Maximizing insights from monogenic immune disorders

Barmada, Anis; Ramaswamy, Anjali; Lucas, Carrie L.

doi:10.1016/j.coi.2021.09.008

Cited by 2 publications

(3 citation statements)

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“…This includes susceptibility to infection or malignancy, autoimmune and autoinflammatory disorders, and allergies. PIDs have historically been branded as monogenic disorders with traditional Mendelian inheritance [ 21 ], but as more PIDs have been identified and we have gained better understanding of immune function and clinical pathogenesis, it has been recognized that these disorders often display variable penetrance and severity [ 22 ]. The term complex immune dysregulation syndrome captures the idea that many cases of aberrant immune activity that share similar presentation nevertheless may have heterogeneous, and sometimes oligogenic, causes [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…For both PIDs and VEOIBD, identifying the specific underlying genomic cause is important for treatment [ 21 , 23 , 30 , 33 ]. Gene-specific targeted therapies enable improved patient management and have been successfully used for several immune conditions [ 1 , 18 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previous cohorts of WES for the diagnosis of PIDs and VEOIBD have prioritized genes known to be associated with immune disorders [ 21 , 27 , 31 ]. Recent studies have shown that periodic reanalysis of variants results in additional diagnoses [ 40 , 41 , 42 , 43 , 44 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

Berger

Arafat

Chandrakasan

et al. 2022

JPM

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Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if targeted RNA sequencing could provide similar benefits for primary immunodeficiencies (PIDs) and very early-onset inflammatory bowel disease (VEOIBD), both of which are difficult to diagnose due to high heterogeneity and variable severity. We performed targeted RNA sequencing of a panel of 260 immune-related genes for a cohort of 13 patients (seven suspected PID cases and six VEOIBD) and analyzed variants, splicing, and exon usage. Exonic variants were identified in seven cases, some of which had been previously prioritized by exome sequencing. For four cases, allele specific expression or lack thereof provided additional insights into possible disease mechanisms. In addition, we identified five instances of aberrant splicing associated with four variants. Three of these variants had been previously classified as benign in ClinVar based on population frequency. Digenic or oligogenic inheritance is suggested for at least two patients. In addition to validating the use of targeted RNA sequencing, our results show that rare disease research will benefit from incorporating contributing genetic factors into the diagnostic approach.

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Section: Introductionmentioning

confidence: 99%