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.

Genetic Approaches to Study Rheumatic Diseases and Its Implications in Clinical Practice

“…In patients with monogenic diseases (FMF, TRAPS, Blau, and CAPS), there are also well-known mutational hotspots, which can be tested using simple and inexpensive Sanger sequencing. 71 However, with the advent of NGS, thousands of genes can be sequenced in parallel, and therefore, genetic testing can be approached agnostically in patients presenting with nonspecific phenotypes. At present, the most widely used NGS applications include targeted disease gene panel (TGP) sequencing, wholeexome sequencing (WES), and whole-genome sequencing (WGS; Table 2).…”

“…This method is still used today in well‐characterized conditions in which gene(s) of known significance result in a highly specific phenotype. In patients with monogenic diseases (FMF, TRAPS, Blau, and CAPS), there are also well‐known mutational hotspots, which can be tested using simple and inexpensive Sanger sequencing 71 …”

Early diagnosis and clinical application of systemic lupus erythematosus based on a nomogram model

“…Patients can exhibit different clinical presentations and autoantibodies, and no single test has sufficient sensitivity or specificity for diagnosis [ 2 ]. The diagnosis of SLE mostly depends on clinical experience and exact serological clues, leading to a high risk of underdiagnosis in early-stage patients [ 3 ], which poses a great challenge for its early diagnosis.…”

Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance

“…The heteromeric y + LAT1 transporter, composed of a light subunit (encoded by SLC7A7 ) and a heavy subunit (encoded by SLC3A2 ), catalyzes the transmembrane efflux of arginine, lysine and ornithine in certain epithelial and non-epithelial cell types ( Broer, 2008 ; Broer and Gauthier-Coles, 2022 ; Palacin et al, 2004 ). LPI is a severe multi-system disorder characterized by growth failure ( Awrich et al, 1975 ; Goto et al, 1984 ; Carpenter et al, 1985 ; Nagata et al, 1987 ; Takada et al, 1987 ; Parini et al, 1991 ; Svedstrom et al, 1993 ; Parenti et al, 1995 ; Parsons et al, 1996 ; Kamoda et al, 1998 ; Korman et al, 2002 ; Moosa et al, 2005 ; Esposito et al, 2006 ; Gomez et al, 2006 ; Ogier de Baulny et al, 2012 ; Ko et al, 2012 ; Guzel-Ozanturk et al, 2013 ; Posey et al, 2014 ; Evelina et al, 2015 ; Bijarnia-Mahay et al, 2016 ; Deogaonkar and Shah, 2016 ; Noguchi et al, 2016 ; Mauhin et al, 2017 ; Stanley et al, 2017 ; Zhang and Cao, 2017 ; Olgac et al, 2020 ; Kang et al, 2019 ; Aljishi et al, 2020 ; Contreras et al, 2021 ; Andrews et al, 2021 ; Al-Qattan et al, 2021 ; Hashmi and Ahmed, 2022 ; Lee et al, 2022 ; Alqarajeh et al, 2020 ; Nicolas et al, 2016 ), short stature ( Awrich et al, 1975 ; Goto et al, 1984 ; Carpenter et al, 1985 ; Nagata et al, 1987 ; Takada et al, 1987 ; Parini et al, 1991 ; Parenti et al, 1995 ; Parsons et al, 1996 ; Kamoda et al, 1998 …”