Gene family information facilitates variant interpretation and identification of disease-associated genes

Lal, Dennis; Samocha, Kaitlin E.; Kosmicki, Jack A.; Robinson, Elise; Møller, Rikke S.; Krause, Roland; Nüernberg, Peter; Weckhuysen, Sarah; Jonghe, Peter De; Guerrini, Renzo; Neupert, Lisa M.; Du, Juliana; Pérez‐Palma, Eduardo; Marini, Carla; Ware, James S.; Kurki, Mitja; Gormley, Padhraig; Tang, Sha; Wu, Sitao; Biskup, Saskia; Poduri, Annapura; Neubauer, Bernd A.; Koeleman, Bobby P. C.; Helbig, Katherine L.; Weber, Yvonne G.; Helbig, Ingo; Majithia, Amit R.; Palotie, Aarno; Daly, Mark J.

doi:10.1101/159780

Cited by 20 publications

(30 citation statements)

References 47 publications

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“…At follow-up, a deterioration from normal intellect/developmental delay to mild ID or from mild ID/developmental delay to moderate ID was seen in seven (19%) patients, whereas 81% did not experience deterioration after seizure onset. At the time of follow-up, 22 All probands were evaluated for their treatment response. Twenty-one of 36 (58%) probands became seizurefree.…”

Section: Resultsmentioning

confidence: 99%

“…The paralog conservation score (parazscore), which quantifies amino‐acid position conservation across human proteins of the same gene family. A significant enrichment of disease‐associated missense variants was observed at paralog‐conserved sites The Grantham score, which accesses the effect of the amino acid substitution based on the properties of the amino acid exchange.…”

Section: Methodsmentioning

confidence: 99%

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The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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Summary Objective Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A‐related epilepsies. Methods A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results We found 36 probands who presented with an SCN8A‐related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure‐free, two‐thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance With this study, we explore the electroclinical features of an intermediate SCN8A‐related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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“…Genetic variants in the genes SCN1A, SCN2A, SCN3A, and SCN8A, encoding the four neuronal voltage-gated sodium channels Na V 1.1, Na V 1.2, Na V 1.3, and Na V 1.6, are responsible for a significant fraction of early onset genetic epilepsies and neurodevelopmental disorders (NDDs). 1 Modern sequencing techniques have revolutionized the way we diagnose the genetic causes for these disorders, opening the door to precision medicine. However, it is often difficult to predict the impact of a variant without prior functional characterization.…”

Section: Introductionmentioning

confidence: 99%

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Brunklaus

Steckler

et al. 2020

Epilepsia

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Objective Voltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN‐related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. Methods We analyzed genotype‐phenotype correlations in large SCN‐patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. Results Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy‐associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain‐of‐function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. Significance Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.

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“…Ca v s that were particularly informative in pathogenic versus neutral variant prediction. First, we simply counted how many genes have the same reference aa as the consensus sequence in the gene family alignment, similar to the parazscore (Lal et al, 2017). Secondly, we constructed estimates of ancestry informed selection pressure to explicitly account for the shared evolutionary history of paralog genes.…”

Section: Ancestry Conditional Site-specific Selection Scorementioning

confidence: 99%

Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels

Heyne

Báez-Nieto

Iqbal

et al. 2019

Preprint

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Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) which is not only corresponding to clinical disease manifestations, but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. Based on known genedisease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence-and structure-based features we predict LOF-or GOFassociated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice.

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Gene family information facilitates variant interpretation and identification of disease-associated genes

Cited by 20 publications

References 47 publications

The spectrum of intermediate SCN8A‐related epilepsy

The spectrum of intermediate SCN8A‐related epilepsy

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels

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