Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies

Abstract

Background: Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity.

Methods: We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identify cases that are explained by a single-gene (monogenic) cause.

Results: From January 2015 to June 2018 15 new cases of childhood-onset SLE were diagnosed in Edmond and Lily Safra Children's Hospital. By WES we identified causative mutations in four subjects in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. No molecular diagnoses were established on clinical grounds prior to genetic testing.

Conclusions: We identified a significant fraction of monogenic SLE etiologies using WES and confirm the genetic locus heterogeneity in childhood-onset lupus. These results highlight the importance of establishing a genetic diagnosis for children with severe or atypical lupus by providing accurate and early etiology-based diagnoses and improving subsequent clinical management.

Keywords: Monogenic; SLE; WES.

Fig. 1

Representative clinical findings in patients with monogenic SLE. Panel A – Occipital and lower extremities lesions noted in patients 1A with C1QC mutation, reveals palmoplantar erosive erythemic plaques and scarring alopecia. Panel B – Abnormal brain MRI scan of patient 2B with PTEN mutation shows non-specific parieto-occipital lesions affecting the white matter and cortical dysplasia. Panel C – Patient 3C with SLC7A7 and MAN2B1 mutations, exhibits a palmar erythema and diffuse abdominal papulosquamous rash. Panel D – Lung wedge biopsy of patient 3C shows: (a) sheets of large vacuolated macrophages in the interstitium (asterisks) and eosinophilic intra-alveolar exudate (arrow) H&E X 100. (b) The intra-alveolar exudate contains cholesterol clefts and it is PAS-positive and diastase resistant (PAS-diastase stain X 200). (c) Mild- to moderate alveolar wall thickening (H&E × 100). (d) Mild fibrosis (Masson trichrome stain × 100). (e) Diffuse inflammatory T-cell infiltration (CD3 immunostain × 200). (f) B- cell aggregates (CD20 immunostain × 200). (g) Part of alveolar spaces contain hemosiderin laden macrophages (Prussian blue stain × 200). Panel E – Chest CT angiography in patient 4D with STAT1 gain of function mutation, shows dilated ascending aorta with severe calcifications