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Homozygous duplication identified by whole genome sequencing causes LRBA deficiency

ABSTRACT: Homozygous duplication identified by whole genome sequencing causes LRBA deficiency

PROVIDER: PRJNA754456 | ENA |

REPOSITORIES: ENA

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Homozygous duplication identified by whole genome sequencing causes LRBA deficiency

Project description:Homozygous duplication identified by whole genome sequencing causes LRBA deficiency

| PRJNA754455 | ENA

Homozygous duplication identified by whole genome sequencing causes LRBA deficiency.

Project description:In more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration.

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iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

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iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

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Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

Project description:Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

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Transcription profiling of Drosophila deficiency hemizygotes and a duplication hemizygote reveals buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster

Project description:Chromosomal instability which involves deletion and duplication of chromosomes or chromosome parts is a common feature of cancers, and deficiency screens are commonly used as a method to find genes involved in different biological pathways. Still, how gene expression from whole chromosomes or large chromosomal domains is affected by deficiencies, duplications or chromosome loss is largely unknown. Using expression microarrays of deficiency hemizygotes and a duplication hemizygote we show that expressed genes are significantly buffered when present in a deficiency hemizygote and that the buffering effect is general and not mainly caused by feedback regulation of individual genes. Differentially expressed genes are in general better buffered than ubiquitously expressed genes when present in one copy. When present in three copies, differentially expressed genes are in general less buffered than ubiquitously expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest that general mechanisms exist to stimulate and to repress gene expression of aneuploidy regions and on the 4th chromosome this compensation is mediated by POF (Painting of Fourth). Experiment Overall Design: We prepared total RNA from flies heterozygous for three different deletions, Df(2L)J-H, Df (2L)ED4470, Df(2L)ED4651, flies heterozygous for the duplication Dp(2;2)Cam3 and flies with only one chromosome 4, or three copies of the 4th chromosome, as well as from wild type control flies. Three biological replicates of all genotypes were prepared.

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Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy

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Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

Project description:Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G>A (p.R167Q) mutation with ~5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.

2020-03-03 | GSE146212 | GEO

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