Inverted duplication with terminal deletion of 5p and no cat-like cry

We report on a 6-year-old boy referred for cytogenetics study. A few non-specific features were observed in the newborn: hypotonia, failure to thrive, seizures, pre-auricular skin tags. Cat-like cry was not identified. No remarkable facial dysmorphism, gastrointestinal, respiratory or cardiac abnormalities were identified. At age 4 years, speech and motor skill delays were apparent. Karyotyping and FISH analysis revealed a de novo rearranged chromosome 5p, with subtelomeric deletion of 5p and a duplication of the cri-du-chat critical region. Array CGH using sub-megabase resolution tiling-set (SMRT) array followed by FISH analysis with labeled BACs showed a deletion of 5pter to 5p15.31 (0-6.9 Mb) and an inverted duplication of the greater part of 5p15.31 to the distal end of 5p14.3 (6.9-19.9 Mb). Although very rare, inverted duplications with terminal deletion (inv dup del) have been reported at different chromosomal ends. Our finding adds a second patient of inv dup del 5p to this growing list, and the potential causative mechanisms for this rearrangement are discussed. Review of the mapping information of cri-du-chat patients and the comparison with a previously reported patient suggested that the critical region for cat-like cry is located within a 0.6 Mb region.     

Physicians' perspectives on the uncertainties and implications of chromosomal microarray testing of children and families

Chromosomal microarray analysis (CMA) has improved the diagnostic rate of genomic disorders in pediatric populations, but can produce uncertain and unexpected findings. This article explores clinicians' perspectives and identifies challenges in effectively interpreting results and communicating with families about CMA. Responses to an online survey were obtained from 40 clinicians who had ordered CMA. Content included practice characteristics and perceptions, and queries about a hypothetical case involving uncertain and incidental findings. Data were analyzed using nonparametric statistical tests. Clinicians' comfort levels differed significantly for explaining uncertain, abnormal, and normal CMA results, with lowest levels for uncertain results. Despite clinical guidelines recommending informed consent, many clinicians did not consider it pertinent to discuss the potential for CMA to reveal information concerning biological parentage or predisposition to late‐onset disease, in a hypothetical case. Many non‐genetics professionals ordering CMA did not feel equipped to interpret the results for patients, and articulated needs for education and access to genetics professionals. This exploratory study highlights key challenges in the practice of genomic medicine, and identifies needs for education, disseminated practice guidelines, and access to genetics professionals, especially when dealing with uncertain or unexpected findings.     

Suppression of the allogeneic response by the anti‐allergy drug N‐(3,4‐dimethoxycinnamonyl) anthranilic acid results from T‐cell cycle arrest

Previously we have shown that indoleamine 2,3‐dioxygenase (IDO) and the tryptophan metabolite, 3‐hydroxykynurenine (3HK) can prolong corneal allograft survival. IDO modulates the immune response by depletion of the essential amino acid tryptophan by breakdown to kynurenines, which themselves act directly on T lymphocytes. The tryptophan metabolite analogue N‐(3,4‐dimethoxycinnamonyl) anthranilic acid (DAA, ‘Tranilast’) shares the anthranilic acid core with 3HK. Systemic administration of DAA to mice receiving a fully MHC‐mismatched allograft of cornea or skin resulted in significant delay in rejection (median survival of controls 12 days, 13 days for cornea and skin grafts, respectively, and of treated mice 24 days (P < 0·0001) and 17 days (P < 0·03), respectively). We provide evidence that DAA‐induced suppression of the allogeneic response, in contrast to that induced by tryptophan metabolites, was a result of cell cycle arrest rather than T‐cell death. Cell cycle arrest was mediated by up‐regulation of the cell cycle‐specific inhibitors p21 and p15, and associated with a significant reduction in interleukin‐2 production, allowing us to characterize a novel mechanism for DAA‐induced T‐cell anergy. Currently licensed as an anti‐allergy drug, the oral bioavailability and safe therapeutic profile of DAA make it a candidate for the prevention of rejection of transplanted cornea and other tissues.     

In the face of pain: the relationship between psychological well-being and disability in women with fibromyalgia

BACKGROUND: Few studies have examined the potentially beneficial role of positive psychological functioning in individuals with chronic pain. This study examined the relationship of psychological well-being (PWB) to pain and disability in women with fibromyalgia (FM) as compared to women with rheumatoid arthritis (RA) and healthy controls (HC). We targeted several domains of PWB that have been associated with health, and also tested whether PWB was related to the women's social network. METHODS: PWB, pain, and disability were assessed in 125 women (57 with FM, 20 with RA, and 48 HC) on two occasions. RESULTS: Women with FM reported lower overall PWB than did RA and HC women. Further, greater PWB was associated with less disability and fatigue, but not pain in women with FM. Self-acceptance, environmental mastery, purpose in life, and positive relations with others emerged as four important constructs in the association between PWB and disability. In addition, PWB mediated the relationship between social network size and disability. CONCLUSIONS: This assessment of PWB provides insight into those psychological domains that should be emphasized in treatments aimed at reducing the disabling aspects of FM.     

A family study implicates GBE1 in the etiology of autism spectrum disorder

Autism spectrum disorders (ASD) are neurodevelopmental disorders with an estimated heritability of >60%. Family-based genetic studies of ASD have generally focused on multiple small kindreds, searching for de novo variants of major effect. We hypothesized that molecular genetic analysis of large multiplex families would enable the identification of variants of milder effects. We studied a large multigenerational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP). We identified a rare heterozygous variant in the gene encoding 1,4-ɑ-glucan branching enzyme 1 (GBE1) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP, and none of four tested unaffected individuals. We genotyped a community-acquired cohort of 389 individuals with ASD and identified three additional probands. Cascade analysis demonstrated that the variant was present in 11 of 13 individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. The variant was not enriched in the combined UK10K ASD cohorts of European ancestry but heterozygous GBE1 deletion was overrepresented in large ASD cohorts, collectively suggesting an association between GBE1 and ASD.     

Allostasis model facilitates understanding race differences in the diurnal cortisol rhythm

The concept of allostasis suggests that greater cumulative stress burden can influence stress-responsive physiology. Dysregulation of allostatic mediators, including the hypothalamic-pituitary-adrenal (HPA) axis, is thought to precede many other signs of age-related pathology as the persistent burden of stressors accumulates over the individual's life span. We predicted that even in young adulthood, HPA regulation would differ between Blacks and Whites, reflecting, in part, higher rates of stressor exposure and greater potential for stressors to "get under the skin." We examined whether stressor exposure, including experiences with racism and discrimination, explained race differences in waking cortisol and the diurnal rhythm. We also examined whether HPA functioning was associated with mental health outcomes previously linked to cortisol. Salivary cortisol was assayed in 275 young adults (127 Blacks, 148 Whites, 19 to 22 years old), four times a day across 3 days. Hierarchical linear models revealed flatter slopes for Blacks, reflecting significantly lower waking and higher bedtime cortisol levels compared to Whites. Associations of HPA functioning with stressors were typically more robust for Whites such that more stress exposure created an HPA profile that resembled that of Black young adults. For Blacks, greater stressor exposure did not further impact HPA functioning, or, when significant, was often associated with higher cortisol levels. Across both races, flatter slopes generally indicated greater HPA dysregulation and were associated with poor mental health outcomes. These differential effects were more robust for Whites. These findings support an allostatic model in which social contextual factors influence normal biorhythms, even as early as young adulthood.     

Transconjunctival excision of an orbital conjunctival cyst using computer‐assisted 3‐D surgical planning in a dog

Investigation of exophthalmos and blood‐colored discharge from the left ventral punctum in a dog was consistent with a conjunctival cyst in the orbit. 3‐D prints of the cyst and surrounding facial bones identified a successful transconjunctival approach without an orbitotomy and patency of the left lacrimal duct was reestablished.

Investigation of exophthalmos and blood‐colored discharge from the left ventral punctum in a dog was consistent with a conjunctival cyst in the orbit. 3‐D prints of the cyst and surrounding facial bones identified a successful transconjunctival approach without an orbitotomy and patency of the left lacrimal duct was reestablished.