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Objective We sought to develop and evaluate an electronic health record (EHR) genetic testing tracking system to address the barriers and limitations of existing spreadsheet-based workarounds. Materials and Methods We evaluated the spreadsheet-based system using mixed effects logistic regression to identify factors associated with delayed follow up. These factors informed the design of an EHR-integrated genetic testing tracking system. After deployment, we assessed the system in 2 ways. We analyzed EHR access logs and note data to assess patient outcomes and performed semistructured interviews with users to identify impact of the system on work. Results We found that patient-reported race was a significant predictor of documented genetic testing follow up, indicating a possible inequity in care. We implemented a CDS system including a patient data capture form and management dashboard to facilitate important care tasks. The system significantly sped review of results and significantly increased documentation of follow-up recommendations. Interviews with key system users identified a range of sociotechnical factors (ie, tools, tasks, collaboration) that contribute to safer and more efficient care. Discussion Our new tracking system ended decades of workarounds for identifying and communicating test results and improved clinical workflows. Interview participants related that the system decreased cognitive and time burden which allowed them to focus on direct patient interaction. Conclusion By assembling a multidisciplinary team, we designed a novel patient tracking system that improves genetic testing follow up. Similar approaches may be effective in other clinical settings. [ABSTRACT FROM AUTHOR]

Prior studies have demonstrated that patients with chromosome 22q11.2 deletion syndrome (22q11.2DS) have lower platelet counts (PC) compared to non‐deleted populations. They also have an increased mean platelet volume. The mechanism for this has been postulated to be haploinsufficiency of the GPIBB gene. We examined platelet parameters, deletion size and factors known to influence counts, including status of thyroid hormone and congenital heart disease (CHD), in a population of 825 patients with 22q11.2DS. We also measured surface expression of GPIB‐IX complex by flow cytometry. The major determinant of PC was deletion status of GP1BB, regardless of surface expression or other factors. Patients with nested distal chromosome 22q11.2 deletions (those with GP1BB present) had higher PCs than those with proximal deletions where GP1BB is deleted. Patients with 22q11.2DS also demonstrated an accelerated PC decrease with age, occurring in childhood. These data demonstrate that genes within the proximal deletion segment drive PC differences in 22q11.2DS and suggest that PC reference ranges may need to be adjusted for age and deletion size in 22q11.2DS populations. Bleeding did not correlate with either platelet count or GPIb expression. Further studies into drivers of expression of GPIb and associations with severe thrombocytopenia and immune thrombocytopenia are needed to inform clinical care. [ABSTRACT FROM AUTHOR]

Telemedicine has long been considered as an attractive alternative methodology in clinical genetics to improve patient access and convenience. Given the importance of the dysmorphology physical examination and anthropometric measurement in clinical genetics, many have wondered if lost information would hamper diagnosis. We previously addressed this question by analyzing thousands of diagnostic encounters in a single practice involving multiple practitioners and found no evidence for a difference in new molecular diagnosis rates. However, our previous study design resulted in variability in providers between in‐person and telemedicine evaluation groups. To address this in our present study, we expanded our analysis to 1104 new patient evaluations seen by one highly experienced clinical geneticist across two 10‐month periods before and after the start of the COVID‐19 pandemic. Comparing patients seen in‐person to those seen by telemedicine, we found significant differences in race and ethnicity, preferred language, and home zip code median income. The clinical geneticist intended to send more genetic testing for those patients seen by telemedicine, but due to issues with test authorization and sample collection, there was no difference in ultimate completion rate between groups. We found no significant difference in new molecular diagnosis rate. Overall, we find telemedicine to be an acceptable alternative to in‐person evaluation for routine pediatric clinical genetics care. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development. [ABSTRACT FROM AUTHOR]

Background Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted. Methods We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions. Results Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports. Conclusion We conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome (NBCCS) is a tumor predisposition condition, the cardinal features of which emerge in adolescence or adulthood. Using statistical optimization, this study proposes NBCCS criteria with improved sensitivity in children less than 18 years of age. Earlier detection may lead to improved surveillance and prevention of sequelae. A survey eliciting medical history was completed by, or on behalf of, individuals with NBCCS. Based on these findings, criteria for suspicion of NBCCS in children were suggested using information from a Bernoulli naïve Bayes classifier relying on the human phenotype ontology. The sensitivity and specificity of the existing and proposed diagnostic criteria were also assessed. Participants (n = 48) reported their first signs of NBCCS appeared at a median age of 8 months, but by our retrospective analysis, they did not fulfill the current diagnostic criteria until a median age of 7 years. This study delineates the early-onset features of NBCCS and proposes criteria that should prompt consideration of NBCCS. Additionally, we demonstrate a method for quantitatively assessing the utility of diagnostic criteria for genetic disorders. [ABSTRACT FROM AUTHOR]

Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype–phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants. This study identifies genotype–phenotype correlations as well as race‐facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long‐term outcomes in individuals with WSS. [ABSTRACT FROM AUTHOR]

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss‐of‐function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4‐related EPF phenotype. This report demonstrates comorbid disorders of Saethre‐Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification. [ABSTRACT FROM AUTHOR]

FLNA is a gene on the X chromosome that encodes Filamin A, a widely expressed protein crucial for forming the cell cytoskeleton and mediating cell signaling. Loss-of-function mutations have been associated with periventricular nodular heterotopia (PVNH) with associated epilepsy and intellectual deficits, as well as cardiovascular disease, connective tissue disorders, pulmonary disease, bleeding diathesis, and gastrointestinal disease. Alternatively, gain-of-function mutations have been described with otopalatodigital spectrum disorders. The loss-of-function variants of FLNA associated with PVNH have historically been considered lethal in males, often prenatally or by the first year of life. However, more surviving males with FLNA variants are being described. Most of the surviving males have missense or distal truncating mutations or a degree of mosaicism. Others are thought to have splice site mutations or in-frame exon skipping leading to production of some degree of functional Filamin A as possible mechanisms of survival. Here, we presented a case of a 20-month-old small but developmentally appropriate and healthy male infant who was prenatally diagnosed with PVNH, and postnatally found to have a nonsense variant of the FLNA gene. This mutation has not been previously clinically described or published to our knowledge. [ABSTRACT FROM AUTHOR]

FLNA is a gene on the X chromosome that encodes Filamin A, a widely expressed protein crucial for forming the cell cytoskeleton and mediating cell signaling. Loss-of-function mutations have been associated with periventricular nodular heterotopia (PVNH) with associated epilepsy and intellectual deficits, as well as cardiovascular disease, connective tissue disorders, pulmonary disease, bleeding diathesis, and gastrointestinal disease. Alternatively, gain-of-function mutations have been described with otopalatodigital spectrum disorders. The loss-of-function variants of FLNA associated with PVNH have historically been considered lethal in males, often prenatally or by the first year of life. However, more surviving males with FLNA variants are being described. Most of the surviving males have missense or distal truncating mutations or a degree of mosaicism. Others are thought to have splice site mutations or in-frame exon skipping leading to production of some degree of functional Filamin A as possible mechanisms of survival. Here, we presented a case of a 20-month-old small but developmentally appropriate and healthy male infant who was prenatally diagnosed with PVNH, and postnatally found to have a nonsense variant of the FLNA gene. This mutation has not been previously clinically described or published to our knowledge. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome‐specific, low copy repeat (LCR)–mediated copy‐number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A–LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full‐scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age. [ABSTRACT FROM AUTHOR]

The article presents a case study related to extremely low-birth-weight, premature infant estimated to be 26 weeks gestational age by ultrasound at presentation was born at the hospital with a maternal history significant for no prenatal care. Topics include the infant has admitted to the intensive care unit following delivery and umbilical artery and vein catheters were placed, and the infant has treated initially with ampicillin and gentamicin while sepsis screening with blood culture.

ABSTRACT As the amount of human genomic sequence available from personal genomes and exomes has increased, so too has the observation of genomic positions having two or more alternative alleles, so-called multiallelic sites. For portions of the haploid genome that are present in more than one copy, including segmental duplications, variation at such multisite variant positions becomes even more complex. Despite the frequency of multiallelic variants, a number of commonly used resources and tools in genomic research and diagnostics do not support these multiallelic variants all together or require special modifications. Here, we explore the frequency of multiallelic sites in large samples with whole exome sequencing and discuss potential outcomes of failing to account for multiple variant alleles. We also briefly discuss some commonly utilized resources that fully support multiallelic sites. [ABSTRACT FROM AUTHOR]

Background: Genome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and prioritization of filtered rare variants. We have developed visually interactive, analytically transparent analysis software that leverages existing disease catalogs, such as the Online Mendelian Inheritance in Man database (OMIM) and the Human Phenotype Ontology (HPO), to integrate patient phenotype and variant data into ranked diagnostic alternatives. Methods: Our tool, "OMIM Explorer" (http://www.omimexplorer.com), extends the biomedical application of semantic similarity methods beyond those reported in previous studies. The tool also provides a simple interface for translating free-text clinical notes into HPO terms, enabling clinical providers and geneticists to contribute phenotypes to the diagnostic process. The visual approach uses semantic similarity with multidimensional scaling to collapse high-dimensional phenotype and genotype data from an individual into a graphical format that contextualizes the patient within a low-dimensional disease map. The map proposes a differential diagnosis and algorithmically suggests potential alternatives for phenotype queries-in essence, generating a computationally assisted differential diagnosis informed by the individual's personal genome. Visual interactivity allows the user to filter and update variant rankings by interacting with intermediate results. The tool also implements an adaptive approach for disease gene discovery based on patient phenotypes. Results: We retrospectively analyzed pilot cohort data from the Baylor Miraca Genetics Laboratory, demonstrating performance of the tool and workflow in the re-analysis of clinical exomes. Our tool assigned to clinically reported variants a median rank of 2, placing causal variants in the top 1 % of filtered candidates across the 47 cohort cases with reported molecular diagnoses of exome variants in OMIM Morbidmap genes. Our tool outperformed Phen-Gen, eXtasy, PhenIX, PHIVE, and hiPHIVE in the prioritization of these clinically reported variants. Conclusions: Our integrative paradigm can improve efficiency and, potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge. [ABSTRACT FROM AUTHOR]

Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases—about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual’s susceptibility to acquiring disease-associated alleles. [ABSTRACT FROM AUTHOR]

Background: Besides its growing importance in clinical diagnostics and understanding the genetic basis of Mendelian and complex diseases, whole exome sequencing (WES) is a rich source of additional information of potential clinical utility for physicians, patients and their families. We analyzed the frequency and nature of single nucleotide variants (SNVs) considered secondary findings and recessive disease allele carrier status in the exomes of 8554 individuals from a large, randomly sampled cohort study and 2514 patients from a study of presumed Mendelian disease having undergone WES. Methods: We used the same sequencing platform and data processing pipeline to analyze all samples and characterized the distributions of reported pathogenic (ClinVar, Human Gene Mutation Database (HGMD)) and predicted deleterious variants in the pre-specified American College of Medical Genetics and Genomics (ACMG) secondary findings and recessive disease genes in different ethnic groups. Results: In the 56 ACMG secondary findings genes, the average number of predicted deleterious variants per individual was 0.74, and the mean number of ClinVar reported pathogenic variants was 0.06. We observed an average of 10 deleterious and 0.78 ClinVar reported pathogenic variants per individual in 1423 autosomal recessive disease genes. By repeatedly sampling pairs of exomes, 0.5 % of the randomly generated couples were at 25 % risk of having an affected offspring for an autosomal recessive disorder based on the ClinVar variants. Conclusions: By investigating reported pathogenic and novel, predicted deleterious variants we estimated the lower and upper limits of the population fraction for which exome sequencing may reveal additional medically relevant information. We suggest that the observed wide range for the lower and upper limits of these frequency numbers will be gradually reduced due to improvement in classification databases and prediction algorithms. [ABSTRACT FROM AUTHOR]

Background Recurrent rearrangements of the human genome resulting in disease and variation are mainly mediated by nonallelic homologous recombination (NAHR) between low-copy repeats. However, other genomic structures, including AT rich palindromes and retroviruses, have also been also reported to underlie recurrent structural rearrangements. Notably, recurrent deletions of Yq12 conveying azoospermia, as well as non-pathogenic reciprocal duplications, are mediated by human endogenous retroviral elements (HERVs). We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV). Results We developed parameters to identify HERV elements similar to those that mediate Yq12 rearrangements as well as recurrent deletions of 3q13.2q13.31. We used these parameters to identify HERV pairs genome-wide that may cause instability. Our analysis highlighted 170 pairs, flanking 12.1% of the genome. We cross-referenced these predicted susceptibility regions with CNVs from our clinical databases for potentially HERV-mediated rearrangements and identified 78 CNVs. We subsequently molecularly confirmed recurrent deletion and duplication rearrangements at four loci in 10 individuals, including reciprocal rearrangements at two loci. Breakpoint sequencing revealed clustering in regions of high sequence identity enriched in PRDM9 mediated recombination hotspot motifs. Conclusions The presence of deletions and reciprocal duplications suggests NAHR as the causative mechanism of HERV-mediated CNV, even though the length and the sequence homology of the HERV elements are less than currently thought to be required for NAHR. We propose that in addition to HERVs, other repetitive elements such as LINEs may also be responsible for the formation of recurrent CNVs via NAHR. [ABSTRACT FROM AUTHOR]

ABSTRACT We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus ( HERV- H) elements of ∼5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination ( NAHR) between HERV- H elements as a mechanism of deletion formation, analogous to HERV- I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease. [ABSTRACT FROM AUTHOR]

ABSTRACT The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46,XY patients and premature ovarian failure (POF) in 46,XX patients. Previous reports have identified four families with a history of both 46,XY DSD and 46,XX POF carrying segregating NR5A1 sequence mutations. Recently, three 46,XY DSD sporadic cases with NR5A1 microdeletions have been reported. Here, we identify the first NR5A1 microdeletion transmitted in a pedigree with both 46,XY DSD and 46,XX POF. A 46,XY individual with DSD due to gonadal dysgenesis was born to a young mother who developed POF. Array CGH analysis revealed a maternally inherited 0.23 Mb microdeletion of chromosome 9q33.3, including the NR5A1 gene. Based on this finding, we screened patients with unexplained 46,XY DSD (n = 11), proximal hypospadias (n = 21) and 46,XX POF (n = 36) for possible NR5A1 copy-number variations (CNVs) via multiplex ligation-dependent probe amplification (MLPA), but did not identify any additional CNVs involving NR5A1. These data suggest that NR5A1 CNVs are an infrequent cause of these disorders but that array CGH and MLPA are useful genomic screening tools to uncover the genetic basis of such unexplained cases. This case is the first report of a familial NR5A1 CNV transmitting in a pedigree, causing both the male and female phenotypes associated with NR5A1 mutations, and the first report of a NR5A1 CNV associated with POF. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Curation and interpretation of copy number variants identified by genome-wide testing is challenged by the large number of events harbored in each personal genome. Conventional determination of phenotypic relevance relies on patterns of higher frequency in affected individuals versus controls; however, an increasing amount of ascertained variation is rare or private to clans. Consequently, frequency data have less utility to resolve pathogenic from benign. One solution is disease-specific algorithms that leverage gene knowledge together with variant frequency to aid prioritization. We used large-scale resources including Gene Ontology, protein-protein interactions and other annotation systems together with a broad set of 83 genes with known associations to epilepsy to construct a pathogenicity score for the phenotype. We evaluated the score for all annotated human genes and applied Bayesian methods to combine the derived pathogenicity score with frequency information from our diagnostic laboratory. Analysis determined Bayes factors and posterior distributions for each gene. We applied our method to subjects with abnormal chromosomal microarray results and confirmed epilepsy diagnoses gathered by electronic medical record review. Genes deleted in our subjects with epilepsy had significantly higher pathogenicity scores and Bayes factors compared to subjects referred for non-neurologic indications. We also applied our scores to identify a recently validated epilepsy gene in a complex genomic region and to reveal candidate genes for epilepsy. We propose a potential use in clinical decision support for our results in the context of genome-wide screening. Our approach demonstrates the utility of integrative data in medical genomics. [ABSTRACT FROM AUTHOR]

Despite the availability of thousands of transit peptide (TP) primary sequences, the structural and/or physicochemical properties that determine TP recognition by components of the chloroplast translocon are not well understood. By combining a series of in vitro and in vivo experiments, we reveal that TP recognition is determined by sequence-independent interactions and vectorial-specific recognition domains. Using both native and reversed TPs for two well-studied precursors, small subunit of ribulose-1,5-bis-phosphate carboxylase/oxygenase, and ferredoxin, we exposed these two modes of recognition. Toc34 receptor (34-kD subunit of the translocon of the outer envelope) recognition in vitro, preprotein binding in organellar, precursor binding in vivo, and the recognition of TPs by the major stromal molecular motor Hsp70 are specific for the physicochemical properties of the TP. However, translocation in organellar and in vivo demonstrates strong specificity to recognition domain organization. This organization specificity correlates with the N-terminal placement of a strong Hsp70 recognition element. These results are discussed in light of how individual translocon components sequentially interact with the precursor during binding and translocation and helps explain the apparent lack of sequence conservation in chloroplast TPs. [ABSTRACT FROM AUTHOR]

To date, over 70 mutations in the TGFBR2 gene have been reported in patients with Loeys-Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2), or other hereditary thoracic aortic aneurysms and dissections. Whereas almost all of mutations analyzed thus far are predicted to disrupt the constitutively active C-terminal serine/threonine kinase domain of TGFBR2, mounting evidence suggests that the molecular mechanism underlying these diseases is more complex than simple haploinsufficiency. Using exon-targeted oligonucleotide array comparative genomic hybridization, we identified an ∼896 kb deletion of TGFBR2 in a 20-month-old female with microcephaly and global developmental delay, but no stigmata of LDS. FISH analysis showed no evidence of this deletion in the parental peripheral blood samples; however, somatic mosaicism was detected using PCR in the paternal DNA from peripheral blood lymphocytes and lymphoblasts. Our data suggest that TGFBR2 haploinsufficiency may cause a phenotype, which is distinct from LDS. Moreover, we propose that somatic mosaicism below the detection threshold of FISH analysis in asymptomatic parents of children with genomic disorders may be more common than previously recognized. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Motivation: Set-based network similarity metrics are increasingly used to productively analyze genome-wide data. Conventional approaches, such as mean shortest path and clique-based metrics, have been useful but are not well suited to all applications. Computational scientists in other disciplines have developed communicability as a complementary metric. Network communicability considers all paths of all lengths between two network members. Given the success of previous network analyses of protein–protein interactions, we applied the concepts of network communicability to this problem. Here we show that our communicability implementation has advantages over traditional approaches. Overall, analyses suggest network communicability has considerable utility in analysis of large-scale biological networks.Availability and implementation: We provide our method as an R package for use in both human protein–protein interaction network analyses and analyses of arbitrary networks along with a tutorial at http://www.shawlab.org/NetComm/.Contact: cashaw@bcm.eduSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

This article presents information on the role of interpersonal perception in dyadic adjustment. The subjects for the study were 20 married couples. All couples were seen by the senior experimenter in their own homes and were given a brief explanation of the research. They were requested not to discuss the nature or content of any of the questions until the testing was complete. Each spouse was asked to complete a copy of the Dyadic Adjustment Scale, after which both filled out a California Psychological Inventory for their partner.

The article presents a factorial analysis of the Beck Depression Inventory (BDI). The BDI currently receives wide application within a range of research and clinical areas and is regarded as one of the better self-report measures of general depression. Further examination of the BDI appears important in several respects. The question arises as to whether the factor structure of the BDI is dependent on the selection of a sub-group of BDI scorers, and the present study addressed that issue.

This article studies face validity versus item subtlety in the Minnesota Multiphasic Personality Inventory (MMPI) D scale. It notes that the distinction between item subtlety and face validity provided the basis to reevaluate findings for subtle items in the MMPI D scale. Results indicated that the inclusion of nonpathological items in the D scale did not lead to greater predictive validity of depression criteria. The need for substantive considerations in scale construction was emphasized further.

The nonethanol congeners of bourbon have been found to possess estrogenic activity when tested using an in vivo oophorectomized rat bioassay, as well as an in vitro estrogen receptor assay system. The phytoestrogen, biochanin A, as well as the plant sterol, β-sitosterol, were identified in the bourbon preparation using gas chromatography/mass spectrometry. These findings, using three methodological approaches, demonstrate that bourbon contains at least one biologically active phytoestrogen and suggest that the effects of alcoholic beverage use or abuse, particularly as they relate to endocrine systems, should not be viewed as resulting solely from exposure to ethanol. [ABSTRACT FROM AUTHOR]

The cover image is based on the Special Issue Article What's New with 22q? An update from the 22q and You Center at the Children's Hospital of Philadelphia, DOI: 10.1002/ajmg.a.40637. Illustration Credit: Eo Trueblood, Lead Illustrator, Stream Studios: Medical Illustration, The Children's Hospital of Philadelphia. [ABSTRACT FROM AUTHOR]