Homozygous duplication identified by whole genome sequencing causes LRBA deficiency

Background and aims Inflammatory bowel diseases (IBD) have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numeric and structural chromosomal abnormalities. Methods We performed a systematic literature search of databases PubMed and Embase; analysed gnomAD, Clinvar, the 100,000 Genomes Project and DECIPHER databases. Further we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility. Results A meta-analysis suggests that monosomy X (Turner syndrome) is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% CI 1.48-2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter Syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low (<2.6%). Conclusions Turner Syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.

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“… 39 Recently, a genome sequencing identified a 12.3 kb homozygous tandem duplication that disrupted the reading frame of the LRBA gene. 40 …”

Section: Resultsmentioning

confidence: 99%

Chromosomal Numerical Aberrations and Rare Copy Number Variation in Patients with Inflammatory Bowel Disease

Dirvanskyte

Gurram

Bolton

et al. 2022

Journal of Crohn's and Colitis

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“…The key terms used in the search were LRBA in HGMD, LRBA deficiency, LRBA variants, LRBA clinical presentation, and LRBA only in PubMed and Scopus. The reports spanned from 2012 to 2023 1,2,4,16–19,21–59 (Table S1). Reports that included well‐specified variants and their associated phenotypes were also included.…”

Section: Methodsmentioning

confidence: 99%

Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation

Perez‐Perez,

Santos‐Argumedo,

Rodriguez‐Alba

et al. 2024

Pediatric Allergy Immunology

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LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early‐onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X‐linked‐like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.

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“…LRBA deficiency (OMIM#614700) is inherited in an autosomal-recessive pattern. Genetic studies confirming biallelic mutations in LRBA are the gold standard for diagnosis, there have, however, been reported cases of failure of whole-exome sequencing (WES) to reveal a genetic aberration which was subsequently revealed through whole-genome sequencing (WGS) (Merico et al 2021 ).…”

Section: Autoimmune Enteropathymentioning

confidence: 99%

Beyond IBD: the genetics of other early-onset diarrhoeal disorders

2023

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Diarrhoeal disorders in childhood extend beyond the inflammatory bowel diseases. Persistent and severe forms of diarrhoea can occur from birth and are associated with significant morbidity and mortality. These disorders can affect not only the gastrointestinal tract but frequently have extraintestinal manifestations, immunodeficiencies and endocrinopathies. Genomic analysis has advanced our understanding of these conditions and has revealed precision-based treatment options such as potentially curative haematopoietic stem cell transplant. Although many new mutations have been discovered, there is frequently no clear genotype–phenotype correlation. The functional effects of gene mutations can be studied in model systems such as patient-derived organoids. This allows us to further characterise these disorders and advance our understanding of the pathophysiology of the intestinal mucosa. In this review, we will provide an up to date overview of genes involved in diarrhoeal disorders of early onset, particularly focussing on the more recently described gene defects associated with protein loosing enteropathy.

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Homozygous duplication identified by whole genome sequencing causes LRBA deficiency

Cited by 5 publications

References 46 publications

Chromosomal Numerical Aberrations and Rare Copy Number Variation in Patients with Inflammatory Bowel Disease

Chromosomal Numerical Aberrations and Rare Copy Number Variation in Patients with Inflammatory Bowel Disease

Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation

Beyond IBD: the genetics of other early-onset diarrhoeal disorders

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