Reanalysis of whole exome sequencing data in patients with epilepsy and intellectual disability/mental retardation

Li, Jinliang; Gao, Kai; Yan, Huifang; XiangWei, Wenshu; Liu, Nana; Wang, Tianshuang; Han, Xu; Lin, Zhongxiao; Xie, Han; Wang, Jingmin; Wu, Ye; Jiang, Yuwu

doi:10.1016/j.gene.2019.03.037

Cited by 61 publications

(63 citation statements)

References 31 publications

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“…The diagnostic yield in this study showed comparable results to other published studies with reanalysis diagnostic yield of 5-36%; and additional diagnostic yield of 5-22% at 6-36 months after initial analysis (Fig. 2) [10][11][12][13][14][15][16][17][18][19][20][21][22][23] .…”

Section: Discussionsupporting

confidence: 86%

“…Among these methods, reanalysis of the exome is the most accessible and inexpensive. Multiple studies with predominantly Caucasian individuals have shown that the diagnostic rate of reanalysis ranges from 6 to 47% [10][11][12][13][14][15][16][17][18][19][20][21][22][23] . Stark et al has estimated that 18months is the most cost-effective time point to perform reanalysis 19 .…”

Section: Introductionmentioning

confidence: 99%

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A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

Fung

Huang

et al. 2020

npj Genom. Med.

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Exome sequencing (ES) has become one of the important diagnostic tools in clinical genetics with a reported diagnostic rate of 25–58%. Many studies have illustrated the diagnostic and immediate clinical impact of ES. However, up to 75% of individuals remain undiagnosed and there is scarce evidence supporting clinical utility beyond a follow-up period of >1 year. This is a 3-year follow-up analysis to our previous publication by Mak et al. (NPJ Genom. Med. 3:19, 2018), to evaluate the long-term clinical utility of ES and the diagnostic potential of exome reanalysis. The diagnostic yield of the initial study was 41% (43/104). Exome reanalysis in 46 undiagnosed individuals has achieved 12 new diagnoses. The additional yield compared with the initial analysis was at least 12% (increased from 41% to at least 53%). After a median follow-up period of 3.4 years, change in clinical management was observed in 72.2% of the individuals (26/36), leading to positive change in clinical outcome in four individuals (11%). There was a minimum healthcare cost saving of HKD$152,078 (USD$19,497; €17,282) annually for these four individuals. There were a total of six pregnancies from five families within the period. Prenatal diagnosis was performed in four pregnancies; one fetus was affected and resulted in termination. None of the parents underwent preimplantation genetic diagnosis. This 3-year follow-up study demonstrated the long-term clinical utility of ES at individual, familial and health system level, and the promising diagnostic potential of subsequent reanalysis. This highlights the benefits of implementing ES and regular reanalysis in the clinical setting.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

Fung

Huang

et al. 2020

npj Genom. Med.

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“…For patient 12, trio ES was performed in the Beijing Key Laboratory of Molecular Diagnosis and Study on Paediatric Genetic Diseases, Beijing, China (Beijing, China). The methodology used has been previously described elsewhere 18. For patient 14, ES was performed at the Laboratório de Sequenciamento em Larga Escala, Faculdade de Medicina da Universidade de São Paulo (São Paulo, Brazil), using a method that has been previously reported 19.…”

Section: Methodsmentioning

confidence: 99%

Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

et al. 2020

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BackgroundRare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described.MethodsClinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation.ResultsClinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1).ConclusionsVariants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

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“…Negative SCN1A analysis does not necessarily exclude the diagnosis, as it may be a falsenegative result 69 or clinical features may be associated with a mutation in another gene 60 , as the DS diagnosis itself is a clinical one. SCN1A testing is also recommended for GEFS+ phenotypes.…”

Section: Assessment and Diagnosismentioning

confidence: 99%

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

Matthews

Balestrini

Sisodiya

et al. 2020

The Lancet Child & Adolescent Health

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Voltage gated sodium channels are essential for excitability of skeletal muscle fibres and neurones. An increasing number of disabling or fatal paediatric neurological disorders linked to mutations of voltage gated sodium channel genes are recognised. Muscle phenotypes include episodic paralysis, myotonia, neonatal hypotonia, respiratory compromise, laryngospasm/stridor, congenital myasthenia and myopathy. Recent evidence suggests a possible link between sodium channel dysfunction and sudden infant death. Increasingly recognised brain sodium channelopathy phenotypes include several epilepsy disorders and complex encephalopathies. Together these early onset muscle and brain phenotypes have a significant morbidity and an appreciable mortality rate but there have been significant advances in understanding the pathophysiological mechanisms underlying them and these have helped to identify effective targeted therapies. The availability of effective treatments underlines the importance of increasing clinical awareness and the need to achieve a precise genetic diagnosis. Here, we describe the expanded range of phenotypes of muscle and brain sodium channelopathies and the underlying knowledge regarding mechanisms of sodium channel dysfunction. We outline a diagnostic approach and review the available treatment options.

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Reanalysis of whole exome sequencing data in patients with epilepsy and intellectual disability/mental retardation

Cited by 61 publications

References 31 publications

A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

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