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Remarkable changes are occurring in the diagnosis and management of individuals with hemophilia A. Genetic testing, including next-generation sequencing, enables family planning, carrier testing, and prenatal diagnosis. Musculoskeletal ultrasound examination facilitates the early detection of acute bleeds and joint disease in clinic, enabling more rapid bleed resolution and treatment planning. Novel therapies offer simpler weekly or monthly administration, some by subcutaneous injection, with better compliance and quality of life, as well as fewer bleeds. Gene therapy provides a 1-time phenotypic "cure" that is cost effective, but may be complicated by waning levels, vector immune responses, and hepatotoxicity.

Purpose Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing. Methods Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing. Results Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2. Conclusion Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.

We genetically evaluated 260 dystrophinopathy patients from Turkey. Karyotyping as an initial test in female patients, followed stepwise by multiplex ligation-dependent probe amplification and by targeted next-generation sequencing of DMD revealed definitive genetic diagnoses in 214 patients (82%), with gross deletions/duplications in 153 (59%), pathogenic sequence variants in 60 (23%), and X-autosome translocation in one. Seven of the gross and 27 of the sequence variants found novel. In silico prediction, co-segregation and transcript assays supported the pathogenic nature of the novel silent (p.Lys534=) and the splice site (c.4345-12C>G) alterations. From a total of 189 singleton cases, 154 (82%) had pathogenic alterations. From 138 of those who had maternal carrier testing, 68 out of 103 (66%) showed gross and 11 out of 35 (31%) showed small pathogenic variants. This suggests that the de novo occurrences in DMD appear approximately 2.1 times more frequently in meiotic unequal crossing-over than in uncorrected replication errors. Our study also disclosed three mothers as obligate gonadal mosaic carriers. Family-based investigation of dystrophinopathy patients is crucial for the ascertainment of novel or rare variants and also for counseling and follow-up care of the families.

The American College of Medical Genetics and Genomics supports parents’ opting in or out of secondary analysis of 59 genes when their child has clinical exome/genome sequencing. We explored the reasons adolescents choose to learn certain types of results and the reasons they want to involve or not involve parents in decision-making. Adolescents recruited without clinical indication were offered independent, followed by joint choices with a parent to learn genomic results. After making independent choices, adolescent/parent dyads were interviewed to explore the reasons for their choices. Interviews were audio-recorded and transcribed. The constant comparative method was used to analyze 64 purposefully selected transcripts that included 31 from adolescents who excluded some or all potential results. Three major themes informed adolescents’ choices: (1) actionability of information, (2) knowledge seeking, and (3) psychological impact. Of adolescents who independently excluded some conditions (n=31), 58% changed their initial choices during the joint interview due to parental influence or improved understanding. Nearly all adolescents (98%) wanted to be involved in the decision-making process, and 53% wanted to make choices independently. Our findings contribute empirical evidence to support the refinement of professional guidelines for adolescents’ engagement and preferences in genetic testing decisions.

Objective: Duchenne muscular dystrophy (DMD) is a severe disorder caused by mutation in the X-linked dystrophin gene, therefor carrier testing is required for all female family members. However, there are cases mutation analysis cannot detect any mutation due to a phenomenon called mosaicism. The case report describes a case of mosaicism in a DMD carrier and discusses the approach in diagnosis and counseling of familial disorder. Case report: The proband was diagnosed with DMD at age six. Sequencing of Dystrophin gene identified a 2-nucleotide deletion c.2032_2033delCA, p.Q678DfsX41. Family investigation suggested that the mother was an obligate carrier of Dystrophin mutation. Sequencing of DNA sample from the mother's peripheral blood did not reveal any mutation, there for we take sample from hair follicle for analysis. The result indicated that the mother was a carrier but was masked from initial analysis by mosaicsism. Conclusion: We suggested that more care need to be taken in identifying cases when no mutation was detected in probable or obligate carrier and prenatal diagnosis should remain an option. Keywords: Duchenne muscular dystrophy, Dystrophin, Mosaicism, Counseling, Prenatal diagnosis

Our study objective was to survey female carriers for Duchenne and Becker muscular dystrophy to identify barriers to carrier testing and the impact of carrier risk knowledge on cardiac and reproductive health management. We surveyed women who have or had biological sons with Duchenne or Becker muscular dystrophy and were enrolled in the US DuchenneConnect patient registry, with questions assessing knowledge of carrier status and recurrence risk, knowledge of care standards for carriers, and barriers to testing. Of the 182 eligible respondents, 25% did not know their carrier status and 14% incorrectly classified themselves as not at risk. Cost of testing was the most commonly identified barrier to testing. Women reporting unknown carrier status were 13 times as likely to express uncertainty regarding their recurrence risk compared to women reporting positive carrier status. 37% of women at an increased risk for cardiomyopathy had never had an echocardiogram. Women who were certain of their positive carrier status were twice as likely to have had an echocardiogram in the last five years compared to women with unknown carrier status. Future research on reducing barriers to counseling and carrier testing, such as cost, may improve care standard adherence.

Genetic testing is now an integral part of most areas of medicine, including neurological disorders. This article provides clinicians with guidance on the issues and pathways for genetic testing, including ethical dilemmas that can arise in the care of families with a confirmed or suspected genetic condition. As genetics moves more into the mainstream, it is increasingly important for non-geneticists to be aware of these issues, the potential pitfalls and when to seek specialist advice. We explain patterns of inheritance, their complexities and the important distinctions between pre-symptomatic, diagnostic and carrier testing. We explain the ethical framework for testing, including confidentiality and consent, and testing in children and in at-risk relatives. We outline core technologies for genetic testing and the importance of close liaison with clinical genetics services and medical genetics laboratories to remain updated with the type, availability and appropriateness of any genetic test. We also summarise new genetic sequencing technologies that are transforming clinical practice.

Carrier screening programs that identify the presence of known mutations have been effective for reducing the incidence of autosomal recessive conditions in the Ashkenazi Jewish (AJ) population and other populations. Yet, these programs have not realized their full potential. Furthermore, many known autosomal recessive and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is unknown. Through literature review and annotation of full sequenced genomes from healthy individuals, we expanded the list of mutations. Mutations were identified in a sample of 128 fully sequenced AJ genomes that were filtered through clinical databases and curated manually for clinical validity and utility using the American College of Medical Genetics and Genomics scoring (ACMG) system. Other known mutations were identified through literature review. A panel of 163 mutations was identified for 76 autosomal recessive, 24 autosomal dominant, and 3 X-linked disorders. Screening for a broader range of disorders not only could further reduce the incidence of autosomal recessive disorders but also could offer the benefits of early or presymptomatic diagnosis. Genet Med 18 5, 522–528.

Genetic counseling is an evolving field in Saudi Arabia. In 2015, genetic counseling was recognized as a Master's program by the Saudi Commission for Health Specialties. Our genetic counselors combine their knowledge of genetics, counseling theory and interpersonal communication to serve Saudi and non-Saudi patients affected with a range of genetic conditions and/or birth defects. Most patients are referred to the clinic from different clinics at King Faisal Specialist Hospital and Research Centre (KFSHRC) and outside of KFSHRC for various indications. Carrier testing and preventative reproduction options rank highly on the reasons for referral to our clinics.The Saudi population has unique customs and beliefs, such as consanguinity and the evil eye. Challenges that are routinely encountered in our genetic counseling clinics include, but are not limited to, preventative reproductive options and termination of pregnancy, manifesting carriers, stigmatization of women and approaches to complex molecular findings. Working with families from different backgrounds and beliefs undoubtedly requires professionals with a distinctive set of skills and a structured clinical setting. This review article presents the scope of genetic counseling practice and tackles some of the challenges faced in providing genetic counseling in Saudi Arabia.

The Meryon Lecture at the 18th Annual Meeting of the Meryon Society Wolfson College, Oxford, UK, 12th September 2014 Neuromuscular disorders in Roma (Gypsies) – collaborative studies, epidemiology, community-based carrier testing program and social activities Ivailo Tournev * a Department of Neurology, Sofia Medical University, Sofia, Bulgaria b Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria c Ethnic Minorities Health Problems Foundation, Sofia, Bulgaria

Objective To explore public perceptions of preconception and prenatal recessive carrier testing. Design Qualitative, descriptive. Setting Chat rooms located in four websites targeted to those who are pregnant or planning a pregnancy. Participants Anonymous comments (N = 1925) in online chat rooms. Methods The Centers for Disease Control and Prevention's (CDC) Analytic validity, Clinical validity, Clinical utility, Ethical, legal, social implications Model Process (ACCE) for evaluating a genetic test guided this deductive-inductive content analysis. Results Participant perceptions of the clinical utility of recessive carrier screening with universal carrier panels are multidimensional. Data analysis revealed four a priori deductive themes present in the data. Secondary inductive analysis produced 20 themes, which exceeded the scope of the CDC's ACCE Model Process for assessing the clinical utility of a genetic test. Conclusion Participant perceptions of carrier testing are important to consider in the clinical utility of carrier testing. Participant perceptions of clinical utility vary from those of the CDC's ACCE Model Process and should be considered in evaluation of the clinical utility of recessive carrier testing in the preconception and prenatal populations.

Background Tan Tock Seng Hospital (TTSH) Cancer Genetics and Genomics Clinic (CGGC) was set up by the Personalised Medicine Services (PMS) and Department of Medical Oncology (DMO) in December 2017 to provide genetic counselling service for inherited cancer syndromes diagnosis, risk assessment and treatment recommendation. Patient’s affordability for genetic testing was noted as one of the greatest challenges. In January 2019, a diagnostic access program was established between AstraZeneca Singapore and PMS to reduce cost barriers for patients who fulfil clinical guidelines for BRCA1/2 testing. Methods This is a retrospective study of BRCA1/2 test utilisation by patients who were seen at CGGC. The oncologist made the decision on the use of a targeted BRCA1/2 or multi-gene panels for genetic testing. The objectives of this study were to examine the clinical utilisation of BRCA1/2 testing, and to determine the proportion of patients who benefited from the access program. Results To date, 101 out of 140 patients were seen at CGGC for BRCA-related testing. Patients’ referral are mainly from DMO and Breast Clinic. With the increased use of PARP inhibitors for germline BRCA-mutated cancers, the number of patients referred to CGGC has increased 20% per month. The percentage of breast, prostate, pancreatic and ovarian cancer patients seen are 75%, 11%, 10% and 5%, respectively. The introduction of the access program has greatly increased the testing rate from 50% to 85%. The positive detection rate was 11%. Among 65 that underwent testing, 7 patients were tested BRCA1/2 mutation positive, which resulted in protein truncation or disruption. However, the take up rate for carrier testing was low, probably due to fear of being affected and insurance discrimination. The variant of unknown significance rate for BRCA1/2 was 14%. Among the 75% tested BRCA1/2 negative, a genetic cause of their cancer cannot be ruled out. For example, 2 BRCA1/2 negative breast cancer patients were tested positive in CHEK2 and PALB2 genes. Conclusions CGGC service in TTSH is growing rapidly and has closed an important gap in our patient treatment journey. The sponsorship by AstraZeneca has greatly benefited our patients who might be at risk of inherited cancer syndromes and would potentially benefit from PARP inhibitors treatment. Legal entity responsible for the study Tan Tock Seng Hospital. Funding AstraZeneca Singapore. Disclosure All authors have declared no conflicts of interest.

Background and objectives Policies for genetic testing in children (GTIC) focus on medical or psychosocial benefit to the child, discouraging or prohibiting carrier testing, and advising caution regarding pre-symptomatic diagnosis if no treatment exists. This study sought to understand parents' perspectives on these issues and determine their experiences and knowledge related to genetic testing for Batten disease — a set of inherited neurodegenerative diseases of childhood onset for which no disease modifying therapies yet exist. Methods Parents of children with Batten disease completed a survey of their knowledge of genetics, experience with genetic testing, and opinions regarding GTIC. Results 54% had sought genetic testing for non-affected family members, including predictive diagnosis of healthy, at-risk children. Participation in any genetic counseling was associated with greater knowledge on questions about genetics. The majority of parents felt it was better to know ahead of time that a child would develop Batten disease, believed that this knowledge would not alter how they related to their child, and that parents should have the final say in deciding whether to obtain GTIC. Conclusions Parents of children with an inherited disease are knowledgeable about genetics and wish to establish predictive or carrier status of at-risk children.

A diagnosis of choroideraemia (CHM) can be made clinically, based on the fundus examination and a family history consistent with X-linked inheritance. Molecular genetic testing offers a means of confirming the clinical diagnosis, establishing carrier status and allows presymptomatic diagnosis for families who wish to pursue these options. The aim of this study was to examine the uptake and assess the results from a diagnostic molecular genetics service for CHM. We have carried out a comprehensive audit of all molecular genetic results of UK NHS patients and families referred to the North West Regional Molecular Genetics Laboratory in Manchester, UK over a 55 month period. 110 people were referred to this service for testing including diagnostic, carrier and predictive requests. Putative pathogenic mutations were identified in 65/83 (78%) of male index cases. The identification of a familial pathogenic change enabled carrier testing in 16 asymptomatic females and predictive testing in 3 males. Case examples illustrate the range of cases referred for testing and also reflect the need for genetic counselling that results from offering a molecular diagnostic service such as this. Clinical molecular testing for CHM is available clinically and can be used to support the clinical diagnosis and management of patients with choroideraemia as well as their families. Case studies demonstrate the need to provide genetic testing to families and the potential clinical utility of testing.

Newborn screening for cystic fibrosis is increasingly available, but cascade testing following the diagnosis in a child has received little attention. We previously reported low levels of cascade testing over time, and this study investigated motivators as well as barriers to testing. Parents were interviewed about communicating the genetic information and also asked to recruit their relatives to receive a specifically developed questionnaire. Thirty parents were interviewed and addresses of 284 relatives were provided; completed questionnaires were received from 225 (79%). A relative’s relationship to the child, as well as knowledge, is associated with having had carrier testing. Relatives’ reasons for testing included curiosity and wanting information for other relatives and for reproductive planning. Reasons for not testing were perceived irrelevance, lacking awareness, and viewing it as something to do in the future. Parents communicated the genetic information to relatives in various ways, which contributed to whether relatives accessed carrier testing. Newborn screening programs should provide support to parents to aid communication of genetic information to relatives. (Ir)relevance of testing is often linked to life stage; ongoing support and communication may allow relatives to learn of their risk and then seek testing, if they wish, at a time perceived to be most relevant to them. Genet Med 2013:15(7):533–540

The Clinical and Functional Translation of CFTR (CFTR2) project presents a novel approach to clinical and functional annotation of mutations identified in disease-causing genes. Phenotype and genotype information on approximately 40,000 cystic fibrosis (CF) patients were collected from registries and large clinics. The disease-liability of the 160 most frequently reported mutations was evaluated by means of a multistage process which involved clinical (sweat chloride average), functional (expression in cell-based systems) and epidemiological (mutation analysis in obligate heterozygotes) steps. The results of this analysis can be consulted in a dedicated website. Data originated by CFTR2 may be valuable in several facets of CF care, including diagnosis, newborn screening, carrier testing, genotype/phenotype correlation and mutation-specific therapeutics.

Congenital amegakaryocytic thrombocytopenia (MIM #604498) (CAMT) is a rare inherited disease presenting as severe thrombocytopenia in infancy. Untreated, many CAMT patients develop aplastic anemia within the first decade of life; the only effective treatment of CAMT is bone marrow transplantation. CAMT is the result of the presence of homozygous or compound heterozygous mutations in the thrombopoietin receptor-encoding gene, MPL. We report here the identification and characterization of a founder mutation in MPL in the Ashkenazi Jewish (AJ) population. This mutation, termed c.79+2T>A, is a T to A transversion in the invariant second base of the intron 1 donor splice site. Analysis of a random sample of 2018 individuals of AJ descent revealed a carrier frequency of approximately 1 in 75. Genotyping of six loci adjacent to the MPL gene in the proband and in the 27 individuals identified as carriers of the c.79+2T>A mutation revealed that the presence of this mutation in the AJ population is due to a single founder. The observed carrier frequency predicts an incidence of CAMT in the AJ population of approximately 1 in 22,500 pregnancies. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation.

Hypertrophic cardiomyopathy is one of the most common inherited cardiac disorders, with a prevalence of 1:500 in the general population. We have recently reported a severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site c.3330+2T>G mutation in the MYBPC3 gene in an Amish community. The affected children typically presented with signs and symptoms of congestive heart failure during the first three weeks of life, and most of them died before one year of age unless they received a heart transplant. Since the condition is inherited in an autosomal dominant pattern with incomplete penetrance, further studies to understand the clinical course in the heterozygous carrier of c.3330+2T>G mutation were performed when we provided the service of carrier testing in the community. The preliminary results indicated a relatively low incidence of the phenotypic expression of hypertrophic cardiomyopathy, although the disease was identified in a few heterozygous carriers before they reached to their adolescence. Significant variation of the phenotypic expression suggests the complexity of the disease development. The Amish community is often composed of genetically and geographically isolated, large, multigenerational families with similar environmental influences, and potentially harbors a reduced number of risk factors compared to a more heterogeneous population. Therefore, our further study will not only benefit the Amish population but also will help us to understand the hypertrophic cardiomyopathy as a whole, for the disease development, diagnosis, treatment, and prognosis. Partnering with the community to establish solid, trustful relationships with the affected families and to provide much needed services to them has been the key to success in the past and will remain essential for our future study.

Healthy women who carry a ''premutation'' in the FMR1 gene (or fragile X mental retardation protein) can pass on a further mutated copy of FMR1 to either male or female offspring, leading to fragile X syndrome (FXS). Premutation carriers do not have manifestations of FXS in cognitive deficits, behavioral abnormalities, or classic physical features, but are at increased risk for development of the ''fragile X-associated disorders'': premature ovarian insufficiency and fragile X-associated tremor and ataxia syndrome. When considering widespread prenatal carrier screening programs for fragile X, significant resources must be available for at-risk individuals, including counseling, accurate diagnostic options for fetal testing, and choice regarding continuation of a pregnancy. Further attention is needed to develop and utilize inexpensive screening tests with adequate sensitivity and specificity to reduce barriers to screening for the population. Recently newer methodologies for high-throughput and inexpensive screening assays, which correctly detect expanded alleles in premutation and full mutation patients with a high degree of sensitivity, show significant promise for reduction in cost with rapid turn around times. With the introduction of widespread screening, individuals will be made aware not only of their risk for offspring with FXS, but will also have knowledge of the potential risk to develop the adult-onset conditions- FXPOI and FXTAS. This introduces more complex counseling challenges. All individuals identified as carriers of intermediate or premutation alleles should be referred for genetic counseling to properly convey risks for allele expansion and to discuss possible future risks of fragile X-associated disease.

Spinal muscular atrophy is an autosomal recessive neurodegenerative disease and the most common genetic cause of infant mortality. The disease results in motor neuron loss and skeletal muscle atrophy. Spinal muscular atrophy is caused by mutations in the telomeric copy of the survival motor neuron 1 (SMN1) gene, but all patients retain a centromeric copy of the gene, SMN2. In the majority of cases, the disease severity correlates inversely with an increased SMN2 gene copy number. Because spinal muscular atrophy is both a severe and common disorder, a direct carrier testing has been beneficial to many families. The survival motor neuron protein is ubiquitously expressed and performs a role in the assembly of the spliceosome. It is still not understood why mutations in the SMN1 gene only seem to affect motor neurons. Progress has been made by developing therapeutic strategies based on understanding the pathogenesis of the disease. This review attempts to highlight some of the recent advances in the understanding of the disease with a focus on molecular diagnostics.

Previous studies have suggested that patient care may be compromised as a consequence of poor communication between clinicians and laboratory professionals in cases in which molecular genetic test results are reported. To understand better the contributing factors to such compromised care, we investigated both pre- and postanalytical processes using cystic fibrosis mutation analysis as our model. We found that although the majority of test requisition forms requested patient/family information that was necessary for the proper interpretation of test results, in many cases, these data were not provided by the individuals filling out the forms. We found instances in which result reports for simulated diagnostic testing described individuals as carriers where only a single mutation was found with no comment pertaining to a diagnosis of cystic fibrosis. Similarly, reports based on simulated scenarios for carrier testing were problematic when no mutations were identified, and the patient's race/ethnicity and family history were not discussed in reference to residual risk of disease. Remarkably, a pilot survey of obstetrician-gynecologists revealed that office staff, including secretaries, often helped order genetic tests and reported test results to patients, raising questions about what efforts are undertaken to ensure personnel competency. These findings are reviewed in light of what efforts should be taken to improve the quality of test-ordering and result-reporting practices.

Although the pace of gene discovery for rare genetic diseases has accelerated during the past decade, in part, due to the success of the Human Genome Project, translation of these discoveries to clinical utility has lagged behind. In particular, identification of the gene responsible for a Mendelian disorder immediately presents the opportunity for molecular genetics diagnostics to confirm clinical diagnoses, provide accurate genetic counseling information and recurrence risks, as well as carrier testing and prenatal diagnosis opportunities for families. To move these discoveries from a research setting to clinical utility, we describe two successful models for partnerships between research laboratories with Clinical Laboratory Improvement Amendments-certified clinical molecular diagnostic laboratories. Contrary to common misconceptions, molecular genetic testing for very rare diseases can be performed in a high-quality clinical setting in a financially self-sustaining or even profitable manner. Key elements to the success of these models include a Clinical Laboratory Improvement Act-certified diagnostic laboratory with a commitment to very rare genetic disease testing, active involvement of genetic counselors and clinical geneticists, and partnerships with research experts and patient support groups specific to each disease.

Purpose: We present the results of carrier studies in 33 relatives of the paternal branch of a spinal muscular atrophy patient with homozygous absence of the SMN1 gene. Methods and Results: Once linkage and quantitative analyses were performed, a number of first-, second- and third-degree relatives were identified as carriers given that they shared the at-risk haplotype and showed one SMN1 copy. In the fourth-degree relatives, linkage analysis demonstrated discordance with the quantitative results because the members with one copy were carriers of the mutation, but in a different haplotype background. We concluded that two independent mutations were present in this branch of the family. Furthermore, the combination of both methods of analysis allowed us to identify carriers with two SMN1 genes in one chromosome and none in the remaining chromosome. Conclusions: Carrier testing in spinal muscular atrophy should be performed by employing both quantitative and linkage analyses in order to guarantee accurate carrier identification.

Educating patients on prenatal genetic screening and carrier testing in a timely and effective manner is faced with barriers including, providers' limited knowledge, and little time available to spend discussing screening and testing during a visit. This paper describes the use of cognitive response interviews (CRI) and usability testing (UT) in the development of an interactive computer assisted instruction (ICAI) program for use by prenatal patients in clinical settings. Lessons learned during the program development process included simplification of content and adaptation of navigational features in response to observations and interviews of a sample of patients representing the intended population. The resulting program functions as a targeted patient education program that maintains the level of medical information needed, as specified by professional practices guidelines, in a patient friendly format. In addition, this ICAI program functions as a research tool that can collect data on program effectiveness. Researchers developing other patient education programs will benefit from the lessons learned during development of this ICAI program by considering rephrasing of content to fit patient understanding, and adding navigational features to help further facilitate effective program use.

The following are the recommendations of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee, convened to assist health care professionals in making decisions regarding genetic diagnosis and testing. The purpose of this document is to provide a brief overview of fragile X syndrome (FXS), and to make recommendations that can serve as general guidelines to aid clinicians in making referrals for diagnostic and carrier testing for this condition. Fragile X syndrome is the most common cause of inherited mental retardation and is caused by a mutation in the X-linked FMR1 gene. DNA studies are used for testing individuals with symptoms of FXS and individuals at risk for carrying the mutation. Genotypes are determined by examining the size of the trinucleotide repeat segment and the methylation status of the FMR1 gene. These guidelines supersede the 1994 ACMG statement of the same name.

Purpose: To estimate CFTR mutation frequencies, clinical sensitivities (proportions of carrier couples or affected fetuses detected), and birth prevalence estimates for broad racial/ethnic groups and for a panethnic U.S. population. Methods: Published sources of information were identified, corrected when appropriate, and summarized. Combining racial/ethnic-specific mutation frequencies and birth prevalence estimates allowed the computation of panethnic estimates. Results: Two of the 25 recommended mutations do not meet the 0.1% threshold in a panethnic population set by the American College of Medical Genetics. The clinical sensitivities are estimated to be 71.9%, 51.7%, 41.6%, 88.6%, and 23.4% for non-Hispanic Caucasians, Hispanic Caucasian, African American, Ashkenazi Jewish Caucasian, and Asian American couples, respectively. Birth prevalence estimates are 1:2,500, 1:13,500, 1:15,100, 1:2,270, and 1:35,100, whereas the number of couples needed to screen to detect an affected fetus are about 3,200, 26,120; 36,040; 2,600, and 129,600, respectively, for the same racial/ethnic groups. Conclusions: Overall, the panethnic estimates for CFTR mutation frequencies are similar to those for non-Hispanic Caucasians. However, large differences in both clinical sensitivity and birth prevalence exist between the broad racial/ethnic groups examined. Whether and how the differences in the numbers of couples needed to screen to detect an affected fetus are to be included in prenatal screening for cystic fibrosis needs to be more explicitly addressed.

This article provides clinicians with an overview of current methods for prenatal genetic screening and diagnosis. Topics include developments in prenatal screening procedures such as ethnicity-based carrier testing, maternal serum screening, and ultrasonography. Diagnostic alternatives to amniocentesis include chorionic villus sampling and preimplantation diagnosis. Future endeavors such as three-dimensional ultrasonography and fetal cell sorting are discussed.

It is good medical practice to offer carrier tests and counselling to the relatives of those affected by recessive disorders. Many are concerned about their own chances of having affected offspring. Cystic fibrosis carrier tests have been feasible since the discovery of the gene in 1989. It was generally agreed that although population screening was not practical, testing should be offered to relatives and their partners. There is evidence that such offers have not always been made and relatives have sometimes found it difficult to be tested. An active cascade programme of the counselling and testing of cystic fibrosis patients' relatives and their partners has operated from Royal Manchester Children's Hospital since 1993. The service operates with dedicated staff, backed up by a specialist cystic fibrosis molecular genetics laboratory and a specialist genetic counselling service. The main target groups are couples or individuals of child-bearing age. There is discouragement of the testing of young children and of grandparents beyond reproductive age, although, if parents or individuals are insistent, testing is often performed, after counselling. An audit of users has shown satisfaction, very few feeling that they were pressured into having the tests. The experience of other centres with cascade-testing in cystic fibrosis is summarised. Cascades can start whenever a sufferer or carrier is identified, although care should be exercised in instituting active cascades in the extended families of newborns identified as carriers in neonatal screening programmes.

The ethics of genetic testing relate in particular to the need to obtain a balance between the possible benefits conferred on and the potential harm done to an individual and their family as a consequence of both the process and the results obtained from genetic investigations. It is not always possible to predict the effect of the receipt of genetic information upon the individual or the family; therefore, the investigation of families for genetic disorders should not be undertaken without careful consideration of the implications of such testing. The implications of genetic testing depend on several factors including the type of genetic investigation proposed, the reasons for the test request and the age of the individual concerned. The purpose of this article is to highlight the key issues involved in the genetic testing of families.

Objective: To describe and discuss our experience with cystic fibrosis (CF) carrier testing in a donor egg program. Design: Retrospective review. Setting: Community hospital-based assisted reproductive technology (ART) program. Patient(s): Forty anonymous white oocyte donor applicants. Intervention(s): Testing with a DNA mutation analysis panel. Main Outcome Measure(s): Frequency of heterozygotes for CF mutation among the donor applicants and the likelihood of carriers and noncarriers being selected by recipients. Result(s): Five of 40 egg donor applicants (12.5%) were found to be heterozygous for a CF mutation; 35 women (87.5%) tested negative. Two of the five CF carriers (40.0%) were selected by five recipient couples and underwent four donation cycles after the recipients' male partners tested negative. Twenty-nine of the 35 noncarrier donors (82.9%) were matched and underwent 81 egg donation cycles. The likelihood of being selected was lower for CF carriers than for noncarriers. Conclusion(s): Our experience strongly supports the recommendation of routine CF testing of prospective white egg donors. Whereas heterozygosity lowers the probability of a donor being matched, it need not exclude her from the donor pool provided the recipient's partner is not a carrier. Empowering recipients to choose their own donors, focused patient education, and genetic counseling with precise determination of residual risk are important prerequisites for inclusion of CF carriers.

Carrier testing for Tay-Sachs disease should be offered to couples when at least one individual is of Ashkenazi Jewish (carrier frequency 1/30), Pennsylvania Dutch, Southern Louisiana Cajun, or Eastern Quebec French Canadian descent. Ideally, testing is done prior to conception. For Ashkenazi Jews, in whom DNA testing identifies 99.9% of carriers, DNA testing is the preferred method to ascertain carriers [14]. For non-Jewish individuals seeking carrier testing, enzyme assay should be done initially and positive or indeterminate results should be confirmed by DNA mutation analysis. If only one partner is descended from a high-risk group, that person should be tested first; only if he/ she is a carrier should the other partner be tested. If the couple is pregnant at the time carrier testing is requested, both partners should have enzyme testing (leukocyte assay for the pregnant woman and serum assay for the father) and DNA testing sent concomitantly to expedite counseling and action. Carriers are individuals with a disease causing DNA mutation or carrier range enzyme analysis results on both serum and leukocytes with no detectable mutation and no pseudodeficiency alleles. Noncarriers are individuals with normal enzyme results or carrier range enzyme results and a pseudodeficiency allele on DNA mutation analysis. If both partners are found to be carriers they should be counseled of a 25% risk of having an affected child with each pregnancy. Options to modify this risk include prenatal diagnosis by amniocentesis or chorionic villus sampling, egg or sperm donation, preimplantation diagnosis or adoption.

As genetic research and technology continues to expand, carrier testing for an increasing number of single gene disorders is becoming available. Tay-Sachs disease and cystic fibrosis are two common recessive conditions with large-scale health implications. Tay-Sachs disease was the first genetic disorder for which community-based screening efforts were utilized and has provided a foundation for the development of other screening programs. Cystic fibrosis testing, on the other hand, has additional complexities and the implementation of population-based screening has been under debate. The many issues (technical, educational, social, psychological and economical) which must be considered as preconceptional and prenatal genetic screening is incorporated into clinical practice are discussed here in the context of Tay-Sachs disease and cystic fibrosis.

The importance of the recent recommendations that address cystic fibrosis carrier screening cannot be overemphasized. For the first time, a systematic approach to offering or making screening available to all pregnant women in the hopes of providing refined risk estimates for a genetic disease has been established. Caucasian of European or Ashkenazi-Jewish descent should be offered screening. Within the proposed guidelines are ethnic-specific carrier frequencies (1/29) used to establish who should be offered testing and to whom testing should be made available. Recent recommendations have made clear that in a pan-ethnic population a frequency of 1/1,000 is required for inclusion into the cystic fibrosis mutation panel. A general framework for screening during pregnancy has been established (either concurrent or sequential). It will be interesting to watch as the fruits of the human genome project are inspected and applied to everyday clinical practice. No doubt the cost of screening will be reduced through advances in technology. The combined efforts of NIH, ACOG, and ACMG have provided the first set of comprehensive standards for screening of recessive diseases. How time changes these guidelines deserves following.

Approximately 94% of spinal muscular atrophy (SMA) patients lack both copies of SMN1 exon 7. We report our SMA genetic testing experience (total 1281 cases), using SMA linkage analysis (32 families), SMA diagnostic testing by PCR-RFLP (restriction fragment length polymorphism) to detect the homozygous absence of SMN1 exon 7 (and exon 8) (533 cases), and an assay to determine copy number of SMN1 exon 7 (SMN1 gene dosage analysis) (716 cases). SMN1 gene dosage analysis is used for SMA carrier testing as well as for the confirmation of a heterozygous SMN1 deletion in symptomatic individuals who do not lack both copies of SMN1. We conclude that comprehensive SMA testing, including SMN1 deletion analysis, SMN1 gene dosage analysis, and linkage analysis, offers the most complete evaluation of SMA patients and their families.

L ittle et al 1 pose an important question: would the universal offer of carrier screening for spinal muscular atrophy (SMA) during prenatal care be cost-effective, ie, provide good value for money spent? The rapid expansion of the availability of molecular genetic tests for rare disorders, with approximately 1700 tests currently available, poses a challenge to health care providers and payers. We as a society do not have sufficient funds to pay for all possible genetic tests, and prioritization in some form must be undertaken. Little et al and the American College of Obstetricians and Gynecologists are to be commended for addressing the balance of technological opportunity in genetic testing and opportunity cost of scarce health care resources implicit in the concept of cost-effectiveness. The decision analysis prepared by Little et al estimated the net costs of screening for SMA, including reductions in costs of care associated with termination of affected fetuses, relative to gains in maternal quality-adjusted life years (QALYs). The approach used is similar to that used in cost-utility analyses of prenatal testing for fragile X syndrome and Down syndrome, the results of which appear to have gained acceptance in the obstetrics and gynecology literature. However, this approach has inherent limitations. The QALY was developed to measure the combined effects of premature death and disability on individuals who suffer from a disease or injury, and the relatively minor spillover effects on the health of other family members typically are ignored in cost-utility analyses. QALYs are not well suited to capture the personal utility or value either of diagnostic or genetic information in general or of prenatal carrier testing in particular. Because Little et al modeled the effects on only the woman of an affected fetus or child, it is not surprising that the projected gain in QALYs from prenatal diagnosis in their model was extremely modest. However, that is not the only possible method to calculate QALYs. For example, using a time-tradeoff method to assess the utility of prenatal screening for Down syndrome, Harris et al found that the QALYs associated with reassurance to women with normal findings dominated the negative effects of positive amniocentesis results. Similar results were found in another study that used the theoretically preferable standard gamble method to evaluate carrier testing for cystic fibrosis (CF). Had Little et al incorporated the same assumed utility of negative carrier test results for SMA as previously estimated in these studies of testing for Down syndrome or CF, the projected QALY gains, and hence the cost-effectiveness of the screening, would have appeared more favorable. It should be noted, however, that the value of reassurance from testing for an additional disorder during pregnancy can be determined only by asking women their perceptions about screening for multiple conditions. The other major drawback of the approach used by Little et al was its emphasis on financial cost savings resulting from the early diagnosis and termination of affected fetuses. This general approach long has been criticized by health economists as inconsistent with economic theory. It implicitly prioritizes testing for disorders that have high lifetime medical costs, such as CF, over disorders, such as SMA, which typically result in early death and, hence, low lifetime medical costs. The prevention of diseases that are fatal in early childhood and have no treatment saves little money relative to disorders that are disabling but not lethal. The results of a standard cost-effectiveness or cost-utility analysis of prenatal carrier screening are greatly influenced by the projected financial savings to the health care system resulting from the termination of affected fetuses. Such an analysis places little or no value on the ability of parents to prepare for the birth of an affected child, to avoid lengthy diagnostic “odysseys,” or to plan future childbearing. The justification of screening as cost-effective based on the frequency of terminations can seem difficult to reconcile with the clinical genetics paradigm of nondirective offer of counseling, carrier testing, and prenatal diagnosis. A simpler economic approach– cost-comparison analysis– calculates the cost per carrier or case detected for different testing strategies. Carrier testing for SMA presumably costs more per case detected than does screening for CF because of the lower prevalence of SMA. The cost-comparison approach leaves it to policy makers to value the detection of carriers. Policy makers may consider the opportunity for informed choice by parents and the seriousness of the disorder as well as the potential reduction in health care costs. In addition to the numbers of cases detected, analysts should report the numbers of false-positive, false-negative, and true-negative test results and stakeholders also should take into account such outcomes of testing and their valuations. From the Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA. Reprints not available from the authors. The findings and conclusions in this report are those of the author and do not necessarily represent the official position of the Centers for Disease Control and Prevention. 0002-9378/free Published by Mosby, Inc. doi: 10.1016/j.ajog.2010.01.031

Purpose: The risk perceptions, psychological status and reproductive plans of 52 carrier by “noncarrier” (mutation screen negative) couples is the subject of this report. Methods: Cystic fibrosis (CF) carrier testing was offered to relatives of individuals with CF. Results: In this population testing was not associated with any significant adverse psychological effects, reproductive uncertainty, or inaccurate risk perceptions. Conclusions: The results of this study have important implications in light of the recent NIH CF Consensus Panel recommendations that CF carrier testing be offered to all high risk adults and all couples planning a pregnancy or seeking prenatal testing.

The autosomal recessive disorder proximal spinal muscular atrophy (SMA, MIM #253300) is a severe neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, which results in progressive proximal muscle weakness and paralysis. SMA is the second most common fatal autosomal recessive disorder after cystic fibrosis, with an esti.mated prevalence of 1 in 10,000 live births and a carrier frequency of 1/40Ð1/60. Childhood SMA is subdivided into three clinical groups on the basis of age of onset and clinical course: type I SMA (Werdnig-Hoffmann) is characterized by severe, generalized muscle weakness and hypotonia at birth or within the first 3 months. Death from respiratory failure usually oc.curs within the first 2 years. Children with type II are able to sit, although they cannot stand or walk unaided and survive beyond 4 years. Type III SMA (Kugelberg-Welander) is a milder form, with onset during infancy or youth: patients learn to walk unaided. The survival motor neuron (SMN) gene comprises nine exons and has been shown to be the primary SMA determining gene. Two almost identical SMN genes are present on 5q13: the telomeric or SMN1 gene, which is the SMA-determining gene, and the centromeric or SMN2 gene. The SMN1 gene exon 7 is homozygously absent in approximately 95% of affected patients, with few exceptions, the remainder are heterozygous for the exon 7 deletion and a small more subtle mutation in the other allele (compound heterozygotes). Although abnormalities of the SMN1 gene are observed in the majority of patients, no phenotypeÐgenotype correlation was observed because SMN1 exon 7 is absent in the majority of patients independent of the type of SMA. This is because routine diagnostic methods do not distinguish between a deletion of SMN1 and a conversion event whereby SMN1 is replaced by a copy of SMN2. There have now been several studies that have shown that the SMN2 copy number influences the severity of the disease. The copy number varies from zero to three copies in the normal population, with approximately 15% of normal individuals having no SMN2. However, milder patients with type II or III have been shown to have more copies of SMN2 than do type I patients. It has been proposed that the extra SMN2 in the more mildly affected patients arise through gene conversions, whereby the SMN2 gene is copied either partially or totally into the telomeric locus. Five base pair changes exist between SMN1 and SMN2 transcripts, and none of these differences change amino acids. Because virtually all SMA individuals have at least one SMN2 gene copy, it was initially not understood why individuals with SMN1 mutations have a SMA phenotype. It has now been shown that the SMN1 gene produces predominately full-length transcript, whereas the SMN2 copy produces predominately an alternatively transcribed (exon 7 deleted) product. The inclusion of exon 7 in SMN1 transcripts and exclusion of this exon in SMN2 transcripts is caused by a single nucleotide difference at +6in SMN exon 7. Although the C to T change in SMN2 exon 7 does not change an amino acid, it does disrupt an exonic splicing enhancer that results in the majority of SMN2 transcripts lacking exon 7. Therefore, SMA arises because the SMN2 gene cannot fully compensate for the lack of SMN1 expression when SMN1 is mutated. However, the small amount of full length transcripts generated by SMN2 is able to produce a milder type II or III phenotype when the copy number of SMN2 is increased. The molecular diagnosis of the SMA consists of the detection of the absence of exon 7 of the SMN1 gene. The homozygous absence of detectable SMN1 in SMA patients is being used as a powerful diagnostic test for SMA. Although the targeted mutation analysis has an excellent sensitivity of approximately 95% in identifying affected homozygotes, it cannot detect SMA carriers who have heterozygous deletions of SMN1. Rather, SMN1 gene dosage analysis is required to detect carriers and is highly accurate when performed in an experienced laboratory. Because SMA is one of the most common lethal genetic disorders, with a carrier frequency of 1/40Ð1/60, direct carrier dosage testing has been beneficial to many families with affected children. A number of quantitative polymerase chain reaction assays have been used for the identification of SMA carriers. There are two limitations of the carrier test. First, approximately 2% of SMA cases arise as the result of de novo mutation events, which is high when compared with most autosomal recessive disorders. The high rate of de novo mutations in SMN1 may account for the high carrier frequency in the general population despite the genetic lethality of the type I disease. The large number of repeated sequences around the SMN1 and SMN2 locus likely predispose this region to unequal crossovers and recombination events and results in the high de novo mutation rate. The de novo mutations have been shown to occur primarily during paternal meiosis. Second, the copy number of SMN1 can vary on a chromosome; we have observed that approximately 5% of the normal population possess three copies of SMN1. It is therefore possible for a carrier to possess one chromosome with two copies and a second chromosome with zero copies. The finding of two SMN1 genes on a single chromosome has serious genetic counseling implications, because a carrier with two SMN1 genes on one chromosome and a SMN1 deletion on the other chromosome will have the same dosage result as a noncarrier with one SMN1 gene on each chromosome 5. Thus, the finding of normal two SMN1 copy dosage significantly reduces the risk of being a carrier; however, there is still a residual risk of being a carrier and subsequently a small recurrence risk of future affected offspring for individuals with 2 SMN1 gene copies. Risk assessment calculations using Bayesian analysis are essential for the proper genetic counseling of SMA families. Currently, only individuals with a family history of SMA are routinely being offered carrier testing. However, more broad-based population carrier screening is currently recommended for a number of other genetic disorders with similar carrier frequencies. The prototype for heterozygote screening was testing for Tay-Sachs disease in the Ashkenazi Jewish population, where carrier testing has been offered since 1969. Carrier screening, followed by prenatal diagnosis when indicated, has resulted in a dramatic decrease in the incidence of Tay-Sachs disease in the Jewish population. It is generally accepted that the following criteria should be met for a screening program to be successful: (1) disorder is clinically severe, (2) high frequency of carriers in the screened population, (3) availability of a reliable test with a high specificity and sensitivity, (4) availability of prenatal diagnosis, and (5) access to genetic counseling. SMA fits the criteria for population-based genetic screening. Carrier screening is recommended upon the availability of educational material that can be utilized by patients and providers. The goal of population based SMA carrier screening is to identify couples at risk for having a child with SMA. Preconception carrier screening allows carrier couples to consider the fullest range of reproductive options. The choice to have a SMA carrier test should be made by an informed decision. Educational brochures are available and provide information about SMA and the inheritance patterns. It is important for couples to understand the dosage testing. Because, SMA is the result of a common single deletion event in 95% of the cases, the carrier test is very sensitive (.90% detection rate). However, the molecular testing does not identify all carriers and therefore false-negatives can occur. Approximately 5% of affected patients are compound heterozygotes, exhibiting a deletion and a point mutation. The dosage testing does not identify such point mutation carriers. It is well known that a false-negative result in SMA carriers occurs when the carrier has two SMN1 genes in cis on the one chromosome 5. Further, approximately 2% of affected individuals have a de novo mutation. Therefore, genetic counseling addressing specifically the possibility of false-negative results must be provided for individuals choosing carrier testing.

Summary Written pamphlets are an important source of information for individuals deciding whether to undergo carrier testing for cystic fibrosis (CF). Adequate understanding of the condition and reproductive options following the diagnosis of a fetus with CF are critical to informed decision making. The information given about CF and reproductive options in 28 pamphlets about carrier testing, from commercial and noncommercial organizations in the United States and the United Kingdom, aimed at prenatal and other populations, was assessed. The amount of information provided about CF showed a range of 1–37 sentences (median 6.5), with most being relatively neutral and with a minority conveying a positive or a negative image. Positive sentences were less common in British, U.S. commercial, and prenatal pamphlets. Statements about life expectancy also varied considerably, both in the ages provided and in the degree of optimism conveyed. In addition, the pamphlets varied in the amount of information they provided about reproductive options following the diagnosis of a fetus with CF. Abortion was mentioned in just 15 pamphlets, more often in the United Kingdom than in the United States and more frequently in pamphlets from noncommercial than in those from commercial organizations. Wide variation in the descriptions of CF and the reproductive options presented raises concerns about the extent to which any one pamphlet may present balanced information. The choices about what information to include in educational materials need to be explicitly considered on the basis of the message intended to be sent.

Evidence-based guidelines on the use of genetic tests in clinical practice require a systematic assessment of their usefulness, which, following a commonly used framework proposed in 1998 by a U.S. Task Force on Genetic Testing, is commonly referred to as clinical utility.Clinical utility in its narrowest sense refers to the ability of a screening or diagnostic test to prevent or ameliorate adverse health outcomes such as mortality, morbidity, or disability through the adoption of efficacious treatments conditioned on test results.2 A screening or diagnostic test alone does not have inherent utility; because it is the adoption of therapeutic or preventive interventions that influences health outcomes, the clinical utility of a test depends on effective access to appropriate interventions. This use is consistent with standard practice in evidence-based medicine, which focuses on objective measures of health status to evaluate interventions. Clinical utility can more broadly refer to any use of test results to inform clinical decision-making. Finally, in its broadest sense, clinical utility can refer to any outcomes considered important to individuals and families (e.g., reproductive decisions and psychosocial support). The field of genetic services, notably genetic counseling for Mendelian disorders, has emphasized the latter aspects of genetic testing.2 This commentary was prompted by a discussion at a workshop on the evaluation of genetic testing sponsored by the Centers for Disease Control and Prevention (CDC) in January 2005. The participants were a diverse group of experts in evidence-based medicine and genetics. The term “clinical utility” was familiar to many participants, and those who used the term were confident that they knew what it meant. However, there was no consensus as to what the term meant, with subgroups holding to different interpretations. This diversity of opinion led us to reflect on the meaning of the term and to review its previous uses. We came to realize that different definitions corresponded to different analytic and disciplinary or policy perspectives. We concur with Scheuner and Rotter3 that multiple perspectives should be considered in the evaluation of genetic testing, a conclusion that we had already reached. This commentary is a first response to their recent editorial. Only by making different perspectives explicit is it possible to reach agreement on the key endpoints to use in evaluating genetic testing for different audiences and purposes. Although different groups will not necessarily agree on which endpoints are most important, which involves value judgments and priorities, we hope that we can contribute to the clarification of these differences of opinion. The utility of genetic testing has different dimensions (public health, clinical, personal, and social), and the term “clinical utility” may be too limiting. In this commentary, we review the evolution of the concept of clinical utility of biochemical or molecular testing for genotypic variations associated with risk of disease. Potential health-related applications include screening, diagnostic, and carrier testing for single-gene disorders, testing of multiple loci to construct disease susceptibility risk profiles, and pharmacogenomic testing to predict drug–genome interactions. Most applications to date fall under the single-gene category, but more are expected for common diseases with complex genetic contributions and gene–environment interactions. We do not consider non–health-related uses of genotyping, such as testing for physical traits such as athletic ability.4

We detected a novel CLN1 mutation (c.125-15t>g) in two Italian siblings. The clinical phenotype is that of a variant late-infantile neuronal ceroid lipofuscinosis and consisted of early-onset visual loss, psychomotor deterioration, and seizures. Ultrastructurally, granular osmiophilic deposits were found in skin biopsy of both patients. The novel mutation occurs in the acceptor sequences for splicing and leads to skipping of multiple exons. This predicts a protein lacking part or all of the active site of the enzyme and the palmitate-binding pocket. Consequently, biochemical activity of the palmitoyl protein thioesterase-1 enzyme was drastically reduced. The new mutation was not identified in a large set of ethnically matched control chromosomes. Our findings support the notion that CLN1 patients are not rare in Southern Europe and facilitate DNA-based mutation and carrier testing in this family.

Summary Background The objective of this study was to show the long-term psychological effects of population-based screening for cystic fibrosis. Methods The sample comprised all carriers (n=435) and, for each carrier, two matched screen-negative individuals (n=870) detected during screening programmes for cystic fibrosis in the general population and in antenatal populations carried out a median of 3 years earlier in six UK centres. Questionnaires were sent to all eligible participants, with reminders sent to non-responders. The main endpoints were understanding of test results, degree of anxiety, perceptions of health, and reproductive intentions, and behaviour. Findings 746 (62%) of 1201 questionnaires were returned. Recall of the meaning of test results was accurate in 225 (80%) of 280 carriers but only 200 (43%) of 466 screen-negative individuals. 46 (16%) of 280 proven carriers believed that their result meant that they were only likely, rather than definitely, to be a carrier; 232 (50%) of 466 of those with a screen-negative result erroneously believed that the result meant that they were definitely not carriers. There was no significant difference between carriers and screen-negative individuals in degree of general anxiety, although 16% of carriers reported feeling worried about their test results. Carriers had a poorer perception of their current health than did non-carriers, even though they had been told that carrier status confers no disadvantages to their own health. There were no differences between carriers and screen-negative individuals in reproductive intentions or behaviour. Interpretation We have shown that in the long-term, retention of the meaning of test results from cystic fibrosis screening is poor. Further research is needed to improve the performance of test-related counselling programmes to ensure that the main objectives of these programmes, to provide information on carrier status and to allow informed reproductive decisions, are met.

Rapid advances in the field of human genetics have led to an increase in the availability of genetic diagnostic tests. This article reviews technical approaches and diseases for which metabolic, newborn screening, molecular, and cytogenetic diagnostic tests are available currently. Overlaps in areas of diagnostic testing that have emerged from the application of new technology in the field of genetics also are discussed, as are criteria and approaches used for identifying conditions for which diagnostic, presymptomatic, prenatal, and carrier testing should be offered. Finally, the delivery of these results and necessary genetic counseling that should accompany this information are reviewed.

Medical genetics is the most rapidly expanding field in medicine. The obstetrician/gynecologist frequently encounters patients with genetic issues that must be evaluated and may require consultation with a specialist. Commonly encountered problems include pregnancy in women of increased maternal age, couples who have had prior aneuploid conceptuses, increased paternal age, hematologic and coagulation abnormalities, autosomal disorders, family histories of mental retardation (including fragile X syndrome), and recurrent pregnancy loss. Carrier testing and prenatal diagnosis are available for an increasingly large number of disorders.

Non-isotopic single-strand conformation polymorphism (SSCP) and direct sequencing was used for carrier diagnosis in four families of DMD/BMD patients with previously characterized point mutations, leading to the identification of eight carriers and four non-carriers. When the mutation caused a distinctly altered migration pattern of the single strands, in principle, the SSCP-technique allowed determination of carrier status in the extended family of the probands without direct sequencing. However, because SSCP measures a function of not only the mutation, but of the entire sequence of the PCR product, it can lead to false negative and/or false positive diagnoses due to intronic and exonic sequence heterogeneity in the family. As we discovered this pitfall in one of the reported families, we concluded that for carrier testing the SSCP approach must be performed in essential conjunction with an independent assessment of the mutation site by direct sequencing.

Introduction: In Victoria, Australia, cascade carrier testing is provided free of charge to people with a family history of cystic fibrosis (CF). Most children with CF are diagnosed by newborn screening which includes DNA testing. The uptake of cascade carrier testing following a child’s diagnosis by newborn screening has not been previously described. The aim of this study is to report the uptake of cascade carrier testing by Victorian families. Method: Examination of pedigrees of children with CF born 2001–2004 revealed the number of relatives eligible for cascade carrier testing. Relatives were eligible if they were aged 18 years or above and the family mutation was known. Uptake of cascade carrier testing was verified with the database of the DNA diagnostic laboratory (the only Victorian laboratory providing CF carrier testing). Results: The pedigrees of 53 children were examined. Cascade carrier testing uptake was 16% (190/1160). Relationship to the child was associated with uptake; parents represented the greatest proportion of tested individuals (81/190) followed by aunts and uncles (47/190) and then grandparents (41/190). There was no difference in the uptake of cascade carrier testing between the maternal relatives and the paternal relatives. Four pedigrees indicated an existing family history of CF. Discussion: The majority of relatives of children with CF have not had cascade carrier testing despite being at high risk. Investigation into barriers and facilitators to cascade carrier testing is being conducted to explore factors associated with uptake.

for all parts of Volume II: Genetic testing raises new issues from those involved in other medical contexts, particularly for children. Most of the concerns relevant to minors are prompted by the familial and predictive aspects of genetic information.It is vital that GPs and other health professionals know more about genetic testing and genetics services in New Zealand, so that they can better facilitate informed consent; recognise and acknowledge any limitations in their expertise, particularly as they will influence their patients when discussing testing possibilities; know when to refer patients for genetic testing; and can offer some degree of genetic counseling, if required.Genetic testing of children who lack capacity to consent to genetic testing for non-medical reasons should be treated with caution. Many adults choose not to discover their own genetic risk status and the threat to the child’s autonomy and right to confidentiality are the reasons for this caution. Also, where there is a lack of evidence about what the test results may signify for the child’s health, this uncertainty is best dealt with by waiting until the child is able to make personal choices.A register should be established to facilitate disclosure to persons who have reached the age of sixteen or eighteen years (or earlier if they are competent and personally seek access to the information) of the fact that they underwent genetic testing as children. Initially, the minors may be informed either that they underwent predictive or carrier testing as children, or that some information is available about genetic risk status should they wish to access it.Such a register is the appropriate method for ensuring that people who undergo testing as children are informed of the fact for the following reasons. Firstly, it would encourage parents and health professionals to disclose test results to children – as the fact of testing will be disclosed to them anyway. Secondly, it gives the person tested a choice regarding whether or not to access the information (assuming that he or she has not already been told). Thirdly, it avoids the difficulties of imposing a new disclosure duty that may have unwieldy and undesirable consequences in terms of monitoring, enforcement and sanctions.Genetic counseling would be required to assist minors in deciding whether to access their test results, and to support them whatever their choice. The privacy of the register and its information must be strictly maintained.

Objective When a child is diagnosed with cystic fibrosis, their siblings are at risk of being carriers. While international guidelines recommend against carrier testing in children, carrier status may be identified incidentally in childhood through 1) newborn screening programs, 2) genetic testing to exclude affected status in a sibling, or 3) prenatal testing. This study aims to assess how genetic health professionals discuss incidental carrier status and explore parents' experiences of receiving this information following the diagnosis of a child with cystic fibrosis. Methods These findings emerged from a broader qualitative study examining requests for and communication of carrier results with 17 key informant health professionals and 32 parents of children with genetic conditions. Inductive content was used to analyse the data. Results The data showed variable practices in the disclosure of incidental carrier findings to parents. Some parents who did not asked to know the carrier status of their child or fetus were given this information, with many not appreciating they will be told. While some parents were relieved to find their children were ‘just carriers', others experienced mixed emotions. Conclusion This paper uses the interview data to discuss whether it is appropriate to report carrier results to parents who do not specifically request testing. It highlights the inconsistency of these practices compared to international recommendations not to grant carrier testing if parents explicitly request testing for their children, assessing the potential for harm.

Objective Carrier testing enables relatives of CF patients to know their status regarding the CFTR mutation that segregates within their family. This test enables prevention in families and thus detection of new 1/4 risk couples. Our study aimed to assess the impact of carrier testing and to search for the predictors of uptake to this test in an area where CF is frequent. Methods Forty patients born in the district of Finistere (Brittany, France) between 1980 and 2004 were enrolled in the study. Family trees were faced with the carrier tests performed in the genetic laboratories of the area. Results Among the 459 non-parent relatives eligible for testing, 185 made the test, leading to an adjusted percentage of uptake of 40.7% (95% CI: [34.1%; 47.3%]). Carrier testing enables detection of 5 new 1/4 risk couples, leading to 8 prenatal diagnoses and 5 terminations. This test also allows to reassure many relatives (as non carrier by testing or deduction, n=247), plus 60 couples (in whom the mate of a carrier relative was negative). Finally, logistic regression adjusted for clustering revealed that the main predictors of being tested were female gender (OR = 1.6, p=0.006), having a high a priori risk (OR 1/2 vs 1/4 = 3.7, p=0.004; OR 2/3 vs 1/4 = 31.8, p Conclusion Our study assesses, for the first time in Europe, uptake of CF carrier testing, a critical tool to reassure non carriers and to detect new at-risk couples. It also highlights factors influencing the choice to be tested. Study funded by Vaincre La Mucoviscidose.