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This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

PURPOSETo provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids (GA4K) program.METHODSExtensive analyses of 960 families with suspected genetic disorders including short-read exome (ES) and genome sequencing (srGS); PacBio HiFi long-read GS (HiFi-GS); variant calling for small-nucleotide (SNV), structural (SV) and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants and pedigrees are stored in PhenoTips database, with data sharing through controlled access (dbGAP).RESULTSDiagnostic rates ranged from 11% for cases with prior negative genetic tests to 34.5% in naïve patients. Incorporating SVs from GS added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs than srGS. Variants and genes of unknown significance (VUS/GUS) remain the most common finding (58% of non-diagnostic cases).CONCLUSIONComputational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated by HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation, and by providing HiFi variant (SNV/SV) resources from >1,000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Holocarboxylase deficiency (HLCSD) is caused by biallelic pathogenic variants in HLCS and is associated with poor feeding, emesis, lethargy, seizures, life-threatening metabolic acidosis, and hyperammonemia. Skin involvement in HLCSD is typically described as scaly, erythrodermic, seborrhea-like, or ichthyosiform, but there is a paucity of reports. We report three patients, including two siblings, with HLCSD and significant cutaneous manifestations including ichthyosiform dermatitis and a presentation with features of annular pustular psoriasis. In this report, we show that persistent, unexplained rash, even in the absence of other clinical findings, should warrant consideration and potential workup for HLCSD.

CDC42BPB encodes MRCKβ (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder characterized by lesions and benign tumors in multiple organ systems including the brain, skin, heart, eyes, kidneys, and lungs. The phenotype is highly variable, although penetrance is reportedly complete. We report the molecular diagnosis of TSC in individuals exhibiting extreme intra-familial variability, including the incidental diagnosis of asymptomatic family members. Exome sequencing was performed in three families, with probands referred for epilepsy, autism, and absent speech (Family 1); epileptic spasms (Family 2); and connective tissue disorders (Family 3.) Pathogenic variants in TSC1 or TSC2 were identified in nine individuals, including relatives with limited or no medical concerns at the time of testing. Of the nine individuals reported here, six had post-diagnosis examinations and three met clinical diagnostic criteria for TSC. One did not meet clinical criteria for a possible or definite diagnosis of TSC, and two had only a possible clinical diagnosis following post-diagnosis workup. These individuals as well as their mothers demonstrated limited features that would not raise concern for TSC in the absence of molecular results. In addition, three individuals exhibited epilepsy with normal brain MRIs, and two without seizures or intellectual disability had MRI findings fulfilling major criteria for TSC highlighting the difficulty providers face when relying on clinical criteria to guide genetic testing. Given the importance of a timely TSC diagnosis for clinical management, such cases demonstrate a potential benefit for clinical criteria to include seizures and an unbiased molecular approach to genetic testing.

Purpose We report for the first time, the use of clinical genome sequencing (GS) in an unbiased pediatric cohort. We describe the clinical validation, patient metrics, ordering patterns, results, reimbursement, and physician retrieval of results for the first consecutive 80 cases. Methods Clinical GS was performed for both inpatients and outpatients undergoing etiologic evaluations. Results were reported in the electronic medical record. Evidence of report retrieval by clinicians and whether interpretation was concordant with laboratory report was obtained through retrospective chart review. Results Twenty definitive diagnoses were made in 19 patients (24%; n = 80). Except for two partial gene deletions, all diagnostic variants would have been detectable by our exome methods. Surprisingly, there was no documentation of communication of results to the family in the medical record for 17.5% of patients, and in 7.5%, physician and laboratory interpretations were discordant. Average insurance reimbursement was 30.2%, with yield for commercial payers significantly higher, at 54.1%. Conclusions The detection rate of GS is equivalent and potentially superior to exome sequencing (ES). Reimbursement rates were variable but overall satisfactory for commercial insurers, and poor for government entities. In addition, we identify opportunities for improvement in the communication of results to families, likely translatable to other tests and other institutions.

The published online version contain mistake in the author list. Instead of "A.M.Ilyas" it should have been "M.Ilyas ".

Background Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage, often leading to immunodeficiency, growth retardation and increased risk of malignancy. Case presentation We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia. She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E. Conclusion This is the second family with POLE1-deficency, with the affected individual demonstrating a more severe phenotype than previously described. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0177-y) contains supplementary material, which is available to authorized users.

Objective To examine depressive disorders and health status in patients with rheumatoid arthritis (RA), controlling for potential confounds. Method Subjects (n = 426) completed measures of depressive symptoms (Center for Epidemiological Studies Depression Scale [CES-D]) and health status (Arthritis Impact Measurement Scales 2 [AIMS2]), via cross-sectional survey. Subjects (n = 299) with few depressive symptoms (CES-D ≤10) were not evaluated further. Subjects with CES-D ≥11 were interviewed using the Primary Care Evaluation of Mental Disorders to diagnose major depressive disorder (MDD; n = 46), dysthymic disorder (DD; n = 21), or minor depressive disorder (MND; n = 18). Results Regression analyses examined differences between the depressive disorders on AIMS2 subscales. Health status scores were similar between the depressive disorder subcategories; significant differences were found between MDD and MND on AIMS2 Physical scores and MDD and DD on AIMS2 Symptom scores. Conclusion Regarding health status, presence of depression itself seems to overshadow differences between depression subtypes; antidepressant treatments/referrals for persons with concomitant RA and any depressive disorder subtype appear warranted.

Objective To examine the factor structure of the Center for Epidemiologic Studies Depression Scale (CES-D) in a sample of patients with rheumatoid arthritis (RA), testing all of the alternative models suggested by the previous evidence Methods The CES-D was administered to a group of RA patients (n = 685) during a structured telephone interview. The telephone interview was repeated 6 months later (n = 537) and 12 months later (n = 453). Confirmatory factor analyses were conducted to test alternative models. Results The correlated 4-factor model and the second-order 4-factor model were the best fitting models. Conclusion The factor structure of the CES-D previously found in the general population was replicated in an RA sample. The results are consistent with previous evidence of criterion contamination in the CES-D when used in an RA sample and provide support for the view that a single summary score may not be the most informative index of the CES-D.

The pharmacology, mechanisms of action, and historic perspectives of tar and anthralin are discussed. Traditional Goeckerman and Ingram regimens are presented in the context of newer advances in psoriasis treatment. Recommendations for therapy with tar and anthralin, either as monotherapy or adjunctive therapy, are reviewed and referenced.

We test two hypotheses relevant to the form-meaning relationship and offer a methodological contribution to the empirical study of near-synonymy within the framework of cognitive linguistics. In addition, we challenge implicit assumptions about the nature of the paradigm, which we show is skewed in favor of a few forms that are prototypical for a given lexical item. If one accepts the claim of construction grammar that the construction is the relevant unit of linguistic analysis, then we should expect to find a relationship between the meanings of words and the constructions they are found in. One way to investigate this expectation is by examining the meaning of constructions on the basis of their lexical profile; this line of research is pursued in collostructional analyses. We have taken a different approach, examining the meaning of near-synonyms on the basis of what we call their "constructional profile". We define a constructional profile as the frequency distribution of the constructions that a word appears in. Constructional profiles for Russian nouns denoting sadness and happiness are presented, based upon corpus data, and analyzed quantitatively (using chi square and hierarchical cluster analysis). The findings are compared to the introspective analyses offered in synonym dictionaries. © 2009 by Walter de Gruyter GmbH.