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Genetics and genomics are increasingly relevant to primary healthcare but training is unavailable to many practitioners. Education that can be accessed by practitioners without cost or travel is essential. The Gen-Equip project was formed to provide effective education in genetics for primary healthcare in Europe and so improve patient care. Partners include patient representatives and specialists in genetics and primary care from six countries. Here, we report the progress and challenges involved in creating a European online educational program in genetics.

Background At least 10 % of patients seen in primary care are said to have a condition in which genetics has an influence. However, patients at risk of genetic disease may not be recognised, while those who seek advice may not be referred or managed appropriately. Primary care practitioners lack knowledge of genetics and genetic testing relevant for daily practice and feel inadequate to deliver genetic services. The aim of this systematic review was to evaluate genetics educational interventions in the context of primary care. Methods Following the process for systematic reviews developed by the Centre for Reviews and Dissemination, we conducted a search of five relevant electronic databases. Primary research papers were eligible for inclusion if they included data on outcomes of interventions regarding genetics education for primary care practitioners. The results from each paper were coded and grouped under themes. Results Eleven studies were included in the review. The five major themes identified inductively (post hoc) were: prior experience, changes in confidence, changes in knowledge, changes in practice, satisfaction and feedback. In five of the studies, knowledge of practitioners was improved following the educational programmes, but this tended to be in specific topic areas, while practitioner confidence improved in six studies. However, there was little apparent change to practice. Conclusions There are insufficient studies of relevant quality to inform educational interventions in genetics for primary care practitioners. Educational initiatives should be assessed using changes in practice, as well as in confidence and knowledge, to determine if they are effective in causing significant changes in practice in genetic risk assessment and appropriate management of patients. Electronic supplementary material The online version of this article (doi:10.1186/s12875-016-0483-2) contains supplementary material, which is available to authorized users.

Genetic advances mean patients at risk of genetic conditions can be helped through testing, clinical screening, and preventive treatment, but they must first be identified to benefit. Ensuring quality of genetic care for patients requires genetic expertise in all health services, including primary care. To address an educational shortfall, a series of e-learning resources was developed in six languages to equip primary care professionals with genetic skills relevant for practice. The purpose of the study was to evaluate these resources using Kirkpatrick's framework for educational outcomes.Mixed methods (qualitative and quantitative) were used over four phases of the study.A high level of satisfaction with the resources was reported. Knowledge and skills improved significantly after using the education material. Participants reported changes in confidence and practice behavior, including family history taking, seeking advice from specialists and referring patients. The resources helped users to learn how to explain genetics. Many visited the resources repeatedly and some used them to educate colleagues or students.Gen-Equip modules are effective in improving genetic knowledge, skills, and attitudes for primary care professionals. They provide both continuing professional development and just-in-time learning for a potentially large global audience at a practical level.

Mutations have recently been identified in the G4.5 gene (Xq28), encoding the tafazzin protein, in patients with Barth syndrome. We performed mutational analysis in 5 families with suspected Barth syndrome. In 4 families a male child had all the cardinal features of this syndrome, and mutations of G4.5 were found in each case. A mutation was also found in a fifth family with an extensive history of early infant death from heart disease. The recognition of 5 unrelated families in 1 hospital during a 7-year period suggests that this disease may be underdiagnosed. (J Pediatr 1999;135:311-5)

Five patients with severe spinal muscular atrophy (SMA) type I, all of whom presented with reduced fetal movements in utero , severe weakness at birth, and short survival time were assessed to attempt to determine whether their phenotype could be explained by their genotype. The diagnosis was confirmed by clinical, electrophysiological and histopathological features. Polymerase chain reaction assays were used to define the molecular diagnosis. A genedosage assay was used to assess the quantity of centromeric survival motor neuron gene ( SMNc ) present. In all cases the telomeric survival motor neuron gene ( SMNt ) was absent. The SMNc gene was present but in reduced copy number compared with a control group of children with less severe type I SMA, so may be important in determining severity. In the differential diagnosis of reduced fetal movements, SMA should be considered. The clinical classification may in future be clarified by molecular genetic findings.

We report renal abnormalities found in four cases of Brachmann-de Lange syndrome (BDLS). In two there were nephrogenic rests and renal cortical cysts, a further case showed cortical cysts, and the fourth had dilated collecting ducts. The literature describing renal abnormalities in BDLS has been reviewed, and this includes a report of one individual with BDLS who developed Wilms' tumor. The genetic basis of BDLS has not been elucidated, although a submmicroscopic abnormality of chromosome 3 seems likely. Nephrogenic rests may be Wilms' tumor precursor lesions and are seen in syndromes associated with Wilms' tumors. Mutations of genes on chromosome 11 are the most common genetic abnormalities associated with Wilms' tumor, but other chromosomes have also been implicated. The frequency of renal abnormalities in the BDLS suggests that the involved gene may be important in renal development and also possibly in Wilms' tumors.

Dominantly acting, allelic mutations of the fibroblastgrowth factor receptor 2 (FGFR2) gene have beendescribed in five craniosynostosis syndromes. In Apertsyndrome, characterised by syndactyly of the handsand feet, recurrent mutations of a serine-prolinedipeptide (either Ser252Trp or Pro253Arg) in the linkerbetween the IgII and IgIII extracellular immuno-globulin-like domains, have been documented in morethan 160 unrelated individuals. We have identified threenovel mutations of this dipeptide, associated withdistinct phenotypes. A C T mutation that predicts aSer252Leu substitution, ascertained in a boy with mildCrouzon syndrome (craniosynostosis with normallimbs) is also present in three clinically normalmembers of his family. A CG TT mutation that predictsa Ser252Phe substitution results in a phenotypeconsistent with Apert syndrome. Finally, a CGC TCTmutation that predicts a double amino acid substitution(Ser252Phe and Pro253Ser) causes a Pfeiffer syndromevariant with mild craniosynostosis, broad thumbs andbig toes, fixed extension of several digits, and onlyminimal cutaneous syndactyly. The observation thatthe Ser252Phe mutation causes Apert syndrome,whereas the other single or double substitutions areassociated with milder or normal phenotypes, high-lights the exquisitely specific molecular pathogenesisof the limb and craniofacial abnormalities associatedwith Apert syndrome. Ser252Phe is the first non-canonical mutation to be identified in this disorder, itsrarity being explained by the requirement for tworesidues of the serine codon to be mutated. Thedescription of independent, complex nucleotide sub-stitutions involving identical nucleotides is unpre-cedented, and we speculate that this may result fromfunctional selection of FGFR mutations in sperm. INTRODUCTIONThere has been considerable progress in understanding the geneticbasis of craniosynostosis, the premature closure of the sutures of theskull. Mutations in fibroblast growth factor receptors (FGFRs) 1–3have been identified in Crouzon, Apert, Pfeiffer, Jackson–Weiss andBeare–Stevenson syndromes, as well as in non-syndromiccraniosynostosis (reviewed in refs 1–3,4,5). Distinct mutations ofFGFR3 have also been identified in hypochondroplasia,achondroplasia and thanatophoric dysplasia, disorders of long bonegrowth (6 and references therein). All FGFR mutations identified todate are dominantly acting and many are highly localised; in the caseof FGFR2 and FGFR3, different syndromes result from allelicmutations of the same gene. This suggests that the mutations act bya variety of distinct gain-of-function mechanisms; this is supportedfor certain mutations by recent functional studies (7–11).A class of FGFR mutations whose mechanism is notunderstood affects the putative linker between the second (IgII)and third (IgIII) extracellular immunoglobulin-like domains ofFGFRs 1, 2 and 3 [mutations of the linker to cysteine, which occurin FGFR3, are likely to act by a different mechanism (9,12) andare not considered further here]. This linker is contained withina sequence of 16 amino acids identical between all four humanFGFRs (13) and muta tions of this region in FGFRs 1, 2 and 3 giverise to distinct syndromes. In FGFR1, a Pro252Arg mutationpresent in nine families with Pfeiffer syndrome (craniosynostosiswith broad big toes and thumbs) is the only constitutional

Just as a person's qualifications can provide only a guide to their future job performance in the context of an interview, so with many medical conditions that have a genetic basis: the exact DNA alteration can only be a guide to predicting the severity of clinical expression in each case. It is the degree of expression that can be all-important for someone inheriting the condition, particularly when that expression may vary within a family.

Summary. Surprisingly, the genetics of preterm delivery have received very little attention in the literature. Possible explanations are the inability to obtain accurate information on the length of gestation in family studies and the heterogeneous nature of this disorder. In contrast to the many studies which consider the relative contribution of both genetic and environmental variance to the total variance of birthweight, few studies have examined the genetic basis of the duration of gestation in man. It is argued that both genetic and epidemiological approaches are needed to separate the effects of heredity and the environment on the duration of gestation.

The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the beta-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of beta-thalassaemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.

Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant hepatitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, no test is available for predictive analysis in at risk pregnancies. As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 families. We have moreover carried out a molecular analysis of candidate genes (β2-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iron metabolism. No pathogenic mutations in these genes were identified that segregate consistently with the disease phenotype in multiplex pedigrees. However, excluding four pedigrees with clear evidence of maternal infection associated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two families with possible matrilineal inheritance of disease in maternal half sibs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants were the sole offspring of consanguineous but otherwise healthy parents. We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transmission of disease in a manner suggesting autosomal recessive inheritance, we also provide the basis for further genome wide studies to define chromosomal determinants of iron storage disease in the newborn. Keywords: iron storage; haemochromatosis; neonatal; liver

A family with five persons affected with fibrodysplasia ossificans progressiva (myositis ossificans progressiva) in three generations is described. This is the first well documented three generation family with this condition and provides further evidence for autosomal dominant inheritance. A wide range of phenotypic severity is apparent, from disabling ectopic bone formation and premature death to an asymptomatic adult with characteristic big toe malformations.