GeneYenta: A Phenotype­Based Rare Disease Case Matching Tool Based on Online Dating Algorithms for the Acceleration of Exome Interpretation

Advances in next‐generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology­based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching.     

Identical COL71A1 heterozygous mutations resulting in different dystrophic epidermolysis bullosa phenotypes

Dystrophic epidermolysis bullosa is a rare blistering condition caused by mutations in the COL7A1 gene. Different clinical variants have been described, with dominant and recessive inheritance, but no consistent findings have been elucidated to establish a genotype–phenotype correlation. We present three unrelated patients with two identical pathogenic compound heterozygous mutations in the COL7A1 gene that developed different clinical forms of dystrophic epidermolysis bullosa—epidermolysis bullosa pruriginosa and mild recessive non‐Hallopeau–Siemens—raising the possibility of other genetic or environmental modifying factors responsible for the phenotype of the disease.     

A Population Based Analysis of Subclinical Psychosis and Help-Seeking Behavior

Clinically defined psychosis is recognizable and distinguishable from nonclinical or subclinical psychosis by virtue of its clinical relevance (ie, its associated distress and its need for care and/or treatment). According to the continuum hypothesis, subclinical psychosis is merely quantitatively different from more extreme phenotypic expressions and as such should also be indicative of distress and help-seeking behavior but to a lesser extent. Using data from the Adult Psychiatric Morbidity Survey, the current study focused on self-reported psychosis and help-seeking experiences in a general population sample free from clinically defined psychosis (N = 7266). After statistically controlling for the effects of a series of potential help-seeking correlates the findings showed that subclinical psychosis symptom experience was significantly associated with various forms of help-seeking behavior. Individuals who reported subclinical experiences of thought control, paranoia, and strange experiences were on average 2 times more likely to attend their general practitioner for emotional problems compared with those individuals who reported no psychosis. Individuals who reported subclinical experiences of paranoia were 3 times more likely to be in receipt of counseling/therapy compared with those with no experience of paranoia. Multiple subclinical psychotic experiences also predicted elevated help-seeking behavior. These findings may have a positive impact on the detection of individuals who are at increased risk of psychological distress and aid in the design and implementation of more effective treatments at both clinical and subclinical levels.     

Multiple in silico tools predict phenotypic manifestations in congenital thrombotic thrombocytopenic purpura

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, recessively inherited genetic disorder with varying clinical presentation that is caused by ADAMTS13 mutations. Several studies have found limited associations between ADAMTS13 mutations and cTTP phenotype. The use of in silico tools that examine multiple mutation characteristics may better predict phenotype. We analysed 118 ADAMTS13 mutations found in 144 cTTP patients reported in the literature and examined associations of several mutation characteristics, including N‐terminal proximity, the evolutionary conservation of the affected amino acid position, as well as amino acid charge/phosphorylation and genetic codon usage to disease phenotype. Structure‐altering mutations were examined for their impact on ADAMTS13 function based on existing ADAMTS13 crystallographic data (AA 77‐685). Our in silico data indicate that: (i) The position of the mutation in the N‐ or C‐terminus, (ii) evolutionary conservation and (iii) codon usage of the affected mutation position are associated with disease parameters, such as age of onset, organ damage and fresh frozen plasma prophylaxis. In conclusion, the usage of multiple in silico tools presents a promising strategy in refining predictions for the diverse presentation of cTTP. Enhancing our utilization of in silico tools to find genotype‐phenotype associations will create better‐tailored approaches for individual patient treatment.     

Variations in alanine aminotransferase levels within the normal range predict metabolic and androgenic phenotypes in women of reproductive age

Abstract

Background and aims. Obesity plays pathogenetic roles in nonalcoholic fatty liver disease (NAFLD) and hyperandrogenic states like polycystic ovary syndrome (PCOS). We tested the hypothesis that alanine aminotransferase (ALT), a marker of NAFLD, is associated with endocrine and metabolic abnormalities in women with normal ALT. Methods and results. Fasting glucose, insulin, total testosterone, DHEA-S, 17-hydroxyprogesterone, prolactin, leptin, soluble leptin receptor, free leptin index (FLI), lipid profile, ALT, gonadotropins, and sex hormone binding globulin (SHBG) were measured in 200 women aged 18–48 years. Beta cell function (%B), insulin sensitivity (%S) and insulin resistance were calculated using the homeostasis model assessment (HOMA-IR). Ninety-two women had PCOS (Rotterdam criteria); 64 had idiopathic hyperandrogenism; 44 were normal controls. ALT showed significant positive correlations with waist circumference (WC), systolic blood pressure, glucose, leptin, FLI, triglycerides, HOMA-IR and androgens and significant inverse correlations with leptin receptor, HDL-C, %S and SHBG. Correcting for WC and fat% showed that the associations between ALT and glucose, HOMA-IR, testosterone and free androgen index are independent of obesity. Binary logistic regression analyses showed significant association of ALT with PCOS and hyperandrogenemia. ALT ≥ 18 IU/L showed significant association with PCOS with Odds Ratio = 2.28 (95% Confidence Interval = 1.03–5.08), p = 0.043. Conclusions. In women of reproductive age, normal levels of ALT are associated with metabolic and androgenic phenotypes. We suggest a paradigm shift and extension of the routine use of ALT beyond the diagnosis of liver disease.     

Redefining the biological basis of lineage-ambiguous leukemia through genomics: BCL11B deregulation in acute leukemias of ambiguous lineage

Acute leukemias of ambiguous lineage (ALAL), including mixed phenotype acute leukemia (MPAL) and related entities such as early T-cell precursor acute leukemia (ETP-ALL), remain diagnostic and clinical challenges due to limited understanding of pathogenesis, reliance of immunophenotyping to classify disease, and the lack of a rational approach to guide selection of appropriate therapy. Recent studies utilizing genomic sequencing and complementary approaches have provided key insights that are changing the way in which such leukemias are classified, and potentially, treated. Several recurrent genomic alterations define leukemias that straddle immunophenotypic entities, such as ZNF384-rearranged childhood B-ALL and B/myeloid MPAL, and BCL11B-rearranged T/myeloid MPAL, ETP-ALL and AML. In contrast, some cases of MPAL represent canonical ALL/AML entities exhibiting lineage aberrancy. For many cases of ALAL, experimental approaches indicate lineage aberrancy arises from acquisition of a founding genetic alteration into a hematopoietic stem or progenitor cell. Determination of optimal therapeutic approach requires genomic characterization of uniformly treated ALAL patients in prospective studies, but several approaches, including kinase inhibitors and BH3 mimetics may be efficacious in subsets of ALAL.