Recent Advances in Imprinting Disorders.

Imprinting disorders (ImpDis) are a group of currently 12 congenital diseases with common underlying (epi)genetic etiologies and overlapping clinical features affecting growth, development and metabolism. In the last years it has emerged that ImpDis are characterized by the same types of mutations and epimutations, i.e. uniparental disomies, copy number variations, epimutations, and point mutations. Each ImpDis is associated with a specific imprinted locus, but the same imprinted region can be involved in different ImpDis. Additionally, even the same aberrant methylation patterns are observed in different phenotypes. As some ImpDis share clinical features, clinical diagnosis is difficult in some cases. The advances in molecular and clinical diagnosis of ImpDis help to circumvent these issues, and they are accompanied by an increasing understanding of the pathomechanism behind them. As these mechanisms have important roles for the etiology of other common conditions, the results in ImpDis research have a wider effect beyond the borders of ImpDis. For patients and their families, the growing knowledge contributes to a more directed genetic counseling of the families and personalized therapeutic approaches.COST (BM1208), Bundesministerium für Bildung und Forschung (Network ‘Imprinting Diseases’, 01GM1513B), German Ministry of research and education (01GM1513B)This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/cge.1282

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

BACKGROUND: Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. MAIN BODY: Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. SHORT CONCLUSION: Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED

Histological Review of Skin cancers in African Albinos: A 10-year Retrospective Review.

Skin cancer is rare among Africans and albinism is an established risk for skin cancer in this population. Ultraviolet radiation is highest at the equator and African albinos living close to the equator have the highest risk of developing skin cancers. This was a retrospective study that involved histological review of all specimens with skin cancers from African albinos submitted to The Regional Dermatology Training Center in Moshi, Tanzania from 2002 to 2011. A total of 134 biopsies from 86 patients with a male to female ratio of 1:1 were reviewed. Head and neck was the commonest (n = 75, 56.0%) site affected by skin cancers. Squamous cell carcinoma (SCC) was more common than basal cell carcinoma (BCC) with a ratio of 1.2:1. Only one Acral lentiginous melanoma was reported. Majority (55.6%) of SCC were well differentiated while nodular BCC (75%) was the most common type of BCC. Squamous cell carcinoma is more common than basal cell carcinoma in African albinos

Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci.

Congenital imprinting disorders (IDs) are characterised by molecular changes affecting imprinted chromosomal regions and genes, i.e. genes that are expressed in a parent-of-origin specific manner. Recent years have seen a great expansion in the range of alterations in regulation, dosage or DNA sequence shown to disturb imprinted gene expression, and the correspondingly broad range of resultant clinical syndromes. At the same time, however, it has become clear that this diversity of IDs has common underlying principles, not only in shared molecular mechanisms, but also in interrelated clinical impacts upon growth, development and metabolism. Thus, detailed and systematic analysis of IDs can not only identify unifying principles of molecular epigenetics in health and disease, but also support personalisation of diagnosis and management for individual patients and families.All authors are members of the EUCID.net network, funded by COST (BM1208). TE is funded by the German Ministry of research and education (01GM1513B). GPdN is funded by I3SNS Program of the Spanish Ministry of Health (CP03/0064; SIVI 1395/09), Instituto de Salud Carlos III (PI13/00467) and Basque Department of Health (GV2014/111017).This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13148-015-0143-

Genome-wide analysis reveals the extent of EAV-HP integration in domestic chicken

Background: EAV-HP is an ancient retrovirus pre-dating Gallus speciation, which continues to circulate in modern chicken populations, and led to the emergence of avian leukosis virus subgroup J causing significant economic losses to the poultry industry. We mapped EAV-HP integration sites in Ethiopian village chickens, a Silkie, Taiwan Country chicken, red junglefowl Gallusgallus and several inbred experimental lines using whole-genome sequence data. Results: An average of 75.22 ± 9.52 integration sites per bird were identified, which collectively group into 279 intervals of which 5% are common to 90% of the genomes analysed and are suggestive of pre-domestication integration events. More than a third of intervals are specific to individual genomes, supporting active circulation of EAV-HP in modern chickens. Interval density is correlated with chromosome length (P<2.31−6), and 27 % of intervals are located within 5 kb of a transcript. Functional annotation clustering of genes reveals enrichment for immune-related functions (P<0.05). Conclusions: Our results illustrate a non-random distribution of EAV-HP in the genome, emphasising the importance it may have played in the adaptation of the species, and provide a platform from which to extend investigations on the co-evolutionary significance of endogenous retroviral genera with their hosts

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood