±0.42 ml/min/g, DM: 1.78±0.45 ml/min/g, HCM: 1.74±0.44 ml/min/g, HCM-DM: 1.39±0.42 ml/min/g; p=0.004). Conclusions We show for the first time that HCM patients with DM comorbidity display greater reductions in myocardial energetics, perfusion, contractile function and higher myocardial scar burden and serum NT-proBNP levels compared to patients with isolated HCM despite similar LV mass and wall thickness and presence of sarcomeric mutations. These adverse phenotypic features may be important components of the adverse clinical manifestation attributable to a combined presence of HCM and DM. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Diabetes UK

CLINICAL, EPIDEMIOLOGICAL AND IMMUNOLOGICAL ASPECTS IN AUTOIMMUNE HEPATITIS

"The typical phenotype of autoimmune hepatitis (AIH) is well recognized, but special subforms such as AIH with sero-negativity for autoantibodies, severe and acute forms of AIH, forms that have concomitant features of primary biliary cirrhosis or occur in the context of other liver diseases, making diagnosis and therapy a challenge for the clinician. The objective of this study was the complex analysis in terms of clinical and phenotypic characteristics of patients with AIH diagnosed at the County Clinical Emergency Hospital of Craiova, between November 2015 and September 2019. In order to carry out this study, we set the following specific objectives: • Determining the demographic and clinical characteristics of patients diagnosed with AIH compared to a group of patients diagnosed with chronic viral hepatitis C (CHC), in terms of age of onset, location, severity of inflammatory lesions and intestinal and extra-intestinal complications; • Evaluation of the biochemical profile in the studied groups by dosing the serum levels of liver enzymes such as transaminases [Aspartate-amino-transferase (AST), Alanine-amino-transferase (ALT), total bilirubin (TBIL), γ-glutamyl-transpeptidase (γ-GT), alkaline phosphatase (ALP)], and total γ-globulins (IgG, IgM, IgA)]; • Evaluation of the serological profile of patients with AIH by determining the presence of autoantibodies [ANA, anti-SMA, anti-soluble-liver-antigen (anti-SLA) antibodies, anti-liver kidney microsomal type 1 (anti-LKM-1) antibodies, anti-liver cytosol antigen type 1 (anti-LC1) antibodies, anti-mitochondrial antibodies (AMA)]. In our study we obtained the following patient profile: female patient, from an urban areas, aged at the time of diagnosis in the decade of age 45-55 years, with sero-positivity for antinuclear autoantibodies (ANA), with elevated levels of liver enzymes, accompanied by polyclonal hyper-gamaglobulinemia (IgG)."

Coexistent Diabetes Is Associated With the Presence of Adverse Phenotypic Features in Patients With Hypertrophic Cardiomyopathy.

OBJECTIVEType 2 diabetes mellitus (T2DM) is associated with worsened clinical outcomes in hypertrophic cardiomyopathy (HCM) patients. We sought to investigate whether HCM patients with T2DM comorbidity exhibit adverse cardiac alterations in myocardial energetics, function, perfusion, or tissue characteristics.RESEARCH DESIGN AND METHODSA total of 55 participants with concomitant HCM and T2DM (HCM-DM) (n = 20) or isolated HCM (n = 20) and healthy volunteers (HV) (n = 15) underwent 31P-MRS and cardiovascular MRI. The HCM groups were matched for HCM phenotype.RESULTSMean ± SD European Society of Cardiology sudden cardiac death risk scores were comparable between the HCM groups (HCM 2.2 ± 1.5%, HCM-DM 1.9 ± 1.2%; P = not significant), and sarcomeric mutations were equally common. HCM-DM patients had the highest median NT-proBNP levels (HV 42 ng/L [interquartile range 35–66], HCM 298 ng/L [157–837], HCM-DM 726 ng/L [213–8,695]; P < 0.0001). Left ventricular (LV) ejection fraction, mass, and wall thickness were similar between the HCM groups. HCM-DM patients displayed a greater degree of fibrosis burden with higher scar percentage and lower global longitudinal strain compared with HCM patients. PCr/ATP (the relative concentrations of phosphocreatine and ATP) was significantly lower in the HCM-DM group than in both HCM and HV (HV 2.17 ± 0.49, HCM 1.93 ± 0.38, HCM-DM 1.54 ± 0.27; P = 0.002). In a similar pattern, stress myocardial blood flow was significantly lower in the HCM-DM group than in both HCM and HV (HV 2.06 ± 0.42 mL/min/g, HCM 1.74 ± 0.44 mL/min/g, HCM-DM 1.39 ± 0.42 mL/min/g; P = 0.002).CONCLUSIONSWe show for the first time that HCM-DM patients display greater reductions in myocardial energetics, perfusion, and contractile function and higher myocardial scar burden and serum NT-proBNP levels compared with patients with isolated HCM despite similar LV mass and wall thickness and presence of sarcomeric mutations. These adverse phenotypic features may be important components of the adverse clinical manifestation attributable to a combined presence of HCM and T2DM.

Phenotypic characteristics of patients with arrhythmogenic left ventricular cardiomyopathy and sustained ventricular tachycardias

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The Padua criteria proposed for the diagnostic approach to Arrhythmogenic Cardiomyopathy (AMC) introduced new diagnostic criteria to recognize patients with a phenotype of the left ventricular variants of AMC (ALVC). Unlike ARVC, the arrhythmogenicity of this left phenotype has not yet been established. Objectives This study aims to analyze the phenotypic characteristics in a group of patients with ALVC and ventricular arrhythmias (VA). Methods Thirty-seven related patients with ALVC and VA were included and these were evaluated at the Inherited Cardiac Disease Unit of a Tertiary Hospital. Results Between 2000 and 2021, a total of 207 patients were diagnosed with ALVC. Thirty-seven patients (18%) presented VA; 25 ( 67%) sustained ventricular tachycardia (SVT), 10 ( 27 %) non sustained ventricular tachycardia (NSVT) and 2 ventricular fibrillation (VF). Eighteen 18/37 (49%) biventricular and 19/37 (51%) dominant . Twenty-five, 67 % male, aged 41.8 ± 13.4 years. A genetic study was performed in 36 ( 97%), and the pathogenic mutations were identified in desmoplakin in eighteen, plakophilin-2, desmoglein-2 and phospholamb in three, titin and filamine in two; desmin, plakoglobin and lamin A in one. There was one variant of uncertain significance in desmocollin-2, desmoplakin and titin. A low amplitude QRS voltages (LAQRS) in limb leads was present in 14/33 patients . Inverted T waves in right (V1-V3) in 4/33 patients and in left precordial (V4-V6) were present in 9/33 patients. The average left ventricular ejection fraction (LVEF) was 41%± 14 and myocardial fibrosis evidenced by contrast-enhanced CMR as LGE was presented in 22 patients. Ventricular arrhythmias with a right bundle branch block (RBBB) morphology were most frequent (7/12 ), denoting the origin from LV. All VT with LBBB morphology appeared in biventricular cases (5/12). Reverse pattern break was present in three patients. EAM showed bipolar or unipolar endocardial scar left ventricle in 6/10 and bipolar or unipolar endocardial scar right ventricle in 3/10 patients. Epicardial scar was present in 4 patients ( 3 LV, 2 RV). An implantable cardioverted defibrillator (ICD) therapy was performed in 25 patients for primary or secondary prevention of sudden death. Heart transplantation was carried out for three patients. Conclusions A substancial number of patients with ALVC have presented ventricular arrhythmias. Ventricular arrhythmias with a right bundle branch block (RBBB) morphology were the most frequent. All of VT with LBBB morphology appeared in biventricular cases. The mutation in DSP was the most prevalent in patients with ALVC and VT. Patients with ALVC and VA are characterized by a ventricular function that is not significantly impaired; however, fibrosis in LGE is widespread.

Delineation of dual molecular diagnosis in patients with skeletal deformity

BackgroundSkeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities.ResultsFrom 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700).ConclusionsThis study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.

Primary ciliary dyskinesia in Volendam: Diagnostic and phenotypic features in patients with a CCDC114 mutation.

Primary ciliary dyskinesia (PCD) is a heterogeneous disease, with impaired mucociliary clearance causing respiratory tract infections. A founding CCDC114 mutation has led to a relatively homogeneous and large Dutch PCD population in Volendam. Our aim was to describe their phenotype. Therefore, all Volendam PCD patients seen at the Amsterdam UMC were included in this study. Data were collected on lung function, microbiology, radiology, and ear‐nose‐throat (ENT) symptoms. A mixed effects model estimated lung function decline in %point per year (95% confidence interval [CI]). Thirty‐three (60%) out of approximately 56 Volendam PCD patients were treated at our center and included in this study. Only 30% of patients had situs inversus. FEV1 declined in children (−1.43%/year, CI: −1.80/−1.05), but not in adults (0.01%/year, CI: −0.36/0.38). Pseudomonas aeruginosa was cultured in 21% of children and 60% of adults, respectively. Patients who have been infected at some point with P. aeruginosa had a steeper decline in FEV1 as compared to patients that have never been infected. Neonatal symptoms (79%) and ENT problems (94%) were common; fertility issues however, were not (11%) common. Compared to other PCD cohorts, the Volendam/CCDC114 patients have a moderately severe phenotype with lung function decline predominantly occurring in childhood.

Abstract 46: Karyotype and phenotype correlation in Turner syndrome in South India

Background: Phenotypic and karyotypic features of Turner syndrome (TS) varies significantly which leads to challenges for the clinicians in diagnosis and management. There are only few committed studies from India regarding TS. This current study analyzes karyotype – phenotype differences among patients with TS.Objectives: To assess the correlation between karyotype and phenotypic features in patients with TS.Methods: This is a cross sectional study of 10 patients diagnosed with Turner syndrome (Jan 2021–Nov 2021). These patients were divided into 4 groups according to their karyotype: Classic (45X, Mosaics (45,X/46,XX), IsochromosomeXq (46,X,iXq and 45,X/46,X,iXq mosaics), others (45,X/46,XY mosaics and structural defects), and analyzed for various phenotypic features.Results: Majority (40%) had classic karyotype followed by mosaic Turner (30%), isochromosomeXq (20%). Age at diagnosis was 16.7 ± 2.5 years, with 8 girls were adolescence and 2 were adult at diagnosis. Short stature and delayed puberty were the most common presenting feature (100%). Cardiac anamoly and renal anamoly were most commonly seen in classic TS (1/10, 10%). Subclinical hypothyroidism (SCH) occurred in patient with classic Turner (1/4, 25%) and patient with isochromosomeXq (1/2, 50%).Conclusion: A significant proportion of girls presented with short stature and or delayed puberty have TS. Phenotypic features including renal malformations, cardiac disease, and dysmorphic features are more prevalent in Classic TS and correlated with degree of X chromosome loss. Thyroid disorders were more common in TS with isochromosomeXq. Mean age at diagnosis of TS is relatively late, a situation which could be improved by providing appropriate awareness among general practitioners and school teachers.

Abstract 11337: Sensitivity Analysis of an Electronic Health Record-Based Algorithm to Facilitate Detection of Familial Hypercholesterolemia: Results in Genetically Confirmed Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder resulting in elevated LDL-C levels and increased risk of cardiovascular disease. Algorithms have been developed to facilitate FH detection. We previously developed a continuous, electronic health record (EHR)-based algorithm using the Dutch Lipid Clinical Network (DLCN) criteria, with automated correction of LDL-C levels for use of lipid-lowering-therapy (LLT). In this study, we performed a sensitivity analysis of the algorithm in patients with previously genetically confirmed FH. Methods: We selected all patients with genetically confirmed FH, seen during 2018 and 2019. DLCN scores were calculated before and after correction for LLT at the most recent visit. The primary outcome was the number of FH patients with DLCN criteria ≥6 points for LDL-C (which would have been an indication for genetic testing) before and after correction for LLT. Secondary endpoint was the additional number of patients with ≥6 points after also adding data on patient- and family history. Results: We included 222 patients with genetically confirmed FH; mean (SD) age: 50 (17) years; female: n=134 (60,4%). In total, 210 patients (94,6%) used some type of LLT. Mean (SD) LDL-C was 3,0 (1,4) mmol/L before correction for LLT and 7,5 (3,7) mmol/L after correction for LLT. Before correction for LLT, the algorithm identified 3 patients (1,4%) with ≥6 DLCN points, increasing to 59 patients (26,6%) after correction for LLT and to 76 patients (34,2%) after adding data on patient-, and family history. Conclusion: We conclude that, even after correction for LLT and addition of data on patient-, and family history, the sensitivity of a DLCN-based algorithm appeared relatively low in a population with genetically confirmed FH. Correction for LLT is important to increase sensitivity of the algorithm. Interestingly, FH detection algorithms inevitably rely on phenotypical characteristics of patients, whereas the present data show that genotypical FH does not necessarily express as phenotypical FH recognized by the DLCN-based algorithm. These data highlight the need for improvement of the DLCN-based algorithm and the importance of cascade testing for FH.

Clinical, Genetic and Orthopedic Characteristics of Desbuquois Dysplasia

Introduction. Desbuquois dysplasia is a rare skeletal dysplasia with an autosomal recessive inheritance, resembling to the group of multiple joint dislocations. The disease is caused by mutations in the CANT1 and XYLT1 genes, the protein products of which are involved in the degradation of proteoglycans, which play an important role in endochondral ossification. The polymorphism of clinical and radiological characteristics and the genetic heterogeneity of Desbuquois dysplasia necessitate the description of the phenotypic characteristics of patients with various types of mutations, which optimize diagnosis. Objective description of the clinical and radiological characteristics of three Russian patients with Desbuquois dysplasia of types 1 and 2 with remarkable orthopedic manifestation, caused by mutations in the CANT1 and XYLT1 genes. Materials and Methods. Genealogical, clinical, radiographic and genetic data of three unrelated Russian patients aged 2 to 8 years was carried out. Genetic testing was carried out using clinical exome sequencing and methyl-sensitive PCR. Results. Two patients were diagnosed with type 1 disease due to a previously described homozygous mutation in the CANT1 gene: c.898CT (p.Arg300Cys), and one type 2 due to heterozygous mutations in the XYLT1 gene. One mutation: c.1651CT (p.Arg551Cys) was detected during exome sequencing, and the second mutation: expansion of GGC repeats in the promoter region of the gene, revealed by methyl-sensitive PCR of the first exon of the gene. The main clinical signs of the disease were micromelic dwarfism, hypermobility in the joints and specific facial dysmorphisms, radiographic analysis revealed characteristic monkey wrench appearance of the proximal femur in all 3 patients, additional ossification center of the second metacarpal, advanced bone age and multiple dislocations in the joints. The patients also had extra-skeletal manifestations (congenital glaucoma, obstructive bronchitis, renal hypoplasia and congenital heart malformations). Conclusion. Genetic heterogeneity and the presence of polymorphism of clinical manifestations make it possible to consider sequencing of the clinical exome as the optimal method for diagnosing Desbuquois dysplasia types 1 and 2. Analysis of the literature and the results of our molecular genetic data indicate the possibility of expansion of the GGC repeat in the XYLT1 gene in patients with clinical manifestations of type 2 Desbuquois dysplasia.

Assessment of significance of erythrocyte indices as metabolic and microvascular complications markers in patients with type 1 and type 2 diabetes mellitus

Erythrocyte morphology is a reflection of both physiological and pathological reactions occurring in the body of patients with diabetes mellitus (hyperglycemia, adipose tissue dysfunction, dyslipidemia, lipid peroxidation, angiopathy, diabetic nephropathy, etc.). There are no available data in the literature that would characterize gradual and progressive changes in the morphology of the erythron system in patients with diabetes mellitus, the more so any analysis of the relationships with pathogenetic factors affecting them.Aim. The aim of the study was to evaluate the nature of erythrocyte index relationships with vascular and metabolic complications of type 1 and type 2 diabetes mellitus. The main objective of the study was to determine the changes in red blood cell indices at different stages of diabetic microangiopathies and in the presence of different indicators of metabolic control.Material and Methods. A total of 122 patients were enrolled in a single-stage, single-center, comparative, controlled study. Patients were assigned to three groups: group 1 comprised patients with type 1 diabetes mellitus (n = 41); group 2 comprised patients with type 2 diabetes mellitus (n = 67); and group 3 comprised control patients (n = 14). Statistical processing of the results was performed using the SPSS Statistics 20 software.Results. Patients with diabetes mellitus are characterized by qualitative changes in the erythron system manifesting as changes in red blood cell indices.The study identified the significant associations between the changes in erythron system (erythrocyte indices) and various phenotypic features of patients with type 1 and type 2 diabetes mellitus, namely: the duration of diabetes of over 10 years, type 2 diabetes mellitus in combination with obesity, and the presence of dyslipidemia, diabetic retinopathy, and poorly controlled diabetes mellitus if glycated hemoglobin exceeded 8% with a subsequent corresponding increase per each 1%.Conclusion. Additional studies are required to implement these markers, in particular, a red cell distribution width, as risk factors for unfavorable prognosis i.e. the risk of developing various diabetes mellitus complications.

Phenotypic characteristics of patients with ARSACS from South India

Early onset autosomal recessive ataxias consist of numerous entities with distinctive phenotypes. In 1978, a spastic ataxic syndrome was reported from Quebec, which was acronymized as ARSACS; autosomal recessive spastic ataxia of Charlevoix-Saguenay. We aim to describe a cohort of patients with ARSACS from a South India.