Saba Jafarpour1, Abhik Banerjee2, Jonathan Santoro3
1Children’s Hospital of Los Angeles, 2Pediatrics, Children's Hospital Los Angeles, 3Department of Neurology, Children's Hospital Los Angeles
Objective:
This study sought to evaluate if variants in genes of immune regulation are present on whole exome sequencing (WES) in persons with DSRD and to determine if these variants are associated with clinical characteristics of disease severity, neurodiagnostic study abnormalities and immunotherapy responsiveness.
Background:
Individuals with Down Syndrome Regression Disorder (DSRD) have been reported to be immunotherapy responsive in several studies. Although hypotheses regarding interferon signaling abnormalities in individuals with DSRD and other autoimmune conditions Down syndrome exist, the heterogeneity both with regards to diagnostic studies and immunotherapy response may indicate multiple mechanisms.
Design/Methods:
A single-center, retrospective, chart-based, review was performed for individuals with DSRD who had whole exome sequencing performed as part of their diagnostic work up. For in silico prediction of variant functional effects, we used Polymorphism Phenotyping v2 (PolyPhen-2), and Sorting Intolerant from Tolerant (SIFT) with Genome Reference Consortium Human Build 37 (GRCh37/hg19) assembly input.
Results:
Of 41 individuals with WES testing, there were 8 individuals who were identified as having variants of unknown significance (20%). Variants (with PolyPhen and SIFT scores) included IRF7 (0.01, 0.53), SMARCAL1 (0.01, 0.31), CTLA4 (0.98, 0.10), LYST (0.01, 0.00), UNC13D (0.93, 0.02), BAZ1A (1.0, 0.0), XIAP (1.0, 0.01), RNASEH2A (1.0, 0.0) and DNASE1L3 (1.0, 0.07). Of these, XIAP (c.655G>A, p.Glu219Lys) and RNASEH2A (c.557G>A, p.R186Q) had SIFT scores predicting abnormal protein function. Individuals with any VUS were more likely to have a preceding trigger (p=0.03, 95%CI: 1.21-97.06), more rapid clinical decline with peak symptoms in less than one month (p=0.01, 95%CI: 1.67-52.06), and more likely to have MRI abnormalities (p<0.001, 95%CI: 4.89-527.71).
Conclusions:
The etiology of DSRD remains unknown although a minority of individuals with DSRD were observed to have VUS’s in genes of immune regulation. While unlikely to be causative, these variants may increase the risk of immune dysregulation in individuals with DS.