Diagnosis Of Proband Research Articles

Ophthalmological Examination and Imaging Features that Better Predict Risk of Angle Closure in Siblings

Characteristics of individuals with angle closure may be useful in targeted screening of family members. Here, we assess if findings gathered during examination and imaging of patients with a known angle closure diagnosis (probands) could better determine the risk of angle closure in the patients' siblings. Cross-sectional study of patients with known angle closure and their siblings. Participants, and Controls: South Indian patients (probands) 30 years and older with open angles, suspect primary angle closure (PACS), or primary angle closure/primary angle closure glaucoma (PAC/PACG), and a biological sibling age 30 years or older (n=292 proband/sibling pairs). Demographic data, relevant ocular history, and a comprehensive ophthalmic examination with Anterior Segment Optical Coherence Tomography (ASOCT) were obtained. Three clinically relevant models were created to analyze the contribution of specific proband factors in predicting sibling angle closure diagnosis, using demographic (age, gender), ocular exam (gonioscopy, optic nerve exam, visual acuity, intraocular pressure [IOP]), and ASOCT features to improve prediction beyond proband diagnosis alone evaluated by log likelihood ratio testing and statistical comparison of receiver operating characteristics (ROC). Sibling angle closure diagnostic accuracy. Demographic and ocular exam metrics did not improve the prediction of sibling angle closure for all three outcomes (sibling diagnosis: (1) PACS/PAC/PACG vs OA, (2) PAC/PACG vs PACS/OA, and (3) PAC/PACG vs PACS), adding no model improvement when compared to diagnosis alone. Models adding ASOCT metrics to the prior model including proband diagnosis, demographics and ocular exam measures led to significantly improved prediction of 2 of the 3 angle closure outcomes. Specifically, improvement was noted via likelihood ratio testing for prediction of PAC/PACG vs PACS/OA (p=0.01), or PAC/PACG vs PACS (p=0.001). For all 3 angle closure outcomes, ROC comparisons demonstrated significant improvement in AUC between the three models predicting sibling outcomes, demonstrating an increase in AUC with each successive nested model across all 3 sibling angle closure outcomes. Structural features of eyes with angle closure may assist in stratifying the risk of angle closure in patients' siblings. Further studies should consider evaluating this approach to achieve more targeted screenings.

Abstract 17005: Brugada Syndrome: Is There a Difference Between Probands and Relatives?

Introduction: Brugada syndrome (BrS) is an inherited arrhythmic disease that is rarely linked to sudden cardiac death (SCD), often associated with SCN5A mutations. Hypothesis: The main objective of this study was to report the demographic, clinical findings and outcomes of a BrS registry in the Maltese Islands, comparing probands and relatives. Methods: Data was collected prospectively in all BrS patients. BrS was defined as per the latest European Society of Cardiology SCD guidelines published in 2022. Patients were placed in two groups (proband vs relative). Results: 120 individuals were included (2.7 per 10,000 individuals) (56.7% male, mean age 44.0±16.5 years at diagnosis, 7.5% athletes). 54 (45.0%) were probands. 61 (50.8%) reported cardiac symptoms. A relevant family history of SCD was present in 55 (46.6%). Follow up period of 49.8 ± 33.3 months. A spontaneous type 1 brugada pattern was the primary method of diagnosis in probands (71.1%), ajmaline provocation in relatives (71.6%) (p<0.001). Probands reported more symptoms (33.1% vs 17.8%, p<0.0001), documented arrhythmias during holter monitoring (29.0% vs 9.3%, p=0.028), and manifested J /ST elevation during stress testing (14.0% vs 5.3%, p=-0.039). The age at diagnosis was similar for probands and relatives. Similar proportions of atrioventricular block (15.7%), prolonged QRS (10.2%), early repolarisation (12.8%), QRS fragmentation (5.6%), low QRS voltages (5.6%) and pathological TWI (8.3%) were observed in both groups. 18 (20.4%) were identified with a SCN5A mutation (P, LP, VUS as per ACMG criteria). 5 patients (4.2%) had a novel variant. 17 (15.3%) were referred for a VT study. 20 (16.7%) had an ICD implanted, more frequent in probands (34.0% vs 3.1%) (p<0.001). 3 were implanted because of OHCA. 27 (22.5%) were implanted with an ILR, commoner in probands (33.3% vs 16.4%, p=0.047). Two patients (10% of ICD subgroup) had an appropriate ICD therapy. One patient is on quinidine because of refractory shocks. Conclusions: The prevalence of BrS in Malta is comparable to other studies. 20.4% (probands) had a SCN5A mutation. The higher incidence of symptoms, arrhythmias, abnormal response during exercise and ICD implantation in probands (vs relatives) may suggest they are a higher risk group.

Improvements in Awareness and Testing Have Led to a Threefold Increase Over 10 Years in the Identification of Monogenic Diabetes in the U.K.

Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of U.K. cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve the awareness and detection of MODY, including education initiatives (Genetic Diabetes Nurse [GDN] project), the MODY probability calculator, and targeted next-generation sequencing (tNGS). We examined how the estimated prevalence of MODY and other forms of monogenic diabetes diagnosed outside the neonatal period has changed over time and how the initiatives have impacted case finding. U.K. referrals for genetic testing for monogenic diabetes diagnosed >1 year of age from 1 January 1996 to 31 December 2019 were examined. Positive test rates were compared for referrals reporting GDN involvement/MODY calculator use with those that did not. A diagnosis of monogenic diabetes was confirmed in 3,860 individuals, more than threefold higher than 2009 (1 January 1996 to 28 February 2009, n = 1,177). Median age at diagnosis in probands was 21 years. GDN involvement was reported in 21% of referrals; these referrals had a higher positive test rate than those without GDN involvement (32% vs. 23%, P < 0.001). MODY calculator usage was indicated in 74% of eligible referrals since 2014; these referrals had a higher positive test rate than those not using the calculator (33% vs. 25%, P = 0.001). Four hundred ten (10.6%) cases were identified through tNGS. Monogenic diabetes prevalence was estimated to be 248 cases/million (double that estimated in 2009 because of increased case finding). Since 2009, referral rates and case diagnosis have increased threefold. This is likely to be the consequence of tNGS, GDN education, and use of the MODY calculator.

Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD) especially in young individuals. It is estimated to affect 1:5,000 individuals in the general population, with >60% of patients bearing one or more mutations in genes coding for desmosomal proteins. Desmosomes are intercellular adhesion junctions, which in cardiac myocytes reside within the intercalated disks (IDs), the areas of mechanical and electrical cell-cell coupling. Histologically, ACM is characterized by fibrofatty replacement of cardiac myocytes predominantly in the right ventricular free wall though left ventricular and biventricular forms have also been described. The disease is characterized by age-related progression, vast phenotypic manifestation and incomplete penetrance, making proband diagnosis and risk stratification of family members particularly challenging. Key protein redistribution at the IDs may represent a specific diagnostic marker but its applicability is still limited by the need for a myocardial sample. Specific markers of ACM in surrogate tissues, such as the blood and the buccal epithelium, may represent a non-invasive, safe and inexpensive alternative for diagnosis and cascade screening. In this review, we shall cover the most relevant biomarkers so far reported and discuss their potential impact on the diagnosis, prognosis and management of ACM.

Genomic Testing for Monogenic Diabetes in the UK: A Three-Fold Increase in Diagnoses Since 2009

Background: Maturity Onset Diabetes of the Young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of UK cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve detection of MODY: the Genetic Diabetes Nurse (GDN) education programme, the MODY probability calculator, and targeted next generation sequencing (tNGS). We aimed to determine an up-to-date prevalence estimate for UK MODY and assess how these initiatives have impacted case finding. Methods:UK referrals for genetic testing for monogenic diabetes diagnosed >1y of age from 1/1/1996 to 31/12/2019 were examined. Positive-test rates were compared for referrals reporting involvement of the GDNs/MODY calculator with those that did not. Findings: A diagnosis of MODY was confirmed in 3860 individuals, >3-fold higher than 2009 (n=1177). Median age at diagnosis in probands was 21y. GDN involvement was reported in 21% of referrals; these referrals had a higher positive-test rate than those without GDN involvement (32% v 23%, p<0.001). MODY calculator usage was indicated on 74% of eligible referrals since 2014; these referrals had a higher positive-test rate than those not using the calculator (32% v 24%, p=0.001). 374 (10%) cases were identified through tNGS. MODY prevalence was estimated to be 248 cases/million (double that estimated in 2009 due to increased case-finding). Interpretation: Since 2009, referral rates and case diagnosis has increased three-fold. This is likely to be the consequence of tNGS, GDN education and the MODY calculator. Funding: NIHR, Scottish Government Declaration of Interest: None

Inheritance pattern of molar-incisor hypomineralization.

The aim of this study was to investigate the segregation patterns of molar incisor hypomineralization (MIH) in families, given the evidence that its etiology is influenced by genetics. Clinically, MIH may be detected in parents and/or siblings of MIH-affected children. Our study included children with at least one first permanent molar affected by MIH (proband) and their first-degree relatives (parents and siblings). The participants were examined clinically to detect MIH, according to the European Academy of Paediatric Dentistry criteria (2003). A total of 101 nuclear families (391 individuals) were studied. Proband diagnosis was followed by MIH classification of the subject, his parents and siblings, as affected, unaffected, or unknown. Segregation analysis was performed using the multivariate logistic regression model of the Statistical Analysis for Genetic Epidemiology package, and segregation models (general transmission, environmental, major gene, dominant, codominant and recessive models). The Akaike information criterion (AIC) was used to evaluate the most parsimonious model. In all, 130 affected individuals, 165 unaffected individuals, and 96 unknown individuals were studied. Severe MIH was found in 50.7% of the cases. A segregation analysis performed for MIH revealed the following different models: environmental and dominance (p = 0.05), major gene (p = 0.04), codominant (p = 0.15) and recessive models (p = 0.03). According to the AIC values, the codominant model was the most parsimonious (AIC = 308.36). Our results suggest that the codominant model could be the most likely for inheriting MIH. This result strengthens the evidence that genetic factors, such as multifactorial complex defect, influence MIH.

Семейные случаи подострой некротизирующей энцефаломиелопатии (синдрома Ли)

Mitochondrial diseases are not uncommon. However, their genetic diagnosis is challenging for practitioners and requires up-to-date hightech methods. Early accurate diagnosis in first probands provides early preclinical genetic testing in all born children in compromised families and prenatal testing in future pregnancies, thereby allowing a differential planning of future pregnancies. This paper discusses a progressive central nervous system disorder, a congenital mitochondrial disease, subacute necrotizing encephalomyelopathy (Leigh syndrome). First, the authors briefly review etiology, prevalence, clinical presentations, diagnostic techniques, and treatment for this disease in children. Then, unique familial cases describing the diversity of clinical presentations are described. The diagnosis was genetically verified in all patients. MR signs always accompany the gradual loss of motor skills at early stages. Blood biochemistry identifies lactic acidosis. KEYWORDS: children, mitochondrial diseases, subacute necrotizing encephalomyelopathy, lactic acidosis, Leigh syndrome, diagnosis, mutations in the SURF1 gene. FOR CITATION: Shishkina E.V., Bazilevskaya T.N., Novikova I.V. et al. Familial cases of subacute necrotizing encephalomyelopathy (Leigh syndrome). Russian Journal of Woman and Child Health. 2021;4(4):370–374 (in Russ.). DOI: 10.32364/2618-8430-2021-4-4-370-374.

Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by high levels of low-density lipoprotein-cholesterol (LDLc), associated to premature cardiovascular disease. The detection of the variants related to FH is important to improve the early diagnosis in probands / index-cases (ICs) and their relatives. We included ICs with FH and their relatives, living in a small region of Minas Gerais state-Brazil, which were classified according to Dutch Lipid Clinic Network Criteria (DLCNC) and submitted to sequencing of genes related to FH (LDLR, APOB, PCSK9, LDLRAP1, LIPA, STAP1, APOE, ABCG5 e ABCG8). In a total of 143 subjects (32 ICs and 111 relatives), eight variants were identified in 91 individuals. From these variants, five were in LDLR [p.(Asp224Asn), p.(Ser854Gly), p.(Cys34Arg), p.(Asp601His), deletion of exon15 in LDLR)], one in APOB [p.(Met499Val)], one in PCSK9 [p.(Arg237Trp)] and one in APOE [p.(Pro28Leu)] genes. The variants were detected in 100% of those subjects classified as definitive, 87% as probable and 69% as possible FH cases based on DLCNC. The LDLc level was higher in individuals with corneal arch and xanthomas or xanthelasmas, as well as in pathogenic or probably pathogenic variants carriers. This study showed higher frequency of LDLR gene variants compared to other genes related to LDL metabolism in individuals with FH in Minas Gerais - Brazil and the presence of FH in relatives without previous diagnosis. Our data reinforce the importance of molecular and clinical evaluation of FH relatives in order to early diagnosis the FH, as well as cardiovascular diseases prevention.

The utility of the 1994 versus the revised 2010 arrhythmogenic right ventricular cardiomyopathy (ARVC) task force diagnostic criteria for identifying mutation-positive probands with ARVC

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterised by structural and functional abnormalities of the right ventricle with or without left ventricular involvement. In 1994, Task Force criteria (TFC) were proposed for the diagnosis of ARVC and were found to be highly specific but lacked sensitivity. In 2010, revised TFC were proposed to increase sensitivity and facilitate diagnosis in those with subtle phenotypes. Purpose To compare the utility of the 1994 vs the 2010 TFC for the diagnosis of mutation-positive probands with ARVC in the IMHOTEP (The African Cardiomyopathy and Myocarditis Registry Program) study. Method 162 participants with the suspicion of ARVC were referred between May 2003 and May 2018. After the exclusion of 12 participants lacking sufficient clinical data, 150 cases were reviewed and classified using both 1994 and 2010 TFC by a diagnostic panel in an hospital. Results 82 participants were found to have an alternative diagnosis or insufficient criteria and were excluded. 68 participants were diagnosed with ARVC by the diagnostic panel and included; 14/68 participants with ARVC were found to be mutation-positive. Mutation-positive probands presented at a significantly younger age compared to the mutation-negative group (29±14 years vs 39±13 years, p=0.009), suggesting an earlier onset of ARVC. Common reasons for presentation in the mutation-positive cohort included palpitations (79%) and presyncope (64%), with twice the number of participants presenting with sustained ventricular tachycardia compared to mutation-negative participants (79% vs 47%, p=0.036). The diagnostic yield of the 2010 vs 1994 TFC in participants with ARVC (n=68) revealed more participants with a definite diagnosis (77% vs 69%, p=0.267). A 67% change in diagnosis from 1994 borderline to 2010 definite was observed. Mutation-positive participants had a higher yield for definite ARVC compared to mutation-negative participants (100% vs 86%). When comparing the mean number of task force (TF) major and minor criteria according to mutation status, we found a significant difference in the mean number of 2010 TF major criteria between mutation-positive and mutation-negative groups, even with the exclusion of gene mutation as a criterion (2.50±0.86 vs 1.74±0.85, p=0.005). We assessed each diagnostic modality's contribution to the 2010 TF major criteria in mutation-positive definite participants and found cardiac magnetic resonance contribution statistically significant, p=0.021. Conclusion Mutation-positive ARVC probands were found to be younger, more likely to present with sustained VT, and fulfilled a significantly higher number of 2010 TF major criteria than mutation-negative probands. The evolution in classification between the 2010 and 1994 TFC suggests that reclassifying participants recruited in traditional ARVC registries according to updated criteria is worthwhile. Funding Acknowledgement Type of funding source: None

Joubert Syndrome with Homozygous Duplication in Exon 7 of SMN2 Gene and c.746G&gt;A (p.R249H) Variant of Uncertain Significance in TRPV4 Gene: A Case Report

The case report presents 5 years old male proband with Joubert syndrome (JS) referred to the Institute with the complaint of developmental delay. Mutation analysis in the proband by MLPA showed homozygous duplication in exon 7 of SMN2 gene. Further, next generation sequencing (NGS) based gene panel study showed one copy of c.746G>A (p.R249H) variant of uncertain significance in exon 5 of TRPV4 gene in heterozygous condition. The same variant was identified in the probands father. Prenatal diagnosis in proband’s mother who was pregnant, revealed heterozygous missense variants of uncertain significance at c.578C>G (p. Thr193Arg) in exon 4 of PNPLA8 gene and c.862C>T (p. Arg288Cys) in exon 6 of KCNH1 gene in the developing foetus. Thus, the advanced genetic analysis along with clinical findings and typical imaging will help in appropriate diagnosis and management of the Joubert syndrome.

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a “phenotype first” approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

SCN5A mutations in 442 neonates and children: Genotype-phenotype correlation and identification of higher-risk subgroups

To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤ 16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤ 1 year at diagnosis in probands and age ≤ 1 year at diagnosis in non-probands were independent predictors of CE. In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤ 1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Exceptional diazoxide sensitivity in hyperinsulinaemic hypoglycaemia due to a novel HNF4A mutation.

SummaryDiazoxide is the first-line treatment for patients with hyperinsulinaemic hypoglycaemia (HH). Approximately 50% of patients with HH are diazoxide resistant. However, marked diazoxide sensitivity resulting in severe hyperglycaemia is extremely uncommon and not reported previously in the context of HH due to HNF4A mutation. We report a novel observation of exceptional diazoxide sensitivity in a patient with HH due to HNF4A mutation. A female infant presented with severe persistent neonatal hypoglycaemia and was diagnosed with HH. Standard doses of diazoxide (5 mg/kg/day) resulted in marked hyperglycaemia (maximum blood glucose 21.6 mmol/L) necessitating discontinuation of diazoxide. Lower dose of diazoxide (1.5 mg/kg/day) successfully controlled HH in the proband, which was subsequently confirmed to be due to a novel HNF4A mutation. At 3 years of age, the patient maintains age appropriate fasting tolerance on low dose diazoxide (1.8 mg/kg/day) and has normal development. Diagnosis in proband’s mother and maternal aunt, both of whom carried HNF4A mutation and had been diagnosed with presumed type 1 and type 2 diabetes mellitus, respectively, was revised to maturity-onset diabetes of young (MODY). Proband’s 5-year-old maternal cousin, also carrier of HNF4A mutation, had transient neonatal hypoglycaemia. To conclude, patients with HH due to HNF4A mutation may require lower diazoxide than other group of patients with HH. Educating the families about the risk of marked hyperglycaemia with diazoxide is essential. The clinical phenotype of HNF4A mutation can be extremely variable.Learning points:Awareness of risk of severe hyperglycaemia with diazoxide is important and patients/families should be accordingly educated.Some patients with HH due to HNF4A mutations may require lower than standard doses of diazoxide.The clinical phenotype of HNF4A mutation can be extremely variable.

Genetic analysis and prenatal diagnosis of Duchenne or Becker muscular dystrophy

Objective: To explore the mutation characteristics of DMD gene in patients with Duchenne or Becker muscular dystrophy and female carriers, to provide effective prenatal diagnosis. Methods: Samples were collected from 94 male patients clinically diagnosed with Duchenne or Becker muscular dystrophy and 121 corresponding female relatives from Qingdao Women and Children's Hospital from June 2011 to October 2018. Multiplex ligation-dependent probe amplification (MLPA) was used to detect their DMD gene, and 23 high risk pregnants were performed prenatal diagnosis. Any candidate of DMD gene single-exon deletion was validated by further PCR amplification. The sample with whole DMD gene deletion was confirmed by chromosomal microarray analysis (CMA) to detect copy number variations and break site. Results: Among 94 clinical Duchenne or Becker muscular dystrophy patients, 66(70.2%, 66/94) were detected gene mutation; 56 cases were exon deletion mutation and 10 cases were duplication mutation. In 121 female relatives, 48 cases (39.7%, 48/121) were diagnosed as carriers. The mutation carrying rate, was 64.5% (40/62) identified in 62 mothers of Duchenne or Becker muscular dystrophy patients. Five Duchenne or Becker muscular dystrophy fetuses and 5 carrier fetuses were prenatally diagnosed in 23 high risk pregnants. Two children with the entire DMD gene deletion were identified more deletions at Xp21, with deletions of 6.66 Mb and 10.64 Mb respectively. Conclusions: MLPA may be an important method to detect DMD gene mutation of deletion and duplication. Therefore, the diagnosis of probands, female carriers and making an effective prenatal diagnosis are essential to reduce the birth of children with Duchenne or Becker muscular dystrophy.

Accuracy of Clinical Diagnostic Criteria for Patients With Vascular Ehlers-Danlos Syndrome in a Tertiary Referral Centre.

Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disease secondary to mutations within the COL3A1 gene. The diagnosis of vascular Ehlers-Danlos syndrome is challenging, and patient selection for genetic testing relies on diagnostic criteria, which have never been evaluated. All patients seen at a dedicated tertiary referral center for a suspicion of vascular Ehlers-Danlos syndrome between January 2001 and March 2016 were retrospectively included in a diagnostic accuracy study. Major and minor diagnostic criteria of the Villefranche classification were tested for sensitivity, specificity, positive and negative predictive values, according to results of genetic testing. N=519 patients were eligible for analysis dividing into n=384 probands and n=135 relatives. A pathogenic COL3A1 variant was identified in n=165 (31.8%) patients. The Villefranche criteria were met for n=248 patients with a sensitivity of 79% (95% CI, 0.72-0.85) and a negative predictive value of 87% (95% CI, 0.83-0.91). Diagnostic accuracy was highest for symptomatic probands (sensitivity 92%; negative predictive value 95%) with limited specificity (60%). Probands ≤25 years had the worst diagnostic performance. The revised diagnostic Criteria (2017) were less accurate than the Villefranche classification (overall diagnostic odds-ratio, 4.17 versus 7.8; probands diagnostic odds-ratio, 4.04 versus 18.1; and probands ≤25 years diagnostic odds-ratio, 2.36 versus 5.1) mainly due to a lack of sensitivity. The Villefranche criteria provide accurate detection of symptomatic probands in specialized practice but have limited specificity. The revised diagnostic criteria for vascular Ehlers-Danlos syndrome have increased specificity, but its overall performance is poorer. The early clinical diagnosis of probands without family history is not addressed by both diagnostic classifications.

Accuracy of Clinical Diagnostic Criteria for Patients with Vascular Ehlers-Danlos Syndrome in a Tertiary Referral Centre.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disease secondary to mutations within the COL3A1 gene. The diagnosis of vEDS is challenging and patient selection for genetic testing relies on diagnostic criteria, which have never been evaluated. All patients seen at a dedicated tertiary referral centre for a suspicion of vEDS between January 2001 and March 2016 were retrospectively included in a diagnostic accuracy study. Major and minor diagnostic criteria of the Villefranche classification were tested for sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV, NPV), according to results of genetic testing. N=519 patients were eligible for analysis dividing into n=384 probands and n=135 relatives. A pathogenic COL3A1 variant was identified in n=165 (31.8%) patients. The Villefranche criteria were met for n=248 patients with a Se of 79% (95%CI: 0.72-0.85) and a NPV of 87% (95%CI: 0.83-0.91). Diagnostic accuracy was highest for symptomatic probands (Se 92%; NPV 95%) with limited Sp (60%). Probands {less than or equal to}25 years had the worst diagnostic performance. The revised diagnostic Criteria (2017) were less accurate than the Villefranche classification (overall Diagnostic odds-ratio (DOR) 4.17 vs. 7.8, probands DOR 4.04 vs. 18.1; probands {less than or equal to}25 years DOR 2.36 vs. 5.1), mainly due to a lack of Se. The Villefranche criteria provide accurate detection of symptomatic probands in specialized practice, but have limited Sp. The revised diagnostic criteria for vEDS have increased Sp, but its overall performance is poorer. The early clinical diagnosis of probands without family history is not addressed by both diagnostic classifications.

Morbid risk of schizophrenia amongst relatives of schizophrenia probands: A family-controlled study.

IntroductionThere is a dearth of data on heritability of schizophrenia in Africa. The few African studies that addressed familial psychiatric morbidity in schizophrenia involved relatively small sample sizes and addressed psychiatric morbidity only in first-degree relatives. The present study sought to improve upon the methodology of previous African studies, and widen the scope to second- and third-degree relatives with a view to enriching the field of genetic epidemiology in Africa.MethodsThis study elicited information on the morbid risk of schizophrenia amongst 5259 relatives of schizophrenia probands (n = 138) and 6734 relatives of healthy controls (n = 138) through direct interview of patients, available relatives of patients and controls. Diagnosis of probands was confirmed using Mini International Neuropsychiatric Interview. Through a direct interview of 138 patients and their available relatives, a family history approach using the Family Interview for Genetic Studies was utilised to obtain information on the morbid risk for all relatives that could be recalled. The same approach was utilised for the interview of the controls (aged 45 years and above) and their relatives. Morbid risk estimates were calculated using the Weinberg shorter method.ResultsMorbid risk for schizophrenia in the first-, second- and third-degree relatives of schizophrenia probands was 10.9% (95% confidence interval [CI] = 10.6–11.2), 4.2% (95% CI = 4.1–4.3) and 3.9% (95% CI = 3.6–4.2), respectively, compared with 2.6% (95% CI = 2.5–2.7), 1.6% (95% CI = 1.5–1.7) and 1.5% (95% CI = 1.4–1.6), respectively, of the healthy control group.ConclusionThe findings support the widely noted impression that schizophrenia significantly aggregates in families of schizophrenia probands more than healthy controls.

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Management impact: effects on quality of life and prognosis in MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant endocrine tumor syndrome, caused by inactivating mutations of the MEN1 tumor suppressor gene at 11q13 locus, which predisposes to develop tumors in target neuroendocrine tissues. As the positional cloning and identification of the causative gene in 1997, genetic diagnosis, by the sequencing-based research of gene mutations, has become an important tool in the early and differential diagnosis of the disease. Application of the genetic test, in MEN1 index cases and in first-degree relatives of mutated patients, has been constantly increasing during the last two decades, also thanks to the establishment of multidisciplinary referral centers and specific genetic counseling, and thanks to the wide availability of high throughput instruments for gene sequencing and gene mutation identification. The MEN1 genetic test helps the specific diagnosis of probands, and allows the early identification of asymptomatic carriers, strongly contributing, together with progressions in tumor diagnostic techniques and in pharmacological and surgical therapeutic approaches, to the reduction of morbidity and mortality associated with the syndrome. International clinical guidelines for MEN1 have been drafted by panels of specialists in the field, with the main goal to improve the management of the disease and grant patients a better quality of life. Here, we review main recommendations and suggestions derived by the last published general guidelines in 2012, and by most recent published studies about MEN1 syndrome diagnosis, clinical management, therapeutic approaches and patients' quality of life.

Parental family history of dementia in relation to subclinical brain disease and dementia risk.

To determine the association of parental family history with risk of dementia by age at onset and sex of affected parent in a population-based cohort. From 2000 to 2002, we assessed parental history of dementia in participants without dementia of the Rotterdam Study. We investigated associations of parental history with risk of dementia until 2015, adjusting for demographics, cardiovascular risk factors, and known genetic risk variants. Furthermore, we determined the association between parental history and markers of neurodegeneration and vascular disease on MRI. Of 2,087 participants (mean age 64 years, 55% female), 407 (19.6%) reported a history of dementia in either parent (mean age at diagnosis 79 years). During a mean follow-up of 12.2 years, 142 participants developed dementia. Parental history was associated with risk of dementia independently of known genetic risk factors (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.12-2.48), in particular when parents were diagnosed at younger age (<80 years: HR 2.58, 95% CI 1.61-4.15; ≥80 years: HR 1.01, 95% CI 0.58-1.77). Accordingly, age at diagnosis in probands was highly correlated with age at diagnosis in their parents <80 years (r = 0.57, p = 0.001) but not thereafter (r = 0.17, p = 0.55). Among 1,161 participants without dementia with brain MRI, parental history was related to lower cerebral perfusion and higher burden of white matter lesions and microbleeds. Dementia risk and MRI markers were similar for paternal and maternal history. Parental history of dementia increases risk of dementia, primarily when age at parental diagnosis is <80 years. Unexplained heredity may be attributed in part to cerebral hypoperfusion and small vessel disease. We found no evidence of preferential maternal compared to paternal transmission.