Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families.

Ablepharon macrostomia syndrome: A distinct genetic entity clinically related to the group of FRAS-FREM complex disorders.

Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners.

Is PATCHED an important candidate gene for neural tube defects? Cranial and thoracic neural tube defects in a family with Gorlin syndrome: a case report.

. The relationship of mutations in the patched gene PTCH and nevoid basal cell carcinoma (NBCC) or Gorlin syndrome is well established. Animal studies have implicated the hedgehog-patched signalling pathway in neurulation and neural tube defects (NTDs).

Barking up the wrong genome--we are not alone.

What Is Known And Objective: Pharmacogenetic studies, to help us understand variability in human drug response, have hitherto focussed largely on our own germline mutations, and in the context of anticancer and antimicrobial drugs, also on mutations of the tumour cell or invader microorganism. Here, we wish to draw attention to how our microbiome may contribute to variability in drug effects.

Comment: Irinotecan, a prodrug which is activated to the topoisomerase I inhibitory metabolite (SN-38), is commonly used for the treatment of a range of cancers.

The Pharmacogenetic Rescue of Side-Lined Anticancer Drugs to the Front-Line: Gefitinib as a Case Example.

Objective: To illustrate the increasing importance of pharmacogenetics in drug development and clinical practice through a critical analysis of the validation and licensing of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as a treatment for non-small cell lung cancer (NSCLC).

Data Sources: Journal articles and the "grey" literature were identified through a systematic search of MEDLINE (to June 2010) and the Web sites of the major drug regulators. References identified through the reference lists of major published reviews of gefitinib and Erb receptors, including EGFR, were also reviewed.

Preventing the aortic complications of Marfan syndrome: a case-example of translational genomic medicine.

The translational path from pharmacological insight to effective therapy can be a long one. We aim to describe the management of Marfan syndrome as a case-example of how pharmacological and genomic insights can contribute to improved therapy. We undertook a literature search for studies of Marfan syndrome, to identify milestones in description, understanding and therapy of the syndrome.

Genetics in family health care: putting it into action.

This article builds on a previous article by suggesting practical ways in which genetics can be integrated into existing family health care practice. Some key skills such as collecting family history information, identifying clinical pointers suggestive of a genetic condition and knowing how to refer individuals for genetic counselling are discussed in detail. When talking about genetics, it is important to use the right words and be aware of the emotional issues that taking a family history may bring to light.

Genetics: what's it got to do with family health care?

Genetics is an important contributory factor in many medical conditions. Having an understanding of the genetic basis of diseases can therefore be helpful in identifying and supporting people who have, or are at risk of having, a genetic condition. Most of the current practical applications relate to conditions which are known to have a definite mode of inheritance (for instance cystic fibrosis or familial hypercholesterolaemia) or which are due to chromosomal anomalies (such as Down syndrome).

A toolkit for incorporating genetics into mainstream medical services: Learning from service development pilots in England.

Background: As advances in genetics are becoming increasingly relevant to mainstream healthcare, a major challenge is to ensure that these are integrated appropriately into mainstream medical services. In 2003, the Department of Health for England announced the availability of start-up funding for ten 'Mainstreaming Genetics' pilot services to develop models to achieve this.

Methods: Multiple methods were used to explore the pilots' experiences of incorporating genetics which might inform the development of new services in the future.

Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17.

Aims: Cytochrome P450 2C19 metabolizes many important drugs. In 2006, a variant allele (CYP2C19*17) associated with increased activity was discovered, but its likely clinical significance is controversial. Investigators disagree about the phenotype to be assigned to the two CYP2C19*17 genotypes.

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example.

Purpose: To illustrate the interface of pharmacogenetics and therapeutic drug monitoring and to estimate target blood level for imatinib in the treatment of chronic myelogenous leukemia

Methods: A literature review to provide the evidence and necessary data to support the case for the interface, and quantitative analysis of the data to estimate the target blood level for imatinib using receiver operating curve (ROC; signal detection theory) analysis.

Results And Discussion: One study estimated the optimum target level of imatinib in chronic myelogenous leukaemia as 1002 ng/mL (1.70 microM) through ROC analysis.

When is a genetic test suitable for prime time? Predicting the risk of prostate cancer as a case-example.

Advances in genomics promise to deliver personalized medicine both for prevention and treatment of disease. Considerable effort is being directed towards translating observed associations between various genetic variants, such as single nucleotide polymorphisms (SNPs), and disease or drug response into clinically useful genetic tests. Unfortunately, because reported associations are usually weak or moderate, tests based on them are generally not accurate enough for use in routine clinical practice, and therefore, ensuring the appropriate use of genetic tests is important.

The development of core learning outcomes relevant to clinical practice: identifying priority areas for genetics education for non-genetics specialist registrars.

Advances in medical genetics are increasingly impacting on clinical practice outside specialist genetic services. It is widely acknowledged that physicians will need to use genetics knowledge and skills in order to incorporate these advances into patient care. In order to determine priority areas for genetics education for non-genetics specialist registrars, an educational needs assessment was undertaken.

Developing a curriculum statement based on clinical practice: genetics in primary care.

Background: Advances in medical genetics are increasingly being incorporated into clinical management outside specialist genetic services. This study was therefore undertaken to develop learning outcomes in genetics for general practice specialty training, using methods to ensure the knowledge, skills, and attitudes relevant to genetics in primary care were identified.

Aim: To identify key knowledge, skills, and attitudes in genetics and to synthesise these into learning outcomes to assist training in genetics for primary care.

A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.

Lysyl hydroxylase 3 (LH3, encoded by PLOD3) is a multifunctional enzyme capable of catalyzing hydroxylation of lysyl residues and O-glycosylation of hydroxylysyl residues producing either monosaccharide (Gal) or disaccharide (Glc-Gal) derivatives, reactions that form part of the many posttranslational modifications required during collagen biosynthesis. Animal studies have confirmed the importance of LH3, particularly in biosynthesis of the highly glycosylated type IV and VI collagens, but to date, the functional significance in vivo of this enzyme in man is predominantly unknown. We report here a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance.

Family communication between children and their parents about inherited genetic conditions: a meta-synthesis of the research.

In families affected by an inherited genetic condition, parents face a difficult task of having to communicate genetic risk information to their children. A systematic review of all major health and medical research databases was undertaken using current guidelines to identify original relevant research papers from 1980 to 2007, which explore the issues surrounding parents and their children's communication about inherited genetic risk. A total of 9698 abstracts were found of which 158 research papers were reviewed as potentially relevant.

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways.

Developmental ocular malformations, including anophthalmia-microphthalmia (AM), are heterogeneous disorders with frequent sporadic or non-Mendelian inheritance. Recurrent interstitial deletions of 14q22-q23 have been associated with AM, sometimes with poly/syndactyly and hypopituitarism. We identify two further cases of AM (one with associated pituitary anomalies) with a 14q22-q23 deletion.

Genetics education for health professionals: strategies and outcomes from a national initiative in the United Kingdom.

The National Health Service (NHS) National Genetics Education and Development Centre was established by the Department of Health in 2004 to help drive and co-ordinate genetics education for health professionals working outside specialist genetic services. This paper reviews the experiences and lessons learned to date. At the outset, it was clear that understanding the learning ethos, preferred delivery methods and attitudes towards genetics of different NHS healthcare groups was vital.

How can genetic tests be evaluated for clinical use? Experience of the UK Genetic Testing Network.

The UK Department of Health supported the establishment of the UK Genetic Testing Network (UKGTN) in 2002. The UKGTN is a collaborative network of NHS molecular genetic laboratories that offer tests for human single gene germ-line disorders. Its objective is to provide high quality and equitable services for patients and their families who require genetic advice, diagnosis and management.

Competences, education and support for new roles in cancer genetics services: outcomes from the cancer genetics pilot projects.

In 2004 the Department of Health in collaboration with Macmillan Cancer Support set up service development projects to pilot the integration of genetics in mainstream medicine in the area of cancer genetics.In developing these services, new roles and responsibilities were devised that required supporting programmes of education and training. The NHS National Genetics Education and Development Centre has worked with the projects to draw together their experience in these aspects.

DISCERN-Genetics: quality criteria for information on genetic testing.

Information currently available to the public is inadequate to support those deciding to consent to a genetic test. As genetic knowledge continues to evolve, more people will be forced to consider the complex issues raised by genetic testing. We developed and tested criteria to guide the production and appraisal of information resources produced for the public on genetic testing.

A "neglected part of the curriculum" or "of limited use"? Views on genetics training by nongenetics medical trainees and implications for delivery.

Purpose: Although the importance of genetics education for health care professionals is increasingly recognized worldwide, little is known about the needs and views of nongenetics postgraduate medical trainees.

Methods: Data on the views of 143 learners from four specialties (family practice, neurology, cardiology, and dermatology) in two regions in England (West Midlands and South Western) were collected using focus groups, questionnaires, and interviews.

Results: Low levels of genetics training were reported by both trainee family practitioners and trainee hospital consultant specialists.