Zollo et al. report that mutations in PRUNE1, a phosphoesterase superfamily molecule, underlie primary microcephaly and profound global developmental delay in four unrelated families from Oman, India, Iran and Italy. The study highlights a potential role for prune during microtubule polymerization, suggesting that prune syndrome may be a tubulinopathy.

EPT1 encodes an enzyme involved in the Kennedy pathway of phospholipid biosynthesis, important for cell membrane integrity. Ahmed et al. identify an EPT1 mutation that impairs enzyme activity and causes complex motor neuron degenerative disease. This is the first human disorder shown to arise through Kennedy pathway dysfunction.

Objective: To identify the genetic cause of pontocerebellar hypoplasia type III (PCH3). Methods:We studied the original reported pedigree of PCH3 and performed genetic analysis including genome-wide single nucleotide polymorphism genotyping, linkage analysis, wholeexome sequencing, and Sanger sequencing. Human fetal brain RNA sequencing data were then analyzed for the identified candidate gene. Results:The affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. Genome-wide single nucleotide polymorphism analysis confirmed the linkage to chromosome 7q we previously reported, and showed no other genomic areas of linkage. Whole-exome sequencing of 2 affected individuals identified a shared homozygous, nonsense variant in the PCLO (piccolo) gene. This variant segregated with the disease phenotype in the pedigree was rare in the population and was predicted to eliminate the PDZ and C2 domains in the C-terminus of the protein. RNA sequencing data of human fetal brain showed that PCLO was moderately expressed in the developing cerebral cortex.Conclusions: Here, we show that a homozygous, nonsense PCLO mutation underlies the autosomal recessive neurodegenerative disorder, PCH3. PCLO is a component of the presynaptic cytoskeletal matrix, and is thought to be involved in regulation of presynaptic proteins and synaptic vesicles. Our findings suggest that PCLO is crucial for the development and survival of a wide range of neuronal types in the human brain. Neurology ® 2015;84:1745-1750 GLOSSARY dbSNP 5 Single Nucleotide Polymorphism Database; ExAC 5 Exome Aggregation Consortium; FPKM 5 fragments per kilobase of exon per million fragments mapped; GATK 5 Genome Analysis Toolkit; indel 5 insertion-deletion; LOD 5 logarithm of odds; NHLBI 5 National Heart, Lung, and Blood Institute; PCH 5 pontocerebellar hypoplasia; PCH3 5 pontocerebellar hypoplasia type III.

Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.

In the current era of cardiovascular disease, the diagnosis of heart failure with preserved ejection fraction (HFpEF) is a well-recognized clinical entity that is equally prevalent but distinctly different from heart failure with reduced ejection fraction (HFrEF). Despite normal EF patients with this disease have similar morbidity and mortality rates compared with HFrEF, as well as a rising rate of hospitalizations. The pathophysiology of HFpEF is incompletely understood. The number of therapies with proven efficacy at improving longterm cardiovascular outcomes is limited. Women with heart failure syndromes, particularly the elderly, are much more likely to have a HFpEF phenotype at the time of their diagnosis. The purpose of this paper is to review the epidemiology, pathophysiology, clinical features, and current management strategies in HFpEF, especially as it pertains to women.