A dataset of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early‐onset monogenic disorders in Indians

Abstract Background Recurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet’s disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations. Objective To investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation. Methods Subjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score. Results We enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results. Conclusions Although recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

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Polygenic Contribution in Individuals With Early-Onset Coronary Artery Disease

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.117.001849 ◽

2018 ◽

Vol 11 (1) ◽

Cited By ~ 23

Author(s):

Sébastien Thériault ◽

Ricky Lali ◽

Michael Chong ◽

James L. Velianou ◽

Madhu K. Natarajan ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Familial Hypercholesterolemia ◽

Genetic Risk ◽

Early Onset ◽

Genetic Risk Score ◽

Fold Increase ◽

Uk Biobank ◽

Monogenic Disorders ◽

Artery Disease

Background Despite evidence of high heritability, monogenic disorders are identified in a minor fraction of individuals with early-onset coronary artery disease (EOCAD). We hypothesized that some individuals with EOCAD carry a high number of common genetic risk variants, with a combined effect similar to Mendelian forms of coronary artery disease, such as familial hypercholesterolemia. Methods and Results To confirm the polygenic contribution to EOCAD (age of ≤40 years for men and ≤45 years for women), we calculated in 111 418 British participants from the UK Biobank cohort a genetic risk score (GRS) based on the presence of 182 independent variants associated with coronary artery disease (GRS182). Participants with a diagnosis of EOCAD who underwent a revascularization procedure (n=96) had a significantly higher GRS182 ( P =3.21×10 −9 ) than those without EOCAD. An increase of 1 SD in GRS182 corresponded to an odds ratio of 1.84 (1.52–2.24) for EOCAD. The prevalence of a polygenic contribution that increased EOCAD risk similar to what is observed in heterozygous familial hypercholesterolemia was estimated at 1 in 53. In a local cohort of individuals with EOCAD (n=30), GRS182 was significantly increased compared with UK Biobank controls ( P =0.001). Seven participants (23%) had a GRS182 corresponding to an estimated 2-fold increase in EOCAD risk; none had a rare mutation involved in monogenic dyslipidemia or EOCAD. Conclusions These results suggest a significant polygenic contribution in individuals presenting with EOCAD, which could be more prevalent than familial hypercholesterolemia. Determination of the polygenic risk component could be included in the diagnostic workup of patients with EOCAD.

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389 A Candidate Gene Study of Rare Monogenic Disorders With IBD-Like Phenotype Identified Rare Variants in XIAP Gene in a Cohort of Early-Onset IBD Patients

Gastroenterology ◽

10.1016/s0016-5085(15)30283-3 ◽

2015 ◽

Vol 148 (4) ◽

pp. S-81-S-82 ◽

Cited By ~ 1

Author(s):

Leila Amininejad ◽

Benoit Charloteaux ◽

Emilie Theatre ◽

Jacques Van Cauter ◽

Pierre Hayard ◽

...

Keyword(s):

Candidate Gene ◽

Early Onset ◽

Rare Variants ◽

Candidate Gene Study ◽

Monogenic Disorders ◽

Gene Study

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Early-Onset Obesity Caused by Monogenic Disorders

Current Pediatrics Reports ◽

10.1007/s40124-017-0132-9 ◽

2017 ◽

Vol 5 (3) ◽

pp. 100-110 ◽

Cited By ~ 1

Author(s):

Laura C. Page ◽

Melody Shi ◽

Michael Freemark

Keyword(s):

Early Onset ◽

Monogenic Disorders

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Comprehensive Targeted Sequencing Identifies Monogenic Disorders in Patients With Early-onset Refractory Diarrhea

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/mpg.0000000000002796 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Takashi Uchida ◽

Tasuku Suzuki ◽

Atsuo Kikuchi ◽

Fumihiko Kakuta ◽

Takashi Ishige ◽

...

Keyword(s):

Early Onset ◽

Targeted Sequencing ◽

Monogenic Disorders

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Functional and in-silico interrogation of rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

10.1101/781088 ◽

2019 ◽

Cited By ~ 3

Author(s):

Jamie M Ellingford ◽

Huw B Thomas ◽

Charlie Rowlands ◽

Gavin Arno ◽

Glenda Beaman ◽

...

Keyword(s):

In Silico ◽

Rna Splicing ◽

Messenger Rna ◽

Diagnostic Testing ◽

Mrna Splicing ◽

Analysis Framework ◽

Variant Prioritization ◽

Monogenic Disorders ◽

Splicing Mutations ◽

Uncertain Significance

AbstractPurposeTo develop a comprehensive analysis framework to identify pre-messenger RNA splicing mutations in the context of rare disease.MethodsWe assessed ‘variants of uncertain significance’ through six in-silico prioritization strategies. Firstly, through comparison to functional analyses, we determined the precise effect on splicing of variants identified through clinical multi-disciplinary meetings. Next, we calculated the sensitivity of in-silico prioritization strategies to distinguish known splicing mutations from common variation (>2% in allele frequency in gnomAD) within relevant disease genes. These approaches defined an accurate in-silico strategy for variant prioritization, which we retrospectively applied to a large cohort of 2783 individuals who had previously received genomic testing for rare genomic disorders. We assessed the clinical impact of such prioritization strategies alongside routine diagnostic testing strategies.ResultsWe identified 21 variants that potentially impacted splicing, and used cell based splicing assays to identify those variants which disrupted normal splicing. These findings underpinned new molecular diagnoses for 14 individuals. This process established that the use of pre-defined thresholds from a machine learning splice prediction algorithm, SpliceAI, was the most efficient method for variant prioritization, with a positive predictive value of 86%. We analysed 1,346,744 variants identified through diagnostic testing for 2783 individuals and observed that splicing variant prioritization strategies would improve clarity in clinical analysis for 15% of the individuals surveyed. Prioritized variants could provide new molecular diagnoses or provide additional support for molecular diagnosis for up to 81 individuals within our cohort.ConclusionWe present an in-silico and functional analysis framework for the assessment of variants impacting pre-messenger RNA splicing which is applicable across monogenic disorders. Incorporation of these strategies improves clarity in diagnostic reporting, increases diagnostic yield and, with the advent of targeted treatment strategies, can directly alter patient clinical management.Key HighlightsWe establish an in-silico and functional analysis framework for the incorporation of splice variant assessment into diagnostic testing that is applicable across monogenic disorders.After assessment of six distinct variant prioritization strategies, we concluded that SpliceAI was the best method to accurately identify genomic variation disrupting normal pre-mRNA splicing. We determined this through (i) functional assessment of novel ‘variants of uncertain significance’ described in this study, and (ii) calculation of sensitivity and specificity for prioritization strategies to distinguish known splicing mutations from common variants in the general population.We describe novel disease-causing variants with support from cell based functional assays which underpin autosomal recessive, autosomal dominant and X-linked Mendelian disorders. This includes variants which are deeply intronic, within the nearby splice region of canonical splice sites and variants which activate cryptic splice sites within the protein-coding regions of genes.We integrated the best performing variant prioritization strategy alongside clinical diagnostic testing for 2783 individuals referred to a well-established targeted gene panel test available through the UK National Health Service. We show that integration of such strategies will increase accuracy and clarity of diagnostic reporting, including the identification of variants which could provide new diagnoses and new carrier findings for referred individuals.Functional assessment is essential for accurate clinical assessment of variants disrupting pre-mRNA splicing. We show through cell based functional assessments that variants impacting splicing may have complex impacts on pre-mRNA splicing, which may cause multiple interpretable consequences according to ACMG guidelines.

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DOP085. A candidate gene study of rare monogenic disorders with IBD-like phenotype identified rare variants in XIAP gene in a cohort of early-onset IBD patients

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jju027.113 ◽

2015 ◽

Vol 9 (suppl 1) ◽

pp. S71-S72

Keyword(s):

Candidate Gene ◽

Early Onset ◽

Rare Variants ◽

Candidate Gene Study ◽

Monogenic Disorders ◽

Gene Study

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The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Scientific Reports ◽

10.1038/s41598-020-73482-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Neel Dhingani ◽

Conghui Guo ◽

Jie Pan ◽

Qi Li ◽

Neil Warner ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Early Onset ◽

Intestinal Atresia ◽

Compound Heterozygous ◽

Functional Studies ◽

Monogenic Disorders ◽

Whole Exome ◽

Inflammatory Bowel ◽

Tetratricopeptide Repeat Domain

Abstract Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

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