Family-Based Whole-Exome Sequencing for Identifying Novel Variants in Consanguineous Families with Schizophrenia

Shirzad, Hadi; Beiraghi, Narges; Kachoui, Mojgan Ataei; Akbari, Mohammad Taghi

doi:10.5812/ircmj.35788

Cited by 2 publications

(2 citation statements)

References 37 publications

(36 reference statements)

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“…At this juncture identifying such highly penetrant rare variants in functionally relevant gene(s) segregating with the disease phenotype in familial forms of SZ is appealing. We and others in the recent past have used small to medium size families with SZ and reported moderately to highly penetrant rare protein coding variants segregating with disease phenotype (Egawa et al, 2016;Homann et al, 2016;Hornig et al, 2017;John et al, 2018John et al, , 2017Kos et al, 2016;Shirzad et al, 2017;Steinberg et al, 2017;Timms et al, 2013;Zhou et al, 2016) Several genes identified in these studies were broadly connected with glutamatergic pathway and supported the commonly accepted glutamatergic dysfunction hypothesis. These studies reaffirm the highly complex and heterogeneous nature of SZ and at the same time provide evidence for a major/predominant role of glutamatergic pathway genes in SZ etiology based on common and rare variants identified in GWASs and WES respectively.…”

Section: Introductionsupporting

confidence: 62%

Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study

John

Kukshal

Sharma

et al. 2019

Schizophrenia Research

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The contribution of both common and rare risk variants to the genetic architecture of schizophrenia (SZ) has been documented in genome-wide association studies, whole exome and whole genome sequencing approaches. As SZ is highly heritable and segregates in families, highly penetrant rare variants are more likely to be identified through analyses of multiply affected families. Further, much of the gene mapping studies in SZ have utilized individuals of Caucasian ancestry. Analysis of other ethnic groups may be informative. In this study, we aimed at identification of rare, penetrant risk variants utilizing whole exome sequencing (WES) in a threegeneration Indian family with multiple members affected. Filtered data from WES, combined with in silico analyses revealed a novel heterozygous missense variant (NM_080841:c.1730C>G:p.T577R; exon18) in Protein tyrosine phosphatase, receptor type A (PTPRA 20p13). The variant was located in an evolutionary conserved position and predicted to be damaging. Screening for variants in this gene in the WES data of an independent SZ cohort (n = 350) of matched ethnicity, identified five additional rare missense variants with MAF < 0.003, which were also predicted to be damaging. In conclusion, the rare missense variants in PTPRA identified in this study could confer risk for SZ. This has also derived support from concordant *

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Section: Introductionsupporting

confidence: 62%

Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study

John

Kukshal

Sharma

et al. 2019

Schizophrenia Research

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“…More recent whole exome sequencing (WES)/whole genome sequencing in small/modest sized multiplex families have added to the list of inherited rare protein coding variants. These include variants in previously analyzed candidate genes namely RELN (Zhou et al, 2016), UNC13B (Egawa et al, 2016), GRM5, LRP1B, and PPEF2 (Timms et al, 2013),GRIN3B (Hornig et al, 2017), SHANK2 and SMARCA1 (Homann et al, 2016), ANKK1 (Shirzad et al, 2016), RBM12 (Steinberg et al, 2017), TAAR1 (John et al, 2017), TIMP2 (John et al, 2018)and PTPRA (John et al, 2018).These insightful studies suggest the importance of such variants with large/moderate effects in disease development or in increasing the risk in the respective families with disease clustering.…”

Section: Introductionmentioning

confidence: 86%

Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouringde novomutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

John

Kukshal

Bhatia

et al. 2019

Preprint

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Clinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rare de novo variant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets with de novo protein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease.More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.Polyphen2_HDIV, Polyphen2_HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, M-CAP and fathmm-MKL_coding and CADD scaled score =>15; or CADD scaled score>=10 and <15 but predicted to be damaging by at least two different software listed above) for further analysis. All these tools were part of Kggseq (Li et al., 2012). All these variants are henceforth referred to as "deleterious shared variants".

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Family-Based Whole-Exome Sequencing for Identifying Novel Variants in Consanguineous Families with Schizophrenia

Abstract: Background: Schizophrenia (SCZ) is a complex neuropsychiatric disorder characterized by pronounced genetic heterogeneity. Much of the genetic architecture of the disorder has not yet been clearly elucidated.

Cited by 2 publications

References 37 publications

Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study

Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study

Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouringde novomutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

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