Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing

Bruel, Ange‐Line; Nambot, Sophie; Quéré, Virginie; Vitobello, Antonio; Thévenon, Julien; Assoum, Mirna; Moutton, Sébastien; Houcinat, Nada; Lehalle, Daphné; Jean-Marçais, Nolwenn; Chevarin, Martin; Jouan, Thibaud; Poé, Charlotte; Callier, Patrick; Tisserand, Emilie; Philippe, Christophe; Mau-Them, Frédéric Tran; Duffourd, Yannis; Faivre, Laurence; Thauvin‐Robinet, Christel

doi:10.1038/s41431-019-0442-1

Cited by 47 publications

(37 citation statements)

References 54 publications

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“…Of all reported alterations of KCNA2 , electrophysiological channel characterization has been available in 13/30 (43%) variants. Six different electrophysiological LOF variants in KCNA2 have been described [ 3 , 13 , 15 , 16 , 20 ], three different KCNA2 variants caused GOF in cellular expression systems [ 3 , 13 , 14 , 16 , 24 , 25 , 26 ] and four variants were reported having mixed functional effects (GOF/LOF) on mutated channels [ 16 , 19 , 34 , 35 ]. Of all reported and novel individuals, 61/76 (80%) harbored variants that have been electrophysiologically characterized.…”

Section: Resultsmentioning

confidence: 99%

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Döring

Schröter

Jüngling

et al. 2021

IJMS

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Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

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Section: Resultsmentioning

confidence: 99%

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Döring

Schröter

Jüngling

et al. 2021

IJMS

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“…Re-evaluation of existing ES data conducted without reannotation using updated software and/ or reference databases has achieved an incremental diagnosis rate of 14% via reanalysis at six to 18 months after the original analysis (Stark et al, 2019). This approach was also applied by Bruel et al (2019), with the authors performing reanalysis immediately after obtaining the original ES result. The particular focus of the Bruel study was to extend variant interpretation to genes not currently associated with disease in OMIM for the purpose of research.…”

Section: Discussionmentioning

confidence: 99%

“…One‐third of the diagnoses in this study have been derived from novel gene discovery, illustrating the significance of pursuing translational research when attempting to solve the unsolved. In particular, international data sharing through platforms such as GeneMatcher (Sobreira et al, 2015) has been a successful strategy employed by several reanalysis studies to date, with collaborations between research groups resulting in numerous diagnoses and novel gene publications (Epilepsy Genetics, 2019; Bowling et al, 2017; Bruel et al, 2019; Eldomery et al, 2017; Hiatt et al, 2018; Nambot et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review

Tan

Stapleton

Stark

et al. 2020

Molec Gen & Gen Med

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“…It has been widely acknowledged that reanalysis of exomes will further increase the molecular diagnostic rate (Baldridge et al, 2017; Bruel et al, 2019; Eldomery et al, 2017; Nambot et al, 2018; Schmitz‐Abe et al, 2019; Shashi et al, 2019). In this report, we adapted our exome analytic pipeline to a patient with nonspecific short stature and microcephaly and established a potential molecular diagnosis by identifying a likely pathogenic mutation in TUBB .…”

Section: Discussionmentioning

confidence: 99%

Clinical variability of TUBB‐associated disorders: Diagnosis through reanalysis

Liu

Shen

Zackai

et al. 2020

American J of Med Genetics Pt A

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A range of clinical findings have been associated with heterozygous mutations in the Beta Tubulin (TUBB) gene, including microcephaly, structural brain abnormalities, intellectual disability, and skin creases. We report a 5-year-old male who presented for evaluation of cleft palate, cardiac defects, growth retardation, hemivertebrae causing scoliosis, and preauricular skin tags. Previous clinical exome sequencing of this patient was nondiagnostic, but reanalysis in the research setting identified a de novo missense c. 925C>G p.(Arg309Gly) mutation in TUBB. This mutation was not found in population allele frequency databases, and was classified to be likely pathogenic. This patient shares some phenotypic characteristics with previous reported patients of TUBB mutations of the two TUBB-related phenotypes: "Cortical dysplasia, complex, with other brain malformations 6" [MIM 615771] and "Circumferential Skin Creases Kunze type (CSC-KT)" [MIM 156610], but has no excess skin creases or structural brain anomalies. We also report previously undescribed features, including transposition of the great arteries and vertebral fusion, thus representing phenotype expansion of TUBB-associated disorders.

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Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing

Cited by 47 publications

References 54 publications

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review

Clinical variability of TUBB‐associated disorders: Diagnosis through reanalysis

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