Characteristics and genetic analysis of patients suspected with early-onset systemic lupus erythematosus

Abstract

Background: Systemic lupus erythematosus (SLE) is rarely diagnosed before 5-years-old. Those with disease onset at a very young age are predicted by a higher genetic risk and a more severe phenotype. We performed whole-exome sequencing to survey the genetic etiologies and clinical manifestations in patients fulfilling 2012 SLICC SLE classification criteria before the age of 5.

Case presentation: Among the 184 childhood-onset SLE patients regularly followed in a tertiary medical center in Taiwan, 7 cases (3.8%) of which onset ≦ 5 years of age were identified for characteristic review and genetic analysis. Compared to those onset at elder age, cases onset before the age of 5 are more likely to suffer from proliferative glomerulonephritis, renal thrombotic microangiopathy, neuropsychiatric disorder and failure to thrive. Causative genetic etiologies were identified in 3. In addition to the abundance of autoantibodies, patient with homozygous TREX1 (c.292_293 ins A) mutation presented with chilblain-like skin lesions, peripheral spasticity, endocrinopathy and experienced multiple invasive infections. Patient with SLC7A7 (c.625 + 1 G > A) mutation suffered from profound glomerulonephritis with full-house glomerular deposits as well as hyperammonemia, metabolic acidosis and episodic conscious disturbance. Two other cases harbored variants in lupus associating genes C1s, C2, DNASE1 and DNASE1L3 and another with CFHR4. Despite fulfilling the classification criteria for lupus, many of the patients required treatments beyond conventional therapy.

Conclusions: Genetic etiologies and lupus mimickers were found among a substantial proportion of patients suspected with early-onset SLE. Detail clinical evaluation and genetic testing are important for tailored care and personalized treatment.

Keywords: Childhood lupus; Genetic study; Lupus mimics; SLC7A7; Systemic lupus erythematous; TREX1.

Fig. 1

Clinical features and genetic analysis of Case 1. a Chilblain lupus erythematosus lesions over the ventral aspect of 4^th toe and dorsal aspect of the index finger and thumb. b The spectrum of brain changes, including encephalopathy with leukodystrophy on brain computed tomography. c Sanger sequencing of identified alterations with whole exome sequencing of a patient and her parents. d The family pedigree of case 1 with the TREX1 mutation

Fig. 2

Renal histology and genetic/complementary DNA analysis of Case 2 & 3. a In the genomic level, the G before the last nucleotide of the intron is mutated to A, causing the splicing site to shift. b Histopathological examination of a renal biopsy showed membranoproliferative glomerulonephritis. An immunofluorescence micrograph illustrating diffuse glomerular C3 deposition. c Complementary DNA (cDNA) analysis revealed a skipping of exon 4. The band on gel electrophoresis confirmed a shorter cDNA product from the patient. d The family pedigree of Case 2 and 3 harboring heterozygous SLC7A7 mutations. The father of Case 2 and 3 deceased and the mother is negative for SLC7A7 mutation