Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

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Prevalence of pathogenic germline risk variants (PVs) in 1,829 renal cell carcinoma (RCC) patients (pts).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.659 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 659-659

Author(s):

Sarah Abou Alaiwi ◽

Amin Nassar ◽

Elio Adib ◽

Elie Akl ◽

Stefan Groha ◽

...

Keyword(s):

Copy Number Variants ◽

Susceptibility Genes ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Commercial Laboratory ◽

Pathogenic Variants ◽

Risk Variants ◽

Predisposition Genes ◽

N 93 ◽

Recombination Pathway

659 Background: Hereditary RCCs account for 3-5% of all RCC cases. The prevalence and significance of germline PVs of RCC have not been fully characterized. Methods: We evaluated the frequency of pathogenic and likely pathogenic variants, referred to as PVs, in 1829 high-risk RCC pts who underwent targeted clinical germline testing (1-134 genes) at a commercial laboratory. PVs, including single nucleotide variants/indels/ copy number variants, were confirmed using orthogonal technology in accordance with Invitae’s standard operating practices. Actionable genes were defined as established cancer-predisposition genes that confer a higher risk for any cancer phenotype and for which enhanced screening and family genetic testing are recommended by the National Comprehensive Cancer Network. We focused our analysis on genes tested in more than 100 pts (n=93). Results: Among 1892 pts, 54.9% were male, and 68.9% were Caucasians, with median age 50 (range:1-87) years at RCC diagnosis. 11.8% (n=215) of pts had at least 2 primary RCCs, and 30.7% (n= 561) had a personal history of another cancer. The cumulative frequency of pts with PVs was 17.7%. PVs in known RCC susceptibility genes such as FH, FLCN, and SDHB were detected in 1.8% (29/1622), 1.22% (120/1634) and 0.64% (11/1727) of pts respectively. PVs in other cancer-associated genes were most frequently reported in CHEK2 (loss-of-function variants, 30/1276, 2.4%), MUTYH (19/1124, 1.7%), and BRCA2 (17/1276, 1.33%). PVs in DNA-damage repair genes (DRG) accounted for 71.8% of PVs and, overall, were detected in 12.7% of pts. Among the DRG, PVs in the homologous recombination pathway (ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RECQL4, WRN) were the most prevalent (7.8%) whereas the mismatch repair pathway (MLH1, MSH2, MSH6, PMS2) was altered in only 0.7% of pts. Of the examined cohort, 9.7% of pts had ≥1 actionable PV. In non-Caucasians, BRCA2 PVs were the most common (6/273, 2.20%). Conclusions: PVs were identified in 17.7% of RCC subjects, most of which (71.8%) were in DRG, with »10% of pts having actionable variants. Our work is concordant with known RCC susceptibility genes and potentially highlights novel risk genes that should be validated in future studies.

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A large deletion in the COL2A1 gene expands the spectrum of pathogenic variants causing bulldog calf syndrome in cattle

Acta Veterinaria Scandinavica ◽

10.1186/s13028-020-00548-w ◽

2020 ◽

Vol 62 (1) ◽

Cited By ~ 1

Author(s):

Joana Gonçalves Pontes Jacinto ◽

Irene Monika Häfliger ◽

Anna Letko ◽

Cord Drögemüller ◽

Jørgen Steen Agerholm

Keyword(s):

De Novo ◽

Genetic Disorders ◽

Polymerase Chain Reaction Analysis ◽

Large Deletion ◽

Whole Genome Sequence ◽

De Novo Mutation ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Pathogenic Variants ◽

Base Pair Deletion

Abstract Background Congenital bovine chondrodysplasia, also known as bulldog calf syndrome, is characterized by disproportionate growth of bones resulting in a shortened and compressed body, mainly due to reduced length of the spine and the long bones of the limbs. In addition, severe facial dysmorphisms including palatoschisis and shortening of the viscerocranium are present. Abnormalities in the gene collagen type II alpha 1 chain (COL2A1) have been associated with some cases of the bulldog calf syndrome. Until now, six pathogenic single-nucleotide variants have been found in COL2A1. Here we present a novel variant in COL2A1 of a Holstein calf and provide an overview of the phenotypic and allelic heterogeneity of the COL2A1-related bulldog calf syndrome in cattle. Case presentation The calf was aborted at gestation day 264 and showed generalized disproportionate dwarfism, with a shortened compressed body and limbs, and dysplasia of the viscerocranium; a phenotype resembling bulldog calf syndrome due to an abnormality in COL2A1. Whole-genome sequence (WGS) data was obtained and revealed a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons of COL2A1. Polymerase chain reaction analysis and Sanger sequencing confirmed the breakpoints of the deletion and its absence in the genomes of both parents. Conclusions The pathological and genetic findings were consistent with a case of “bulldog calf syndrome”. The identified variant causing the syndrome was the result of a de novo mutation event that either occurred post-zygotically in the developing embryo or was inherited because of low-level mosaicism in one of the parents. The identified loss-of-function variant is pathogenic due to COL2A1 haploinsufficiency and represents the first structural variant causing bulldog calf syndrome in cattle. Furthermore, this case report highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for genetic disorders in cattle.

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Recent Advances in Understanding the Genetic Architecture of Autism

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-121219-082309 ◽

2020 ◽

Vol 21 (1) ◽

pp. 289-304 ◽

Cited By ~ 1

Author(s):

Caroline M. Dias ◽

Christopher A. Walsh

Keyword(s):

Genetic Architecture ◽

De Novo ◽

Clinical Care ◽

Copy Number Variants ◽

Autism Spectrum ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Recent Advances ◽

Insight Into

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes—have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants—both inherited and de novo—have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

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One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106189 ◽

2019 ◽

Vol 57 (1) ◽

pp. 53-61 ◽

Cited By ~ 4

Author(s):

Florentia Fostira ◽

Irene Kostantopoulou ◽

Paraskevi Apostolou ◽

Myrto S Papamentzelopoulou ◽

Christos Papadimitriou ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Susceptibility Gene ◽

Gene Panel ◽

Control Analysis ◽

Loss Of Function ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Clinical Changes

BackgroundGene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.MethodsTo further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.ResultsHerein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.ConclusionStudying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

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Genetic identification and characterization of Lynch syndrome in a multi-ethnic biobank.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1520 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1520-1520

Author(s):

Rachel Rosenblum ◽

Sabrina A. Suckiel ◽

Gillian M. Belbin ◽

Sinead Cullina ◽

Judy H. Cho ◽

...

Keyword(s):

Lynch Syndrome ◽

Diagnostic Criteria ◽

Sequence Data ◽

Genetic Identification ◽

European Ancestry ◽

Gene Variants ◽

Loss Of Function ◽

Mmr Genes ◽

Pathogenic Variants ◽

Increased Risk

1520 Background: Lynch syndrome (LS), caused by germline pathogenic variants in mismatch repair (MMR) genes, results in increased risk of colorectal, endometrial, and other cancers. LS has a prevalence of ~1 in 440 in European ancestry populations; prevalence data in other populations are limited. We identified and characterized carriers of pathogenic MMR gene variants in the multi-ethnic Bio Me Biobank in New York City. Methods: Exome sequence data from ~31,000 Bio Me participants were evaluated for known (per ClinVar) and predicted (loss-of-function) pathogenic variants in MMR genes. Population groups were defined by genetic ancestry. Participant questionnaires and electronic health records (EHRs) of carriers were reviewed for personal or family history of malignancy. Results: We identified 48 carriers of 33 distinct pathogenic variants in PMS2 (48%), MLH1 (27%), MSH6 (15%), and MSH2 (10%), for an estimated prevalence of ~1/640 in the Bio Me Biobank. Prevalence was higher among individuals of Non-Jewish European (N = 14; 1/400) and African (N = 14; 1/490) ancestries, compared to Puerto Rican (N = 8; 1/640), Ashkenazi Jewish (N = 6; 1/690), and other/mixed (N = 6) ancestries. Carriers had a median age of 56 (range 27 to 77) years and were 50% female. Overall rate of malignancy among carriers was 38%, with the lowest rate in PMS2 (26%) and the highest rate in MSH6 (57%) variant carriers. We found a high prevalence of endometrial cancer (21% of female carriers) and a lower prevalence of colorectal cancer (4% of all carriers). Only 2 carriers (4%) had a diagnosis of LS in their EHRs, and only 1 carrier met Amsterdam diagnostic criteria for LS. Conclusions: These data show that ~0.15% of participants in a multi-ethnic biobank are carriers of pathogenic MMR gene variants and suggest that the prevalence is higher in European and lower in non-European ancestry populations. Notably, most carriers do not have a clinical diagnosis of LS and do not meet diagnostic criteria for LS. Carriers demonstrate variable rates of cancer, which may contribute to under-diagnosis of LS. Genomic screening for pathogenic MMR variants may lead to earlier diagnosis of LS and improved outcomes.

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Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Molecular Psychiatry ◽

10.1038/s41380-020-01006-9 ◽

2021 ◽

Author(s):

Xiaoming Jia ◽

Fernando S. Goes ◽

Adam E. Locke ◽

Duncan Palmer ◽

Weiqing Wang ◽

...

Keyword(s):

Bipolar Disorder ◽

Meta Analysis ◽

Common Variant ◽

European Ancestry ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Protein Coding ◽

Significant Enrichment ◽

Coding Variants

AbstractBipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

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Genomic analyses of all known putative familial hypercholesterolemia mutations showcase the value and limitations of public familial hypercholesterolemia mutation databases

European Heart Journal ◽

10.1093/ehjci/ehaa946.2994 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

K Dobretz ◽

A.S Karunajeewa ◽

B Judja-Sato ◽

T Von Kaenel ◽

F Mach ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Copy Number Variants ◽

P Value ◽

Funding Source ◽

Single Nucleotide Variants ◽

Additional Information ◽

Pathogenic Variants ◽

Variant Frequency ◽

Frequent Variant ◽

Mutation Databases

Abstract Background/Introduction Familial hypercholesterolemia (FH) is genetically very heterogeneous and genomic and locus-specific public databases describing putative FH mutations are assumed to be of limited clinical utility because of classification errors. Purpose A description of all currently known publicly available putative FH mutations in order to determine the reliability of the classification of FH mutations described. Methods The LOVD and ClinVar databases were interrogated for the phenotype and genes of interest. Additional information on each variant was obtained using the Bioconductor toolset, gnomAD, and GETex. Results Currently know putative FH variants included 4,529 variants (97.2%) in the classical FH-genes LDLR (61%), PCSK9 (10%), and APOB (29%). Single nucleotide variants constituted 83% and 17% were copy number variants. Exonic variants contributed 78%, 14% of the variants were intronic, 7% large CNV, and 1% in upstream or downstream regions. Of the 4,529 variants, 45% were classified as pathogenic or likely-pathogenic (Fig. 1a). The ratio of exonic/intronic variants was 10.1 for pathogenic variants, 6.9 for likely pathogenic variants, 2.8 for likely benign and 1.4 for benign variants (p-value for class difference <2x10–6). For 502 frameshift mutations in exons that are particularly damaging, only 93.2% were classified as pathogenic or likely-pathogenic and 1.7% as benign or likely benign (Fig. 1b). Across 222 exon-covering deletions of >100 nucleotides, also particularly damaging, only 90.5% were classified as pathogenic or likely-pathogenic. Of the 4,529 variants, 1,561 (34.5%) were polymorphic in gnomAD. For these variants, the gnomAD sample size was on average 227420 (26102–282902). Of all 1,561 polymorphic variants in gnomAD 182 (11.6%) were classified as pathogenic or likely-pathogenic (Fig. 1c) and the variant frequency ranged from 10–4 to 10–6 (average 1.8x10–5), 43 with a frequency >1.8x10–5. Among variants found in gnomAD and classified as non-pathogenic, we observed ∼2000x higher frequencies (average 0.04). Of the 4,529 variants, 100 matched eQTLs or sQTLs in GTEx, none was annotated as pathogenic (Fig. 1d). Conclusion We review all currently known putative FH mutations with pathogenic or likely-pathogenic variants being mostly exonic. Highly damaging mutations are largely classified as pathogenic or likely-pathogenic, but up to 9% are not classified as pathogenic in the two public FH mutation databases. Assuming an FH population prevalence of 1/250 and 2000 pathogenic variants with the most frequent variant 10x more frequent than the average, we expect most pathogenic FH mutations at frequencies <2x10–5. We found 46 pathogenic or likely pathogenic variants to have a frequencies of >2x10–5 in the general population, evidence for misclassification. No pathogenic FH variant was found among GETEx eQTLs or sQTLs. Our data showcase the utility and weaknesses of the current public FH mutation databases. FH variants overview Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Hôpitaux Universitaire de Genève - Fonds privés

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Molecular Inversion Probe-Based Sequencing of USH2A Exons and Splice Sites as a Cost-Effective Screening Tool in USH2 and arRP Cases

International Journal of Molecular Sciences ◽

10.3390/ijms22126419 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6419

Author(s):

Janine Reurink ◽

Adrian Dockery ◽

Dominika Oziębło ◽

G. Jane Farrar ◽

Monika Ołdak ◽

...

Keyword(s):

Screening Tool ◽

Usher Syndrome ◽

Copy Number Variants ◽

Genetic Diagnosis ◽

Cost Effective ◽

Single Nucleotide Variants ◽

Effective Screening ◽

Pathogenic Variants ◽

Future Therapy ◽

Molecular Inversion Probe

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.

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BAP1: The first mutated gene causing familial uveal melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10521 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10521-10521

Author(s):

Johan Hansson ◽

Charlotta All-Eriksson ◽

Hildur Helgadottir ◽

Daniel Edsgard ◽

Rainer Tuominen ◽

...

Keyword(s):

Uveal Melanoma ◽

Massively Parallel Sequencing ◽

Sequence Data ◽

Susceptibility Gene ◽

Young Female ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Causative Gene ◽

Familial Predisposition ◽

Rare Malignancy

10521 Background: Uveal melanoma (UM) is a rare malignancy with a poor prognosis. Familial predisposition to UM is rare and accounts for only a few percent of all cases. The genetic background of hereditary UM is unknown and the aim of our project was to identify susceptibility gene(s) for UM. Methods: We identified a family with hereditary predisposition for UM – the proband of which is a young female diagnosed with UM at age 16 who within 6 months developed liver metastases. We also identified two older paternal relatives who were diagnosed with UM at 39 and 44 years of age, respectively. We performed massively parallel sequencing using the Illumina Hiseq2000 technology on germline DNA from the proband, her parents and a healthy sibling. After QC and mapping against the human reference genome the average coverage across the exome was between 35 and 86 for the four sequenced samples. Results: Out of more than 260,000 single nucleotide variants (SNVs) and small insertion / deletion variants (indels), 51 gene variants were filtered out by being novel, shared by the affected proband and her father (considered an obligate mutation carrier), but not by the healthy mother, of predicted functional importance and /or located within strongly conserved regions. The strongest candidate among these was a loss of function-variant in the BAP1 gene, since BAP1 has been suggested as a tumor suppressor in several cancer-related syndromes, including cases of UM. The sequence data indicated an insertion of one base-pair in exon 3 of the BAP1 genecausing a frame-shift and subsequently a truncated protein lacking all its functional domains. The mutation was also present in UM tumor tissue from the two deceased paternal relatives and was found to segregate with the UM phenotype in the family. We also detected loss of heterozygosity in the tumor of the proband, supporting BAP1 as the causative gene in this family. Conclusions: The identification of BAP1 as the gene responsible for this syndrome is the first demonstration of a germline mutation causing UM. This enables us to identify and monitor risk individuals belonging to mutation positive families with predisposition to UM, and possibly other cancer syndromes. We are continuously screening other cases of familial UM for mutations in BAP1.

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Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome

Frontiers in Neurology ◽

10.3389/fneur.2021.761892 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peter Sparber ◽

Svetlana Mikhaylova ◽

Varvara Galkina ◽

Yulia Itkis ◽

Mikhail Skoblov

Keyword(s):

Missense Variant ◽

Febrile Seizures ◽

Dravet Syndrome ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Pathogenic Variants ◽

Uncertain Significance ◽

Functional Investigation ◽

Coding Variants

Pathogenic variants in the SCN1A gene are associated with a spectrum of epileptic disorders ranging in severity from familial febrile seizures to Dravet syndrome. Large proportions of reported pathogenic variants in SCN1A are annotated as missense variants and are often classified as variants of uncertain significance when no functional data are available. Although loss-of-function variants are associated with a more severe phenotype in SCN1A, the molecular mechanism of single nucleotide variants is often not clear, and genotype-phenotype correlations in SCN1A-related epilepsy remain uncertain. Coding variants can affect splicing by creating novel cryptic splicing sites in exons or by disrupting exonic cis-regulation elements crucial for proper pre-mRNA splicing. Here, we report a novel case of Dravet syndrome caused by an undescribed missense variant, c.4852G>A (p.(Gly1618Ser)). By midigene splicing assay, we demonstrated that the identified variant is in fact splice-affecting. To our knowledge, this is the first report on the functional investigation of a missense variant affecting splicing in Dravet syndrome.

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