Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

BACKGROUND: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate. METHODS: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES. RESULTS: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice. CONCLUSIONS: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.

Preadaptation to efficient respiratory maintenance is essential both for maximal longevity and the retention of replicative potential in chronologically ageing yeast.

Only recently have the studies of yeast ageing started to focus on the S288c-derived strains used extensively in genomics and on the longest lifespans. Chronological longevity (stationary (G(0)) survival) of such strains is greater when cells are pre-grown on a respiratory carbon source, as compared to when they are pre-grown on glucose (the latter a respiration-repressing sugar). Prior adaptation to efficient respiratory maintenance also ensures that such chronologically aged yeast cells still display a full replicative lifespan should they reenter the cell cycle. In contrast, cells that are pre-grown on glucose exhibit marked and progressive losses of replicative potential as they age chronologically in stationary phase. Increasing the respiratory activity in glucose-grown cultures by HAP4 gene overexpression increased survival and reversed the loss of replicative potential during a subsequent stationary phase. Adaptation to efficient respiratory maintenance is therefore important, not just for maximal longevity, but also for the maintenance of a full replicative lifespan by chronologically ageing cultures of yeast. In such respiration-adapted cultures, losses of the Sch9 protein kinase or Yca1 caspase both shortened lifespan. In contrast loss of Yap1, the major transcriptional regulator of the oxidative stress response, generated a small increase in chronological lifespan in certain strain backgrounds. It would appear, therefore, that any induction of oxidative stress response genes in chronologically ageing yeast is not operating to generate an increase in longevity, even though such protective effects might be expected from the increased proxidant status of these cells over time.