The Schizophrenia Variant V1282F in SCN2A Causes Functional Impairment of NaV1.2

Neuropsychiatric disorders such as schizophrenia are challenging to treat due to the biological complexity of the disease and the lack of knowledge of the underlying pathophysiology. Whole exome and genome sequencing studies have identified disease-linked rare variants in patients with large effect size. Here, we functionally characterize the schizophrenia linked variant V1282F in SCN2A, encoding the sodium channel Nav1.2. This variant was introduced into isogenic lines of hiPSCs using CRISPR/CAS9 genome editing tools. hiPSCs were then differentiated into cortical neurons to understand how the variant and gene may be contributing to disease. We observed a significant (~25%) decrease in sodium current in the V1282F neurons compared to control neurons, suggesting the mutation is causing a loss-of-channel function. These results were supported by recordings in recombinant cells overexpressing either the mutant or wildtype Nav1.2, with the mutant channel having significantly (~75%) lower current amplitude than wildtype. We hypothesize that this phenotype may contribute to disease either through the direct loss of neuronal activity or through subsequent abnormal neurodevelopment.

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Construction of an exome-wide risk score for schizophrenia based on a weighted burden test

10.1101/145961 ◽

2017 ◽

Cited By ~ 3

Author(s):

David Curtis

Keyword(s):

Risk Score ◽

Rare Variants ◽

Risk Scores ◽

Individual Risk ◽

Data Sets ◽

Weighted Sum ◽

Polygenic Risk ◽

Whole Exome ◽

Sequencing Studies ◽

Burden Test

SummaryPolygenic risk scores obtained as a weighted sum of associated variants can be used to explore association in additional data sets and to assign risk scores to individuals. The methods used to derive polygenic risk scores from common SNPs are not suitable for variants detected in whole exome sequencing studies. Rare variants which may have major effects are seen too infrequently to judge whether they are associated and may not be shared between training and test subjects. A method is proposed whereby variants are weighted according to their frequency, their annotations and to the genes they affect. A weighted sum across all variants provides an individual risk score. Scores constructed in this way are used in a weighted burden test and are shown to be significantly different between schizophrenia cases and controls using a five-way cross validation procedure. This approach represents a first attempt to summarise exome sequence variation into a summary risk score, which could be combined with risk scores from common variants and from environmental factors. It is hoped that the method could be developed further.

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Successful identification of rare variants using oligogenic segregation analysis as a prioritizing tool for whole-exome sequencing studies

BMC Proceedings ◽

10.1186/1753-6561-5-s9-s11 ◽

2011 ◽

Vol 5 (S9) ◽

Cited By ~ 8

Author(s):

France Gagnon ◽

Nicole M Roslin ◽

Mathieu Lemire

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Segregation Analysis ◽

Rare Variants ◽

Whole Exome ◽

Sequencing Studies

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Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽

10.3390/genes12030430 ◽

2021 ◽

Vol 12 (3) ◽

pp. 430

Author(s):

Steven R. Bentley ◽

Ilaria Guella ◽

Holly E. Sherman ◽

Hannah M. Neuendorf ◽

Alex M. Sykes ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Rare Variants ◽

Strong Family History ◽

Disease Mutations ◽

Whole Exome ◽

History Of ◽

Functional Consequences ◽

Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

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Exome sequencing in paediatric patients with movement disorders

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01688-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Anna Ka-Yee Kwong ◽

Mandy Ho-Yin Tsang ◽

Jasmine Lee-Fong Fung ◽

Christopher Chun-Yu Mak ◽

Kate Lok-San Chan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Movement Disorders ◽

Rare Variants ◽

Diagnostic Yield ◽

Neurological Diseases ◽

Genetic Diagnosis ◽

Potential Treatment ◽

Paediatric Patients ◽

Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

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Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

International Journal of Molecular Sciences ◽

10.3390/ijms22073625 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3625

Author(s):

Filomena Napolitano ◽

Giorgia Bruno ◽

Chiara Terracciano ◽

Giuseppina Franzese ◽

Nicole Piera Palomba ◽

...

Keyword(s):

Pompe Disease ◽

Rare Variants ◽

Clinical Symptoms ◽

Late Onset ◽

Respiratory Muscles ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Enzyme Replacement ◽

Whole Exome ◽

Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

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Genome-Wide Association and Whole Exome Sequencing Studies reveal a Novel Candidate Locus for Restless Legs Syndrome

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2021.104186 ◽

2021 ◽

pp. 104186

Author(s):

Ufuk Ergun ◽

Bahar Say ◽

Sezen Guntekin Ergun ◽

Ferda Emriye Percin ◽

Levent Inan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Restless Legs Syndrome ◽

Genome Wide Association ◽

Candidate Locus ◽

Restless Legs ◽

Genome Wide ◽

Whole Exome ◽

Sequencing Studies

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Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00455-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Alessandro Gialluisi ◽

Mafalda Giovanna Reccia ◽

Nicola Modugno ◽

Teresa Nutile ◽

Alessia Lombardi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Candidate Genes ◽

Rare Variants ◽

Late Onset ◽

High Specificity ◽

Diagnostic Tools ◽

Multi Stage ◽

Whole Exome ◽

Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

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319 Analysis of Rare Variants Identified by Whole Exome Sequence in Veo-IBD Patients Under Autosomal Recessive Model of Transmission

Gastroenterology ◽

10.1016/s0016-5085(15)30248-1 ◽

2015 ◽

Vol 148 (4) ◽

pp. S-71

Author(s):

Judith R. Kelsen ◽

Noor Dewany ◽

Eric Rappaport ◽

Petar Mamula ◽

David Piccoli ◽

...

Keyword(s):

Autosomal Recessive ◽

Rare Variants ◽

Recessive Model ◽

Whole Exome ◽

Exome Sequence ◽

Autosomal Recessive Model

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Biallelic Mutations in Ubiquitin-Specific Peptidase 53 (USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature

Pediatric and Developmental Pathology ◽

10.1177/10935266211051175 ◽

2021 ◽

pp. 109352662110511

Author(s):

Mukul Vij ◽

Srinivas Sankaranarayanan

Keyword(s):

Liver Transplantation ◽

Liver Disease ◽

Liver Biopsy ◽

Intrahepatic Cholestasis ◽

Cholestatic Liver Disease ◽

Review Of Literature ◽

Biallelic Mutation ◽

Whole Exome ◽

Sequencing Studies ◽

Biallelic Mutations

Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 ( USP53). We identified novel biallelic mutations in the USP53 gene in a 7-month-old infant with pruritus and progressive intrahepatic cholestasis. His liver biopsy showed portal and perivenular fibrosis with bland bilirubinostasis. His parents were asymptomatic heterozygous for the same mutation. He is currently on vitamin supplements and cholestyramine and his family has also been counseled for liver transplantation. Our report confirms that patients with biallelic mutation in USP53 develop cholestatic liver disease.

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