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BackgroundPrader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects.MethodsHigh-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age.ResultsWe summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200).ConclusionsWe report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age.

Prader-Willi syndrome (PWS), is a complex genetic disease affecting 1/15,000 individuals, characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Clinical features include central hypotonia, poor suck, learning and behavior problems, growth hormone deficiency with short stature, hyperphagia, and morbid obesity. Despite significant advances in genetic testing, the mean age for diagnosis in PWS continues to lag behind. Our goal was to perform a pilot feasibility study to confirm the diagnosis utilizing different genetic technologies in a cohort of 34 individuals with genetically confirmed PWS and 16 healthy controls from blood samples spotted and stored on newborn screening (NBS) filter paper cards. DNA was isolated from NBS cards, and PWS testing performed using DNA methylation-specific PCR (mPCR) and the methylation specific-multiplex ligation dependent probe amplification (MS-MLPA) chromosome 15 probe kit followed by DNA fragment analysis for methylation and copy number status. DNA extraction was successful in 30 of 34 PWS patients and 16 controls. PWS methylation testing was able to correctly identify all PWS patients and MS-MLPA was able to differentiate between 15q11-q13 deletion and non-deletion status and correctly identify deletion subtype (i.e., larger Type I or smaller Type II). mPCR can be used to diagnose PWS and MS-MLPA testing to determine both methylation status as well as the type of deletion or non-deletion status from DNA extracted from NBS filter paper. We propose that PWS testing in newborns is possible and could be included in the Recommended Uniform Screening Panel after establishing a validated cost-effective method.

Ehlers‐Danlos syndrome (EDS) consists of a heterogeneous group of genetically inherited connective tissue disorders. A family with three affected members over two generations with features of Dermatosparaxic EDS (dEDS) autosomal dominant transmission was reported by Desai et al. and having a heterozygous nonsynonymous missense variant of ADAMTSL2 (c.1261G > A; p. Gly421Ser). Variation in this gene is also reported to cause autosomal recessive geleophysic dysplasia. We report five unrelated patients with the Gly421Ser variant identified from a large series of patients presenting with features of connective tissue disorders, each with a positive family history consistent with autosomal dominant transmission. Clinical features of a connective tissue disorder included generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Overall, our analyses including bioinformatics, protein modeling, and gene‐protein interactions with the cases described would add evidence for the Gly421Ser variant in ADAMTSL2 as causative for variable expressivity of autosomal dominant connective tissue disorders. [ABSTRACT FROM AUTHOR]

This study examined associations between body habitus and functions of aggression, in a sample of 474 college students from the Midwestern region of the United States (age range = 18-25y; 73% Caucasian). Two instruments of aggression, the Reactive-Proactive Aggression Questionnaire from Dodge & Coie (DC) and Raine et al. (RPQ) were given as self-assessments. Body habitus measures standardized by age and gender specific weight and height were collected. Subjects considered to have a large body habitus in our study had both weight and height measures above the 75th percentile. Large body habitus was positively correlated with both proactive and reactive functions of aggression among adult males but not females; however, regression analyses indicated that body habitus was most strongly and robustly associated with proactive aggression. Findings suggest that even in a healthy homogeneous population, large body size in males is associated with aggression, particularly proactive aggression including bullying rather than retaliatory aggression. The presence of a large body physique may reinforce aggressive behavioral traits acquired through life experiences and activities evoking physical dominance. Alternatively, the relationship may reflect neurological processes related to size influenced by genetic factors and hormones leading to antisocial behaviors requiring future research on the role of genes for aggression. [ABSTRACT FROM AUTHOR]

Summary: Background: Postsecondary students in Western countries exhibit a high prevalence of cannabis and tobacco use disorders. The etiology of these problems is contributed by several psychosocial factors, including childhood adversity and trauma; however, the mechanisms whereby these environmental determinants predispose to the use of these substances remain elusive, due to our poor knowledge of genetic and biological moderators. Converging evidence points to the monoamine oxidase A (MAOA) gene as a moderator of the effects of lifetime stress on the initiation of substance use. Aims: Building on these premises, in this study, we analyzed whether MAOA upstream variable number tandem repeat (uVNTR) alleles interact with child maltreatment history to predict for lifetime cannabis and tobacco consumption. Materials and methods: Five hundred college students (age: 18–25 years) from a large Midwestern University were surveyed for their child maltreatment history (encompassing emotional, physical, and sexual abuse, as well as emotional and physical neglect) and lifetime consumption of cannabis and tobacco. Saliva samples were obtained to determine the MAOA uVNTR genotype of each participant. Results: In female students, lifetime tobacco and cannabis use was predicted by the interaction of physical and emotional abuse with high‐activity MAOA allelic variants; conversely, in males, the interaction of low‐activity MAOA alleles and physical abuse was associated with lifetime use of tobacco, but not cannabis. Discussion: These findings collectively suggest that the vulnerability to smoke tobacco and cannabis is predicted by sex‐dimorphic interactions of MAOA gene with childhood abuse. Conclusion: These biosocial underpinnings of tobacco and cannabis use may prove important in the development of novel personalized preventive strategies for substance use disorders in adolescents. [ABSTRACT FROM AUTHOR]