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Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.

ABSTRACT: BACKGROUND:Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies. METHODS:This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60?months, experiencing first unprovoked seizure after 2?years of age. RESULTS:The average age at enrolment was 39.9?months, with a mean age at seizure onset of 30.9?months and a mean time interval between seizure onset and targeted resequencing of 9?months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G?>?C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects. CONCLUSIONS:Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.

SUBMITTER: Amadori E

PROVIDER: S-EPMC7339579 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.

Amadori Elisabetta E Scala Marcello M Cereda Giulia Sofia GS Vari Maria Stella MS Marchese Francesca F Di Pisa Veronica V Mancardi Maria Margherita MM Giacomini Thea T Siri Laura L Vercellino Fabiana F Serino Domenico D Orsini Alessandro A Bonuccelli Alice A Bagnasco Irene I Papa Amanda A Minetti Carlo C Cordelli Duccio Maria DM Striano Pasquale P

Italian journal of pediatrics 20200706 1

<h4>Background</h4>Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is ...[more]

PMID: 32631363

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Project description:BackgroundFor a number of persons with rare diseases (RDs) a definite diagnosis remains undiscovered with relevant physical, psychological and social consequences. Undiagnosed RDs (URDs) require other than specialised clinical centres, outstanding molecular investigations, common protocols and dedicated actions at national and international levels; thus, many "Undiagnosed RDs programs" have been gradually developed on the grounds of a well-structured multidisciplinary approach.MethodsThe Italian Undiagnosed Rare Diseases Network (IURDN) was established in 2016 to improve the level of diagnosis of persons with URD living in Italy. Six Italian Centres of Expertise represented the network. The National Centre for Rare Diseases at the Istituto Superiore di Sanità coordinates the whole project. The software PhenoTips was used to collect the information of the clinical cases.ResultsOne hundred and ten cases were analysed between March 2016 and June 2019. The age of onset of the diseases ranged from prenatal age to 51 years. Conditions were predominantly sporadic; almost all patients had multiple organs involvements. A total of 13/71 family cases were characterized by WES; in some families more than one individual was affected, so leading to 20/71 individuals investigated. Disease causing variants were identified in two cases and were associated to previously undescribed phenotypes. In 5 cases, new candidate genes were identified, although confirmatory tests are pending. In three families, investigations were not completed due to the scarce compliance of members and molecular investigations were temporary suspended. Finally, three cases (one familial) remain still unsolved. Twelve undiagnosed clinical cases were then selected to be shared at International level through PhenomeCentral in accordance to the UDNI statement.ConclusionsOur results showed a molecular diagnostic yield of 53,8%; this value is comparable to the diagnostic rates reported in other international studies. Cases collected were also pooled with those collected by UDNI International Network. This represents a unique example of global initiative aimed at sharing and validating knowledge and experience in this field. IURDN is a multidisciplinary and useful initiative linking National and International efforts aimed at making timely and appropriate diagnoses in RD patients who still do not have a confirmed diagnosis even after a long time.

Project description:Currently less than half of the estimated number of people with dementia in England receive a formal diagnosis of dementia or have contact with specialist dementia services. Case finding focused on high risk groups may be an effective way to identify the undiagnosed. This joint Surrey Downs Clinical Commissioning Group and Surrey and Borders NHS Foundation Trust quality improvement project aimed to increase the rate of dementia diagnosis across Surrey Downs using specialist link nurses (SLNs). Thirty three GP surgeries covering the entire Surrey Downs area took part in the project. Individuals at high risk of developing dementia were identified from GP electronic disease registers, and were offered screening at their GP practices by SLNs, using a combination of mini cognitive test (Mini-Cog) and functional assessment questionnaire (FAQ). Suitable individuals who screened positive were seen by their GP and where appropriate referred to secondary care services for further evaluation. Based on the presence of risk factors, 6657 (11.9%) people were identified from a total population of 55 845 over 65s, and 1980 (29.7%) completed the screening assessment. Three hundred and fifty eight (18.1%) individuals screened positive and were referred to their GP, who referred 205 (57.2%) of them to the memory services for further assessment. Of those referred, 164 (80%) had a comprehensive specialist assessment. Forty one (20%) declined further assessment, and their GPs were informed. The mean age of the cohort who completed the comprehensive assessment was 82.3 years (SD=4.26), and were predominantly white and male. Fifty four (32.9%) had mild cognitive disorder (MCD), and 101 (61.6%) patients were diagnosed with dementia. The most common dementia was mixed type (43; 42.6%), followed by Alzheimer's dementia (32; 31.7%). The most common risk factor among patients with cognitive impairment (MCD or dementia) was hypertension (69; 44.5 %), followed by ischemic heart disease (64, 41.3%). Nurse led case finding for cognitive impairment in a high risk population identifies people with dementia who are not yet formally diagnosed. The combined use of brief instruments to assess cognitive functioning and functional capabilities is helpful in identifying individuals with possible dementia.

Dataset Information

Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.

Publications

Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.

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