ABSTRACT
Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.
ABSTRACT
Research on early renal function decline in diabetes is hampered by lack of simple tools for detecting trends (particularly systematic decreases) in renal function over time when GFR is normal or elevated. This study sought to assess how well serum cystatin C meets that need. Thirty participants with type 2 diabetes in the Diabetic Renal Disease Study met these three eligibility criteria: GFR >20 ml/min per 1.73 m2 at baseline (based on cold iothalamate clearance), 4 yr of follow-up, and yearly measurements of iothalamate clearance and serum cystatin C. With the use of linear regression, each individual's trend in renal function over time, expressed as annual percentage change in iothalamate clearance, was determined. Serum cystatin C in mg/L was transformed to its reciprocal (100/cystatin C), and linear regression was used to determine each individual's trend over time, expressed as annual percentage change. In paired comparisons of 100/cystatin C with iothalamate clearance at each examination, the two measures were numerically similar. More important, the trends in 100/cystatin C and iothalamate clearance were strongly correlated (Spearman r = 0.77). All 20 participants with negative trends in iothalamate clearance (declining renal function) also had negative trends for 100/cystatin C. Results were discordant for only three participants. In contrast, the trends for three commonly used creatinine-based estimates of GFR compared poorly with trends in iothalamate clearance (Spearman r < 0.35). Serial measures of serum cystatin C accurately detect trends in renal function in patients with normal or elevated GFR and provide means for studying early renal function decline in diabetes.
