Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

A whisper-game perspective on the family communication of DNA-test results: a retrospective study on the communication process of BRCA1/2-test results between proband and relatives

Objective of this paper is to study how DNA-test result information was communicated and perceived within families. A retrospective descriptive study in 13 probands with a BRCA1/2 unclassified variant, 7 with a pathogenic mutation, 5 with an uninformative result, and in 44, 14, and 12 of their 1st and 2nd degree relatives respectively. We examined differences and correlations between: (a) information actually communicated (b) probands' perception, (c) relatives' perception. The perception consisted of recollections and interpretations of both their own and their relatives' cancer-risks, and heredity-likelihood (i.e. likelihood that cancer is heritable in the family). Differences and low correlations suggested few similarities between the actually communicated information, the probands' and the relatives' perception. More specifically, probands recalled the communicated information differently compared with the actually communicated information (R = .40), and reinterpreted this information differently (R = .30). The relatives' perception was best correlated with the proband's interpretation (R = .08), but this perception differed significantly from their proband's perception. Finally, relatives reinterpreted the information they received from their proband differently (R = .25), and this interpretation was only slightly related with the original message communicated by the genetic-counsellor (R = .15). Unclassified-variants were most frequently misinterpreted by probands and relatives, and had the largest differences between probands' and relatives' perceptions. Like in a children's whisper-game, many errors occur in the transmission of DNA-test result information in families. More attention is required for how probands disseminate information to relatives. Genetic-counsellors may help by supporting the probands in communicating to relatives, e.g. by providing clear summary letters for relatives

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Grazing weaners on oats: the effect of compensatory gain on productivity and profitability

In central Queensland, it is common industry practice to graze growing cattle on forage oats, before returning them to a grass pasture, despite the potential for compensatory gain. Producers have indicated they do not understand compensatory gain and its impact on profitability (Bowen and Hopkins 2016). The objective of this study was to demonstrate the effects of compensatory gain on productivity and profitability resulting from grazing weaners on oats in the dry season followed by grass pastures in the wet season

Immunodeficiency and the risk of serious clinical endpoints in a well studied cohort of treated HIV-infected patients

OBJECTIVE: To investigate the relative predictive value of CD4+ metrics for serious clinical endpoints. DESIGN: Observational METHODS: Patients (3012; 20317 person-years) from control arms of ESPRIT and SILCAAT trials were followed prospectively. We used Cox regression to identify CD4+ metrics (latest, baseline and nadir CD4+count, latest CD4+%, time spent with CD4+count below certain thresholds and CD4+ slopes) independently predictive of i)all-cause mortality; ii) non-AIDS deaths; iii) non-AIDS (cardiovascular, hepatic, renal and non-AIDS malignancy) and iv) AIDS events. Akaike Information Criteria (AIC) was calculated for each model. Significant metrics (p<0.05) were then additionally adjusted for latest CD4+ count. RESULTS: Non-AIDS deaths occurred at a higher rate than AIDS deaths (rate-ratio: 6.48, 95%CI: 5.1–8.1) and similarly, non-AIDS events (rate-ratio: 1.72, 95%CI: 1.65–1.79). Latest CD4+count was strongly predictive of lower risk of death (HR per log(2) rise: 0.48, 95%CI: 0.43–0.54), with lowest AIC of all metrics. CD4+ slope over 7-visits, after additional adjustment for latest CD4+count, was the only metric to be independent predictor for all-cause (HR for slope<-10/mm(3)/month vs. 0±10: 3.04, 95%CI: 1.98–4.67) and non-AIDS deaths (HR for slope <-10/mm(3)/month vs. 0±10: 2.62, 95%CI: 1.62–4.22). Latest CD4+ count (per log(2) rise) was the best predictor across all endpoints (i–iv) and predicted hepatic (HR: 0.46, 95%CI: 0.33–0.63) and renal events (HR: 0.39, 95%CI: 0.21–0.70), but not cardiovascular events (HR: 1.05, 95%CI: 0.77–1.43) or non-AIDS cancers (HR: 0.78, 95%CI: 0.59–1.03). CONCLUSION: Latest CD4+count is the best predictor of serious endpoints. CD4+ slope independently predicts all-cause and non-AIDS deaths