Citations

175 Background: The efficient delivery of adjuvant and salvage therapy after radical prostatectomy in patients with prostate cancer is hampered by a lack of biomarkers to assess the risk of clinically significant recurrence and progression. Methods: Mayo Clinic Radical Prostatectomy Registry (RP) patient specimens were selected from a case-control cohort with 14 years median follow-up for training and initial validation of an expression biomarker genomic classifier (GC). An independent, blinded case-cohort study of high-risk RP subjects was used to validate GC, comparing the performance of GC to a multivariate logistic regression clinical model (CM) and GC combined with clinical variables (genomic-clinical classifier, GCC) for predicting clinical recurrence (defined as positive bone or CT scan within 5 years after biochemical recurrence). The concordance index (c-index) and Cox model were used to evaluate discrimination and estimate the risk of clinical recurrence. Results: In the training subset (n=359), both GC and GCC had a c-index of 0.90 whereas CM had a c-index of 0.76. In the internal validation set (n=186), GC and GCC had a c-index of 0.76 and 0.75, while CM had a c-index of 0.69. In an independent high-risk study (n=219), GC and GCC had a c-index of 0.77 and 0.76, while CM had a c-index of 0.68. In subset analysis of Gleason score 7 patients within the high-risk group, GC and GCC showed improved discrimination with c-index of 0.78 and 0.76, respectively compared to 0.70 for CM. In the high-risk group, the risk of recurrence by GC model score quartiles at 5 years after RP was estimated at 1%, 5%, 5% and 18%. Conclusions: The GC model shows improved performance over CM in the prediction of clinical recurrence in a high-risk cohort and in subset analysis of Gleason score 7 patients. The addition of clinical variables to the GC model did not significantly contribute to classifier performance in patients with high-risk features. We are further testing the performance of the GC and GCC models and their usefulness in guiding decision-making (e.g., for the adjuvant therapy setting) in additional studies of prostate cancer clinical risk groups.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular findings of aneurysm and/or dissection of cerebral, thoracic, or abdominal arteries and skeletal findings. We report a case of a novel pathogenic variant in TGFBR2 and phenotype consistent with classic LDS. The proband was a 10-year-old presenting to the genetics clinic with an enlarged aortic root (Z-scores 5-6), pectus excavatum, and congenital contractures of the right 2nd and 3rd digit. Molecular testing of TGFBR2 was sent to a commercial laboratory and demonstrated a novel, likely pathogenic, variant in exon 4, c.1061T>C, p.(L354P). Molecular modeling reveals alteration of local protein structure as a result of this pathogenic variant. This pathogenic variant has not been previously reported in LDS and thus expands the pathogenic variant spectrum of this condition.

Lysozyme amyloidosis (ALys) is a rare form of hereditary amyloidosis that typically manifests with renal impairment, gastrointestinal (GI) symptoms, and sicca syndrome, whereas cardiac involvement is exceedingly rare and neuropathy has not been reported. Here, we describe a 40-year-old man with renal impairment, cardiac and GI symptoms, and peripheral neuropathy. Renal biopsy specimen analysis revealed amyloidosis with extensive involvement of glomeruli, vessels, and medulla. Amyloid was also detected in the GI tract. Echocardiographic and electrocardiographic findings were consistent with cardiac involvement. Proteomic analysis of Congo red–positive renal and GI amyloid deposits detected abundant lysozyme C protein. DNA sequencing of the lysozyme gene in the patient and his mother detected a heterozygous c.305T>C alteration in exon 3, which causes a leucine to serine substitution at codon 102 (Human Genome Variation Society nomenclature: p.Leu102Ser; legacy designation: L84S). We also detected the mutant peptide in the proband’s renal and GI amyloid deposits. PolyPhen analysis predicted that the mutation damages the encoded protein. Molecular dynamics simulations suggested that the pathogenesis of ALys p.Leu102Ser is mediated by shifting the position of the central β -hairpin coordinated with an antiparallel motion of the C-terminal helix, which may alter the native-state structural ensemble of the molecule, leading to aggregation-prone intermediates.

Key Clinical MessageA de novo GFAP variant, p.R376W, was identified in a child presenting with hypotonia, developmental delay, and abnormal brain MRI. Following the 2015 ACMG variant classification guidelines and the functional studies showing protein aggregate formation in vitro, p.R376W should be classified as a pathogenic variant, causative for Alexander disease.

Amyloidosis is characterized by extracellular deposition of misfolded proteins as insoluble fibrils. Most renal amyloidosis cases are Ig light chain, AA, or leukocyte chemotactic factor 2 amyloidosis, but rare hereditary forms can also involve the kidneys. Here, we describe the case of a 61-year-old woman who presented with nephrotic syndrome and renal impairment. Examination of the renal biopsy specimen revealed amyloidosis with predominant involvement of glomeruli and medullary interstitium. Proteomic analysis of Congo red–positive deposits detected large amounts of the Apo-CII protein. DNA sequencing of the APOC2 gene in the patient and one of her children detected a heterozygous c.206A→T transition, causing an E69V missense mutation. We also detected the mutant peptide in the proband’s renal amyloid deposits. Using proteomics, we identified seven additional elderly patients with Apo-CII–rich amyloid deposits, all of whom had kidney involvement and histologically exhibited nodular glomerular involvement. Although prior in vitro studies have shown that Apo-CII can form amyloid fibrils and that certain mutations in this protein promote amyloid fibrillogenesis, there are no reports of this type of amyloidosis in humans. We propose that this study reveals a new form of hereditary amyloidosis (AApoCII) that is derived from the Apo-CII protein and appears to manifest in the elderly and preferentially affect the kidneys.

ABSTRACT Introduction: There are not uniform standards for nerve conduction testing across the United States. The objective of this study is to present a set of methodologically sound criteria to evaluate the literature for the purpose of identifying high‐quality normative nerve conduction studies (NCS) suitable for widespread use. Methods: The Normative Data Task Force (NDTF) was formed to review published studies on methodological issues related to NCS. A set of criteria was then developed to evaluate the literature. These criteria and their rationale are described. Results: We identified 7 key issues that reflect high quality in NCS. For each issue, specific review criteria were developed. Conclusion: Rigorous criteria enable identification of high‐quality studies dealing with nerve conduction reference values. This represents the first step toward the overarching goal of recommending NCS techniques and reference values for electrodiagnostic medicine. Muscle Nerve 54 : 366–370, 2016

ABSTRACT Introduction: To address the need for greater standardization within the field of electrodiagnostic medicine, the Normative Data Task Force (NDTF) was formed to identify nerve conduction studies (NCS) in the literature, evaluate them using consensus‐based methodological criteria derived by the NDTF, and identify those suitable as a resource for NCS metrics. Methods: A comprehensive literature search was conducted of published peer‐reviewed scientific articles for 11 routinely performed sensory and motor NCS from 1990 to 2012. Results : Over 7,500 articles were found. After review using consensus‐based methodological criteria, only 1 study each met all quality criteria for 10 nerves. Conclusion: The NDTF selected only those studies that met all quality criteria and were considered suitable as a clinical resource for NCS metrics. The literature is, however, limited and these findings should be confirmed by larger, multicenter collaborative efforts. Muscle Nerve 54 : 371–377, 2016

Background— The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation. Methods and Results— Evaluation of cardiac structure and function by echocardiography in patients with hypoplastic left heart and their first-degree relatives identified 5 individuals with right ventricular ejection fraction ≤40% after Fontan operation. Whole genome sequencing was performed on DNA from 21 family members, filtering for genetic variants with allele frequency <1% predicted to alter protein structure or expression. Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6 , encoding myosin heavy chain 6, in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms. Protein modeling of the 4 highly conserved amino acid substitutions, residing in both head and tail domains, predicted perturbation of protein structure and function. Conclusions— In contrast to dominant MYH6 mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive MYH6 mutations in patients with hypoplastic left heart and reduced systemic right ventricular ejection fraction. These findings implicate a shared molecular basis for the developmental arrest and latent myopathy of left and right ventricles, respectively.