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The history of the beginnings of medical genetics in France is discussed, based on the personal perspective provided by recorded interviews with 16 early French workers in the field. The weakness of French genetics overall up to the beginning of the Second World War meant that post-war medical genetics had to start from new, with its origins largely derived from the medical fields of child health and the prevention of genetic disorders, rather than from basic science. The key people responsible for initiating these developments were Robert Debré and Maurice Lamy at Hôpital Necker in Paris and those interviewed included a number of their colleagues and successors, including Jean Frézal, Pierre Maroteaux, Josué Feingold, André and Joelle Boué, and Jean-Claude Kaplan. A separate group of paediatricians, originally at Hôpital Trousseau under Raymond Turpin, including Jérôme Lejeune, Marthe Gautier and Roland Berger, was responsible for major advances in human cytogenetics. Outside Paris, workers were interviewed from Marseille, Strasbourg and Nancy, although not from Lyon, where Jacques-Michel Robert was an early pioneer, particularly of genetic counselling. Challenges in the development of medical genetics in France included the advent of prenatal diagnosis with its ethical issues, the emergence of medical genetics as a distinct specialty from paediatrics, and its spread from Paris across France. These and other aspects are described by those interviewed from their own experiences, given in Appendix S1, while the fully edited transcripts for most interviews are accessible on the Web: www.genmedhist.org/interviews., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The development of human genetics world-wide during the twentieth century, especially across Europe, has occurred against a background of repeated catastrophes, including two world wars and the ideological problems and repression posed by Nazism and Communism. The published scientific literature gives few hints of these problems and there is a danger that they will be forgotten. The First World War was largely indiscriminate in its carnage, but World War 2 and the preceding years of fascism were associated with widespread migration, especially of Jewish workers expelled from Germany, and of their children, a number of whom would become major contributors to the post-war generation of human and medical geneticists in Britain and America. In Germany itself, eminent geneticists were also involved in the abuses carried out in the name of 'eugenics' and 'race biology'. However, geneticists in America, Britain and the rest of Europe were largely responsible for the ideological foundations of these abuses. In the Soviet Union, geneticists and genetics itself became the object of persecution from the 1930s till as late as the mid 1960s, with an almost complete destruction of the field during this time; this extended also to Eastern Europe and China as part of the influence of Russian communism. Most recently, at the end of the twentieth century, China saw a renewal of government sponsored eugenics programmes, now mostly discarded. During the post-world war 2 decades, human genetics research benefited greatly from recognition of the genetic dangers posed by exposure to radiation, following the atomic bomb explosions in Japan, atmospheric testing and successive accidental nuclear disasters in Russia. Documenting and remembering these traumatic events, now largely forgotten among younger workers, is essential if we are to fully understand the history of human genetics and avoid the repetition of similar disasters in the future. The power of modern human genetic and genomic techniques now gives a greater potential for abuse as well as for beneficial use than has ever been seen in the past.

The European Society of Human Genetics (ESHG) was founded on 15 March 1967, after preliminary discussions at the International Human Genetics Congress in Chicago the previous year and in Copenhagen in early 1967. Its initial meeting was held on 18-19 November 1967, also in Copenhagen, and annual meetings have been held from that time until the present, apart from years in which the International Congress of Human Genetics was also being held. The character of the Society during its early years was strongly influenced by its founding and permanent Secretary, Jan Mohr, head of the Copenhagen Institute of Medical Genetics, whose records are archived in the Tage Kemp/Jan Mohr Archive, now part of the Danish National Archives. These records show Jan Mohr's determination to keep the activities of the Society limited to the holding of an annual meeting to enhance contacts between European human geneticists, and to resist expansion to other activities. Pressures for a wider role of ESHG became irresistible in the late 1980s and a revised constitution, adopted in 1991, reshaped the Society into a more conventional and less restrictive structure. This has allowed it to play a wider and increasingly influential role in the development of human and medical genetics across Europe, with its own Journal, a range of committees covering different aspects of the field and a series of valuable reports on specific important topics, to be described in a forthcoming article on the Society's more recent history.European Journal of Human Genetics advance online publication, 10 May 2017; doi:10.1038/ejhg.2017.34.

Some of the pioneers of human genetics across Europe are described, based on a series of 100 recorded interviews made by the author. These interviews, and the memories of earlier workers in the field recalled by interviewees, provide a vivid picture, albeit incomplete, of the early years of human and medical genetics. From small beginnings in the immediate post-World War 2 years, human genetics grew rapidly across many European countries, a powerful factor being the development of human cytogenetics, stimulated by concerns over the risks of radiation exposure. Medical applications soon followed, with the recognition of human chromosome abnormalities, the need for genetic counselling, the possibility of prenatal diagnosis and later, the applications of human molecular genetics. The evolution of the field has been strongly influenced by the characters and interests of the relatively small number of founding workers in different European countries, as well as by wider social, medical and scientific factors in the individual countries.European Journal of Human Genetics advance online publication, 10 May 2017; doi:10.1038/ejhg.2017.47.

A series of 100 recorded interviews with human and medical geneticists has been carried out and some general results are reported here. Twenty countries across the world are represented, mostly European, with a particular emphasis on the United Kingdom. A priority was given to older workers, many of whom were key founders of human genetics in their own countries and areas of work, and over 20 of whom are now no longer living. The interviews also give valuable information on the previous generation of workers, as teachers and mentors of the interviewees, thus extending the coverage of human genetics back to the 1930s or even earlier. A number of prominent themes emerge from the interview series; notably the beginnings of human cytogenetics from the late 1950s, the development of medical genetics research and its clinical applications in the 1960s and 1970s, and more recently the beginnings and rapid growth of human molecular genetics. The interviews provide vivid personal portraits of those involved, and also show the effects of social and political issues, notably those arising from World War 2 and its aftermath, which affected not only the individuals involved but also broader developments in human genetics, such as research related to risks of irradiation. While this series has made a start in the oral history of this important field, extension and further development of the work is urgently needed to give a fuller picture of how human genetics has developed., Competing Interests: The author records no conflict of interest.

The 50th anniversary of Mary Lyon's 1961 Nature paper, proposing random inactivation in early embryonic life of one of the two X chromosomes in the cells of mammalian females, provides an opportunity to remember and celebrate the work of those involved. While the hypothesis was initially put forward by Lyon based on findings in the mouse, it was founded on earlier studies, notably the work of Susumu Ohno; it was also suggested independently by Beutler and colleagues using experimental evidence from a human X-linked disorder, glucose-6-phosphate dehydrogenase deficiency, and has proved to be of as great importance for human and medical genetics as it has for general mammalian genetics. Alongside the hypothesis itself, previous cytological studies of mouse and human chromosomes, and the observations on X-linked mutants in both species deserve recognition for their essential role in underpinning the hypothesis of random X-inactivation, while subsequent research on the X-inactivation centre and the molecular mechanisms underlying the inactivation process represent some of the most outstanding contributions to human and wider mammalian genetics over the past 50 years.

Paul Polani (1914-2006) was one of the key figures internationally in the beginnings and development of medical genetics. Best remembered scientifically for his highly original work on the basis of human sex chromosome disorders, notably Turner syndrome, he pioneered the application of basic biological research to clinical genetic problems. The unit that he founded in 1960, at Guys Hospital, London, provided an unparalleled model for combined research and service in medical genetics across a wide range of laboratory areas and helped to establish medical genetics as a specific discipline.

The correct determination of the human diploid chromosome number as 46, by J-H Tjio and A Levan, at the University of Lund, Sweden, occurred 50 years ago, in December 1955; the finding was published in April 1956, ending a period of more than 30 years when the number had been thought to be 48. The background to the discovery and the surrounding factors are reassessed, as are the reasons why previous investigators persistently misidentified the precise number. The necessity for multiple technological advances, the power of previously accepted conclusions in influencing the interpretation of later results, and the importance of other work already undertaken in Lund, are all relevant factors for the occurrence of this discovery, the foundation for modern human cytogenetics, at this particular time and place.

A 54 year old man presented with numerous cutaneous schwannomas, cranial nerve lesions, and spinal cord lesions, but no evidence of vestibular nerve involvement. There was no family history of neurocutaneous lesions. To help discriminate between the various possible diagnoses in this patient, molecular analysis of two cutaneous schwannomas was undertaken. An identical point mutation in the NF2 gene in the two anatomically distinct tumours was found, confirming this as a case of NF2 mosaicism.

The importance of human genetics in the work of William Bateson (1861-1926) and in his promotion of Mendelism in the decade following the 1900 rediscovery of Mendel's work is described. Bateson had close contacts with clinicians interested in inherited disorders, notably Archibald Garrod, to whom he suggested the recessive inheritance of alkaptonuria, and the ophthalmologist Edward Nettleship, and he lectured extensively to medical groups. Bateson's views on human inheritance were far sighted and cautious. Not only should he be regarded as one of the founders of human genetics, but human genetics itself should be seen as a key element of the foundations of mendelian inheritance, not simply a later development from knowledge gained by study of other species.

The Treasury of Human Inheritance represents the most extensive, and one of the earliest series of documentations and analyses of human genetic disorders. Published between 1909 and 1958, from The Galton Laboratory, London, most of the numerous sections were written by Julia Bell, who represents a key figure in the development of human and medical genetics. Her combination of mathematical training, genetic knowledge and clinical expertise yielded numerous important insights into human inheritance first appearing in the Treasury; it remains a valuable scientific as well as an historical record of the genetics of a range of important inherited disorders.

Objective: To determine the prevalence and causation of late onset cerebellar ataxia (LOCA) in south east Wales, United Kingdom., Methods: A population based study of LOCA was conducted in a defined geographical region with a total population of 742,400. Multiple sources of ascertainment were used to identify all cases prevalent on 1 January 2001. The inclusion criteria were: a predominantly progressive cerebellar ataxia with onset of symptoms at age > or = 18 years; and disease duration of > or = 1 year. Cases with known acquired ataxias, ataxic syndromes with associated prominent autonomic dysfunction and/or atypical parkinsonism suggestive of multiple system atrophy and disorders with ataxia as a minor feature were excluded., Results: We identified 76 index cases of LOCA, of whom 63 were sporadic, idiopathic LOCA (ILOCA) and 13 were familial LOCA, of whom six had either spinocerebellar ataxia type 6, Friedreich's ataxia or dominant episodic ataxia. The mean annual incidence rate for the period 1999-2001 was 0.3/100,000 population/year. The crude prevalence rates were 8.4 per 100,000 (95% CI 7.2 to 11.6) for ILOCA and 1.8 per 100,000 (95% CI 0.8 to 2.7) for inherited LOCA. Of the 54/63 (85.7%) patients with ILOCA who were assessed, mean (SD) age at onset of symptoms was 53.8 (14.1) years (range 19 to 78) with a male:female ratio of 2.1:1. The mean disease duration was 8.7 (6.3) years (range 1 to 31). The most frequent presenting complaint was disturbance in gait (90.7%). One-third had a relatively pure cerebellar syndrome (33.3%) and two-thirds (66.7%) had additional extracerebellar neurological features. The majority (92%) were ambulant but only 9.3% were independently self-caring., Conclusion: This population based study provides insight into LOCA within a defined region and will inform decisions about the rational use of healthcare resources for patients with LOCA.

Objectives: To characterise the neuropathological phenotypes of two affected individuals from a family with an unusual clinical phenotype resembling motor neurone disease and dementia., Methods: Histological sections of cerebral cortex, basal ganglia, brain stem, cerebellum, and spinal cord were stained with haematoxylin-eosin, luxol fast blue, silver stains, anti-tau, anti-ubiquitin, anti-alpha-synuclein, and anti-neurofilament., Results: Numerous ubiquitin positive, tau and alpha-synuclein negative intraneuronal inclusions were present in the cerebral cortex (particularly within the dentate gyrus), cerebellar cortex, brain stem, and spinal cord. The cerebellar ubiquitinated inclusions were located in the proximal dendrite of the Purkinje cells. Loss of Purkinje cells and occasional silver and neurofilament positive axonal swellings (torpedoes) were also seen within the cerebellar cortex. The main difference between the two cases was the severity of the spinal cord involvement: no significant pathology was present within one, but obvious motor neurone disease within the other., Conclusions: The clinical and neuropathological findings in this family are best described as an example of familial motor neurone disease with dementia. Intraneuronal ubiquitin inclusions together with agyrophilic, neurofilament positive torpedoes were present within the cerebellar cortex, both previously unrecognised findings in this group of diseases.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.

Background: The peroneal muscular atrophy syndrome is the most common inherited disorder of the peripheral nervous system and has extensive clinical and genetic heterogeneity. Cranial nerve involvement is rare, though there are distinct peroneal muscular atrophy syndromes in which vocal cord paralysis is a characteristic feature. Among these dHMN-VII and HMSN-IIC are clinically similar but are differentiated by sensory involvement in HMSN-IIC. The gene for dHMN-VII, designated DHMNVP, has been localised to chromosome 2q14, but the location of the gene for HMSN-IIC is currently unknown. It has been suggested that dHMN-VII and HMSN II-C are allelic disorders., Objective: To assess the contribution of the dHMN-VII predisposition gene to peroneal muscular atrophy syndromes associated with vocal cord weakness., Methods: Linkage analysis of microsatellite markers at chromosome 2q14 was undertaken on two families, one affected by HMSN-IIC and a second manifesting vocal cord paralysis and sensorineural deafness in addition to distal muscular atrophy., Results: Two-point LOD scores at chromosome 2q14 markers encompassing the DHMNVP gene were negative in both families., Conclusions: These results suggest that at least one further gene predisposing to distal muscular weakness in association with vocal cord paralysis is likely to exist, and that dHMN-VII and HMSN-IIC are unlikely to be allelic disorders. Analyses of further HMSN-IIC families are required to confirm this.

Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive disorder characterized by short stature due to defective growth of the vertebral bodies. In addition, deformities of the femoral heads result in early onset secondary osteoarthritis of the hips. The disorder affects males only with heterozygous female carriers showing no consistent abnormalities. The gene causing SEDT, which is located on Xp22.12-p22.31, consists of 6 exons of which only exons 3, 4, 5, and 6 are translated to yield an 140 amino acid protein, referred to as SEDLIN. SEDLIN mutations have been observed in SEDT patients, and we have undertaken studies to characterize such mutations in four unrelated SEDT kindreds by DNA sequence analysis. We identified two nonsense and two intragenic deletional frameshift mutations. The nonsense mutations occurred in exons 4 (TGG-->TGA, Trp70Stop) and 6 (CGA-->TGA, Arg122Stop). Both of the intragenic deletions, which were approximately 750 bp and 1300-1445 bp in size, involved intron 5 and part of exon 6 and resulted in frameshifts that lead to premature termination (Stop) signals. Thus, all four mutations are predicted to result in truncated proteins. The results of our study expand the spectrum of SEDLIN mutations associated with SEDT, and this will help to elucidate further the role of this novel protein in the etiology of this form of osteochondrodysplasia.

Distal hereditary motor neuronopathy type VII (dHMN-VII) is an autosomal dominant disorder characterized by distal muscular atrophy and vocal cord paralysis. We performed a genomewide linkage search in a large Welsh pedigree with dHMN-VII and established linkage to chromosome 2q14. Analyses of a second family with dHMN-VII confirmed the location of the gene and provided evidence for a founder mutation segregating in both pedigrees. The maximum three-point LOD score in the combined pedigree was 7.49 at D2S274. Expansion of a polyalanine tract in Engrailed-1, a transcription factor strongly expressed in the spinal cord, was excluded as the cause of dHMN-VII.

Stickler syndrome is a dominantly inherited disorder characterized by arthropathy, midline clefting, hearing loss, midfacial hypoplasia, myopia, and retinal detachment. These features are highly variable both between and within families. Mutations causing the disorder have been found in the COL2A1 and COL11A1 genes. Premature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding. These produce a characteristic congenital "membranous" anomaly of the vitreous of all affected individuals. Experience has shown that vitreous slit-lamp biomicroscopy can distinguish between patients with COL2A1 mutations and those with dominant negative mutations in COL11A1, who produce a different "beaded" vitreous phenotype. Here we characterize novel dominant negative mutations in COL2A1 that result in Stickler syndrome. Both alter amino acids in the X position of the Gly-X-Y triple-helical region. A recurrent R365C mutation occurred in two unrelated sporadic cases and resulted in the membranous vitreous anomaly associated with haploinsufficiency. In a large family with linkage to COL2A1, with a LOD score of 2.8, a unique L467F mutation produced a novel "afibrillar" vitreous gel devoid of all normal lamella structure. These data extend the mutation spectrum of the COL2A1 gene and help explain the basis for the different vitreous phenotypes seen in Stickler syndrome.

Data on all presymptomatic genetic tests for Huntington's disease (HD) in the UK have been collected over the 10 year period since testing became available as a service. A total of 2937 completed tests have been performed up to the end of 1997, 2502 based on specific mutation testing, feasible since late 1993.A total of 93.1% of these were at 50% prior risk, with a significant excess of females (58.3%); 41.4% of results were abnormal or high risk, including 29.4% in subjects aged 60 or over. The trend in test numbers has currently levelled out at around 500 per year. Almost all presymptomatic tests are carried out in National Health Service genetics centres, with a defined genetic counselling protocol and with availability now in all regions of the UK. The introduction and establishment of HD presymptomatic testing shows that this form of predictive medicine for Mendelian disorders can be successfully incorporated into National Health Service structures. The comprehensive collection of simple data allows trends in demand and outcomes to be monitored and has also been the foundation for more detailed specific studies. A comparable approach to data collection in other genetic disorders will be important as presymptomatic testing becomes more generally feasible.

Age of onset (AO) of Huntington disease (HD) is known to be correlated with the length of an expanded CAG repeat in the HD gene. Apolipoprotein E (APOE) genotype, in turn, is known to influence AO in Alzheimer disease, rendering the APOE gene a likely candidate to affect AO in other neurological diseases too. We therefore determined APOE genotype and normal CAG repeat length in the HD gene for 138 HD patients who were previously analysed with respect to CAG repeat length. Genotyping for APOE was performed blind to clinical information. In addition to highlighting the effect of the normal repeat length upon AO in maternally inherited HD and in male patients, we show that the APOE epsilon2epsilon3 genotype is associated with significantly earlier AO in males than in females. Such a sex difference in AO was not apparent for any of the other APOE genotypes. Our findings suggest that subtle differences in the course of the neurodegeneration in HD may allow interacting genes to exert gender specific effects upon AO.

Semi-structured interviews were conducted with a cohort of 22 test applicants who requested Huntington's disease (HD) predictive testing in South Wales, and a random sample of 32 non-requesters, drawn from the South Wales HD register. Apart from identifying differences between the groups, the study afforded the opportunity to listen, at length, to at-risk individuals' accounts of living at risk and their thoughts about predictive testing and genetic services. Emergent themes included difficulties in family communication and the uncertainties inherent in being at risk and undergoing testing. Important factors in decision making about testing were: moral imperatives to clarify one's genetic status: views about the controllability of the future; family attitudes and norms; and the impact of a test result on family members. At-risk individuals' perceptions of the genetics service were that contact with the service would result in pressure to be tested and a need for test applicants to present a favourable view of coping capacities to secure testing. In addition, there was an expectation of ongoing contact with HD families at the initiative of the service providers. Implications of the findings for the way in which predictive testing services are structured and introduced to the at-risk population are discussed.

In Wales, predictive testing for Huntington's disease (HD) has not been offered proactively to families and uptake of testing is low in comparison to other centres. Little is known of those not requesting testing, particularly those not in direct contact with the genetics service. This study examined differences between a cohort of 22 test applicants and a random group of 32 'non-requesters', drawn from the South Wales HD register. Respondents were interviewed by means of a semi-structured schedule in their own homes. The study groups differed significantly on a number of variables including: knowledge of the availability of testing; perceived attitudes of family members and significant others to testing; length of knowledge and perceived stressfulness of being at risk; and perceived ability to cope with an unfavourable result. Overall, knowledge of testing procedures was poor and at-risk individuals' understanding of genetic terminology was at odds with scientific distinctions. Discussion focuses on the organisational and psychological factors associated with lack of knowledge of the availability of testing and the interpretation of reported coping capacities.

Life insurance is a key element of the UK social structure in terms of family protection and house purchase; it thus needs to be viewed in this broad context, rather than solely as a commercial activity. Insurers have not so far actively requested genetic tests for life insurance, but have insisted on knowing of and being able to act on existing genetic test information. The main reason given for this has been to avoid serious adverse selection; however, this has never been adequately estimated. Review of the different major categories of Mendelian genetic disorders suggests that the scope for adverse selection is extremely limited and that insurers would lose little, and possibly gain more, by foregoing the disclosure and use of this information in relation to life insurance policies of 'normal' size and nature. The likely future use in service of genetic tests based on susceptibility or population screening makes it especially important that the issue is rapidly resolved for Mendelian disorders; so far there is no sign that insurers are willing to achieve this.

A major advance in the molecular diagnosis of facioscapulohumeral muscular dystrophy is the recently reported elimination of confounding DNA fragments arising from homologous sequences located at 10q26. In order to evaluate the specificity and sensitivity of this important diagnostic test, we have compared a group of 130 patients fulfilling the diagnostic criteria for FSHD with 200 control subjects not known to have an increased risk of having an FSHD mutation. Among the FSHD cases the smallest BlnI/EcoRI fragment sizes ranged from 10 to > 48 kb with 94.6% (95% CI 89.2-97.8%) of cases having fragment sizes of 34 kb or less. Among the 400 chromosomes from controls the smallest BlnI/EcoRI fragment observed with the EcoRI/BlnI double restriction enzyme digest was 38 kb +/- 2 kb, suggesting a test specificity at a fragment size < 34 kb of or very near to 100% (lower 95% CI 98.2%). Test sensitivity at < 34 kb is estimated at 94.6% (95% CI 89.2-97.8%), all outliers having fragments > 38 kb. The Southern blot analysis with DNA probe p13E-11 has created a valuable molecular diagnostic test for FSHD.

Population carrier screening for cystic fibrosis (CF) was offered to all patients aged 16-45 in one general practice in South Wales, excluding those in couples with a current pregnancy. Out of 1553 patients in this group, 481 subjects were tested, giving an overall uptake rate of more than 30%. The rate of uptake varied with the mode of invitation. Twenty-six carriers were identified, giving a prevalence of identified carriers of 5.4% (1 in 18.5) for those with no family history of CF. A further 18 carriers were identified by cascade testing of these 26. We describe the practical difficulties encountered in setting up this programme in primary care in South Wales. Questionnaires were administered or distributed to all subjects before and after testing. The response rate for the pre-test questionnaire was 95%, and 40-50% for the post-test questionnaires. These showed that, at 3 months post-test, 1 in 4 screen-negative subjects did not appreciate that they had a residual risk of being a carrier. At the same time, 15% of this group thought that there was a 1 in 4 chance of a child being affected if one parent was screen-positive (carried an identified mutation) and the other was screen-negative, and 40% thought there was no risk. Anxiety in relation to testing did not appear to be a major problem, although individual patterns of response to carrier status varied widely and more sensitive indicators of psychosocial impact of genetic tests are required. A pilot study of couple screening showed that this approach is unlikely to be useful in primary care, although we did not assess couple testing during pregnancy. For any programme of CF carrier screening to be established in primary care, it will be necessary to involve the primary care team from the earliest planning stage, so that the opportunity costs, training needs and other costs of the programme can be fully resourced.

Cardiac disease is a well-known complication of myotonic dystrophy, understanding of which has been increased by recent advances in both molecular techniques and cardiological investigations. Conduction disturbances and tachyarrhythmias occur commonly in myotonic dystrophy. These have been shown to have a broad correlation in severity with both neuromuscular disease and the extent of the molecular defect in some, but not all, studies. Clinical evidence of generalised cardiomyopathy is unusual. The rate of progression differs widely between individuals; sudden death may be caused by ventricular arrhythmias or complete heart block, and this can be at an early stage of disease. A familial tendency towards cardiac complications has been shown in some studies. The histopathology is of fibrosis, primarily in the conducting system and sino-atrial node, myocyte hypertrophy and fatty infiltration. Electron microscopy shows prominent I-bands and myofibrillar degeneration. Myotonin protein kinase, the primary product of the myotonic dystrophy gene, may be located at the intercalated discs and have a different isoform in cardiac tissue. The role of other genes or the normal myotonic dystrophy allele in myotonic heart disease has yet to be determined. Suggestions for clinical management include a careful cardiac history and a 12-lead ECG at least every year, with a low threshold for use of 24 h Holter monitoring. Extra care should be taken before, during and after general anaesthetics, which carry a high frequency of cardiorespiratory complications. Finally, myotonic dystrophy should be considered in previously undiagnosed patients presenting to a cardiologist or general physician with suspected arrhythmia or conduction block.

Adolescents who are actively requesting Huntington's predictive testing of their own accord pose a dilemma to those providing testing. In the absence of empirical evidence as regards the impact of genetic testing on minors, current policy and guidelines, based on the ethical principles of non-maleficence and respect for individual autonomy and confidentiality, generally exclude the testing of minors. It is argued that adherence to an age based exclusion criterion in Huntington's disease predictive testing protocols is out of step with trends in UK case law concerning minors' consent to medical treatment. Furthermore, contributions from developmental psychology and research into adolescents' decision making competence suggest that adolescents can make informed choices about their health and personal lives. Criteria for developing an assessment approach to such requests are put forward and the implications of a case by case evaluation of competence to consent in terms of clinicians' tolerance for uncertainty are discussed.

Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease (HD). In the diagnostic setting it is necessary to define the limits of the CAG size ranges on normal and HD-associated chromosomes. Most large analyses that defined the limits of the normal and pathological size ranges employed PCR assays, which included the CAG repeats and a CCG repeat tract that was thought to be invariant. Many of these experiments found an overlap between the normal and disease size ranges. Subsequent findings that the CCG repeats vary by 8 trinucleotide lengths suggested that the limits of the normal and disease size ranges should be reevaluated with assays that exclude the CCG polymorphism. Since patients with between 30 and 40 repeats are rare, a consortium was assembled to collect such individuals. All 178 samples were reanalyzed in Cambridge by using assays specific for the CAG repeats. We have optimized methods for reliable sizing of CAG repeats and show cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms. Seven HD patients had 36 repeats, which confirms that this allele is associated with disease. Individuals without apparent symptoms or signs of HD were found at 36 repeats (aged 74, 78, 79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years), and 39 repeats (aged 67, 90, and 95 years). The detailed case histories of an exceptional case from this series will be presented: a 95-year-old man with 39 repeats who did not have classical features of HD. The apparently healthy survival into old age of some individuals with 36-39 repeats suggests that the HD mutation may not always be fully penetrant.

Neurofibromatosis type 1 (NF1), also called von Recklinghausen disease or peripheral neurofibromatosis, is a common autosomal dominant disorder characterised by multiple neurofibromas, café au lait spots, and Lisch nodules of the iris, with a variable clinical expression. The gene responsible for this condition, NF1, has been isolated by positional cloning. It spans over 350 kb of genomic DNA in chromosomal region 17q11.2 and encodes an mRNA of 11-13 kb containing at least 59 exons. NF1 is widely expressed in a variety of human and rat tissues. Four alternatively spliced NF1 transcripts have been identified. Three of these transcript isoforms (each with an extra exon: 9br, 23a, and 48a, respectively) show differential expression to some extent in various tissues, while the fourth isoform (2.9 kb in length) remains to be examined. The protein encoded by NF1, neurofibromin, has a domain homologous to the GTPase activating protein (GAP) family, and downregulates ras activity. The identification of somatic mutations in NF1 from tumour tissues strongly supports the speculation that NF1 is a member of the tumour suppressor gene family. Although the search for mutations in the gene has proved difficult, germline mutation analysis has shown that around 82% of all the fully characterised NF1 specific mutations so far predict severe truncation of neurofibromin. Further extensive studies are required to elucidate the gene function and the mutation spectrum. This should then facilitate the molecular diagnosis and the development of new therapy for the disease.

Objective: To correlate the degree of CAG repeat expansion with neuropathological findings in Huntington's disease., Methods: The CAG repeat polymorphism was analysed in a large series of brain samples from 268 patients with a clinical diagnosis of Huntington's disease in which full neuropathological data was available., Results: Analysis by polymerase chain reaction was successful in 63% of samples (169 of 268). Repeat expansions were detected in 152 of 153 (99%) samples with a neuropathological diagnosis of Huntington's disease. The exceptional case (22 CAG repeats) showed mild but definite pathological changes and had a typical clinical illness with a positive family history; it raises the possibility that an alternative mutation in the Huntington's disease gene may be responsible although it is more likely that a mutation in another gene has resulted in an Huntington's disease-like phenotype. Four of 16 cases without pathological changes of Huntington's disease also possessed an expanded repeat sequence; a glioblastoma masked the pathological changes of Huntington's disease in one case but the other three cases had a typical clinical history and a positive family history. These three cases may reliably be classified as Vonsattel's Huntington's disease grade 0. Three of 12 cases with a normal repeat length and no morphological changes of Huntington's disease showed other neuropathology; two had Alzheimer's disease and the other had multiple sclerosis. Review of the clinical notes of two other cases indicated a diagnosis of tardive dyskinesia complicating phenothiazine treatment of schizophrenia. The remaining pathology negative/expansion negative cases had been referred because of a family history of Huntington's disease; all but one were themselves symptom free. Apart from emphasising the possibility that an alternative mutation may result in a clinical phenocopy of Huntington's disease, this case suggests that such a clinical phenocopy may occur without gross or light microscopical neuropathological changes (Vonsattel's Huntington's disease grade 0)., Conclusions: The study confirms the value of molecular genetic analysis in cases of suspected Huntington's disease and shows the importance of detailed neuropathological study in the few cases of suspected Huntington's disease with normal CAG repeat lengths.

Neurofibromatosis type 1 is one of the most common inherited disorders with an incidence of 1 in 3000. The search for NF1 mutations has been hampered by the overall size of the gene, the large number of exons, and the high mutation rate. To date, fewer than 90 mutations have been reported to the NF1 mutation analysis consortium and the details on 76 mutations have been published. We have identified five new mutations using single strand conformation polymorphism (SSCP) and heteroduplex analysis (HA) and three intragenic deletions with the microsatellite markers. Of the five new mutations, two were in exon 27a, two in exon 45, and one in exon 49 and these include 4630delA, 4572delC, R7846X, T7828A, and one in the 3' untranslated region (3' UTR). The two nucleotide alterations in exon 27a and the one in exon 45 are predicted to produce a truncated protein.