SavvyCNV: genome-wide CNV calling from off-target reads

Laver, Thomas W; Franco, Elisa De; Johnson, Matthew; Patel, Kashyap; Ellard, Sian; Mn, Weedon; Flanagan, Sarah E.; Wakeling, Matthew N.

doi:10.1101/617605

Cited by 11 publications

(7 citation statements)

References 25 publications

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“…Read depth was determined for the whole exome using GATK DepthOfCoverage, conforming to GATK Best Practices. Copy number variants (CNVs) were detected using SavvyCNV [ 13 ]. Variants were then filtered on call quality, gnomAD allele frequency, presence in databases of pathogenic variants, and inheritance pattern.…”

Section: Methodsmentioning

confidence: 99%

Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia

et al. 2021

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The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a homozygous frameshift alteration occurring in the last coding exon of the protein tyrosine phosphatase type 23 (PTPN23) gene in an extended Palestinian family associated with autosomal recessive complex HSP. PTPN23 encodes a catalytically inert non-receptor protein tyrosine phosphatase that has been proposed to interact with the endosomal sorting complex required for transport (ESCRT) complex, involved in the sorting of ubiquitinated cargos for fusion with lysosomes. In view of our data, we reviewed previously published candidate pathogenic PTPN23 variants to clarify clinical outcomes associated with pathogenic gene variants. This determined that a number of previously proposed candidate PTPN23 alterations are likely benign and revealed that pathogenic biallelic PTPN23 alterations cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, which may occur without intellectual impairment or involve more severe neurological disease. Together, these findings highlight the importance of the inclusion of the PTPN23 gene on HSP gene testing panels globally.

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Section: Methodsmentioning

confidence: 99%

Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia

et al. 2021

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“…Individuals with likely pathogenic and pathogenic variants according to American College of Medical Genetics and Genomics guidelines were excluded (14). We calculated homozygosity from the off-target reads of a targeted next-generation sequencing gene panel using a SavvyHomozygosity tool (https://github.com/rdemolgen/SavvySuite) (15). We only took forward patients with calculated homozygosity .6.5% to increase the likelihood of identifying a novel homozygous pathogenic variant.…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

“…GATK HaplotypeCaller was used to identify variants that were annotated using Alamut batch version 1.11 (SOPHiA Genetics, Rouen, France), and variants that failed the QD2 VCF filter or had less than five reads supporting the variant allele were excluded. Copy number variants were called by SavvyCNV, which uses read depth to judge copy number states (https://github.com/rdemolgen/SavvySuite) (15).…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

et al. 2021

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse b-cells, its precise role in human b-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired b-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human b-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of b-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human b-cell function and demonstrate the crucial role of MANF in this process.

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“…Further studies are required to investigate the cause of hyperinsulinism in these patients and in those with other copy number variant (CNV) syndromes which feature congenital hyperinsulinism such as Turner’s syndrome where the causative gene(s) have also not been definitively identified 23 , 24 . These large deletions can be screened for by targeted panels using an off-target CNV caller such as SavvyCNV 12 .…”

Section: Discussionmentioning

confidence: 99%

“…In the remaining three patients a deletion on 9p was detected using SavvyCNV (release 1) using off-target reads from the next-generation sequencing analysis of the known congenital hyperinsulinism genes. This technique calls 97.5% of true CNVs >1Mb 12 .…”

Section: Methodsmentioning

confidence: 99%

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

et al. 2020

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Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

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SavvyCNV: genome-wide CNV calling from off-target reads

Abstract: 8

Cited by 11 publications

References 25 publications

Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia

Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia

Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

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