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Background: Rare genetic disorders may result in death before a definitive clinical diagnosis is established. Aim: This study aims to outline the processes and challenges in managing, from a genetic perspective, couples who lost children affected by rare genetic disorders. Results: Six couples who experienced child loss due to rare genetic disorders, seen by the primary author at genetic evaluation and counseling sessions, were retrospectively analyzed. Four out of 6 couples reported consanguinity. Exome and genome sequencing were performed for the parents. Carrier status of two rare lethal metabolic disorders was confirmed in one consanguineous couple. Three couples were carriers of 3 other rare diseases. Variants of LYST, MPV17, HEXB, ITGB4, CD3E, ASPM, TK2, COL11A2, and LAMB3 genes were identified. Six out of 10 were pathogenic variants, out of which 4 correlated with the demised children’s phenotypes. One couple was negative for pathogenic variants. The last couple did not undergo genetic testing since they were beyond the fertile window. Conclusion: Appropriate parental genetic evaluation and counseling are mandatory for selecting the right genetic test to certify the diagnosis postmortem, by virtue of molecular autopsy by proxy. Clarifying a rare disorder diagnosis can help couples to avoid recurrence and plan early for their next pregnancies. [ABSTRACT FROM AUTHOR]

In Germany, the debate on preimplantation and prenatal testing is heavily influenced by the idea of an antagonism between prospective parents and their potential children. Underlying this antagonism is the assumption that prospective parents follow an ableist logic and do not regard the lives of children with a chronic illness as “worth living”. Taking the example of two rare genetic illnesses, Marfan Syndrome and Cystic Fibrosis, we investigate how persons who themselves are affected by these conditions view preimplantation or prenatal testing for their condition in the context of reproductive decision-making. Our empirical research shows that chronically ill patients’ appreciation of their own life as a “life worth living” does not always translate into an unequivocal wish and readiness to give birth to a child that is affected by their condition as well and argue that taking their views into consideration adds an additional level of complexity to the debate.

BackgroundRare genetic disorders may result in death before a definitive clinical diagnosis is established.AimThis study aims to outline the processes and challenges in managing, from a genetic perspective, couples who lost children affected by rare genetic disorders.ResultsSix couples who experienced child loss due to rare genetic disorders, seen by the primary author at genetic evaluation and counseling sessions, were retrospectively analyzed. Four out of 6 couples reported consanguinity. Exome and genome sequencing were performed for the parents. Carrier status of two rare lethal metabolic disorders was confirmed in one consanguineous couple. Three couples were carriers of 3 other rare diseases. Variants of LYST, MPV17, HEXB, ITGB4, CD3E, ASPM, TK2, COL11A2, and LAMB3 genes were identified. Six out of 10 were pathogenic variants, out of which 4 correlated with the demised children’s phenotypes. One couple was negative for pathogenic variants. The last couple did not undergo genetic testing since they were beyond the fertile window.ConclusionAppropriate parental genetic evaluation and counseling are mandatory for selecting the right genetic test to certify the diagnosis postmortem, by virtue of molecular autopsy by proxy. Clarifying a rare disorder diagnosis can help couples to avoid recurrence and plan early for their next pregnancies.

Background: Beta thalassemia, related to HBB mutation and associated with elevated hemoglobin A2 (HbA2), is an important genetic hemoglobinopathy with high incidences of disease and carrier rates in Singapore. Carrier screening is essential to facilitate prenatal counseling and testing. However, when individuals with elevated HbA2 do not have an identifiable HBB disease‐associated variant, there is ambiguity on risk to their offspring. Methods: We describe a case report of a proband with elevated HbA2, no identifiable HBB disease‐associated variant, whose partner was a beta thalassemia carrier. Through clinical HBB gene sequencing, multiplex ligation‐dependent probe amplification (MLPA) analysis, as well as targeted Nanopore long read sequencing of selected genes, we performed a complete analysis of HBB including the promoter region, 5′UTR and coding gene sequence, as well as evaluation for potential modifier variants and other rare structural variants. Results: This process identified that the proband was heterozygous for KLF1:c.544T>C (p.Phe182Leu), a potential functional polymorphism previously known to be associated with benign elevated HbA2 levels. The presence of disease variants in the HBB locus was excluded. Conclusion: This finding provided clarity and enabled family planning for the proband and her family. [ABSTRACT FROM AUTHOR]

BRCA1/2 mutations account for 5 to 10% of breast and 15% of ovarian cancers. Various guidelines on BRCA1/2 genetic counseling and testing have been issued, and the criteria have evolved over the years. Oncogenetic counseling aims to inform patients about the possibility and implications of undergoing predictive testing and risk management programs. We analyzed a cohort of 50 subjects with a previous personal history of breast or ovarian cancer who had not been tested for BRCA1/2 mutations at the time of diagnosis but were found eligible according to the most recent guidelines. All patients were offered pre-test oncogenetic counseling and BRCA1/2 genetic testing. The mean time from cancer diagnosis to genetic counseling was over 10 years. We analyzed socio-demographic and psychological parameters associated with the decision to undergo BRCA1/2 genetic testing or the reasons behind the withdrawal. Thirty-nine patients underwent BRCA1/2 genetic testing. Patients who accept the genetic test communicate more easily with family members than those who refuse. Factors associated with test refusal are having a long-term partner and having a negative perception of life. There is a trend, although not statistically significant, toward younger age at cancer diagnosis, more likely to participate in cancer screening programs (71.8% vs. 45.5%), and more likely to have daughters (63.3% vs. 37.5%) in the group that accepted the test. The offer of BRCA testing was well accepted by our study population, despite the many years since the cancer diagnosis. With the perspective of further broadening the access criteria to genetic testing, it is important to understand how to best approach pre-test counseling in long-surviving patients with a previous diagnosis of cancer. [ABSTRACT FROM AUTHOR]

Genomic testing increasingly challenges health care providers and patients to understand, share, and use information. The provision of polygenic risks is anticipated to complicate comprehension, communication, and risk perception further. This manuscript aims to illuminate the challenges confronting families with multiple genetic risks for Parkinson's disease. Identifying and planning for such issues may prove valuable to family members now and in the future, should neuroprotective or genotype‐specific therapies become available. We present qualitative data from interviews with a multi‐generational family carrying pathogenic variants in the glucocerebrosidase (GBA1) and leucine‐rich repeat kinase 2 (LRRK2) genes which are associated with an increased risk for developing Parkinson's disease (PD). The family includes two brothers (heterozygous for LRRK2 p.G2019S and homozygous for GBA1 p.N409S) and their four descendants. The brothers were concordant for GD and discordant for PD. Genetic counseling and testing were provided to four of the six participants. Two years later, semi‐structured interviews were conducted with the initial participants (n = 4) and two additional first‐degree relatives. Interviews were transcribed and thematically analyzed, providing the basis for this report. Illuminated topics include the perceived risk of developing PD, recall of genetic information, and family communication. With the expanding use of exome and genome sequencing, we anticipate that genetic counselors will increasingly face the challenges demonstrated by this case involving multiple genetic risks for PD, limited data to clarify risk, and the inherent variability of family communication, genetic knowledge, and risk perception. This clinical case report provides a compelling narrative demonstrating the need for additional research exploring these multifaceted topics relevant to both families facing these challenges and providers striving to assist, support and guide their journey. [ABSTRACT FROM AUTHOR]

Expanded carrier screening (ECS) intends to broadly screen healthy individuals to determine their reproductive chance for autosomal recessive (AR) and X‐linked (XL) conditions with infantile or early‐childhood onset, which may impact reproductive management (Committee Opinion 690, Obstetrics and Gynecology, 2017, 129, e35). Compared to ethnicity‐based screening, which requires accurate knowledge of ancestry for optimal test selection and appropriate risk assessment, ECS panels consist of tens to hundreds of AR and XL conditions that may be individually rare in various ancestries but offer a comprehensive approach to inherited disease screening. As such, the term "equitable carrier screening" may be preferable. This practice guideline provides evidence‐based recommendations for ECS using the GRADE Evidence to Decision framework (Guyatt et al., BMJ, 2008, 336, 995; Guyatt et al., BMJ, 2008, 336, 924). We used evidence from a recent systematic evidence review (Ramdaney et al., Genetics in Medicine, 2022, 20, 374) and compiled data from peer‐reviewed literature, scientific meetings, and clinical experience. We defined and prioritized the outcomes of informed consent, change in reproductive plans, yield in identification of at‐risk carrier pairs/pregnancies, perceived barriers to ECS, amount of provider time spent, healthcare costs, frequency of severely/profoundly affected offspring, incidental findings, uncertain findings, patient satisfaction, and provider attitudes. Despite the recognized barriers to implementation and change in management strategies, this analysis supported implementation of ECS for these outcomes. Based upon the current level of evidence, we recommend ECS be made available for all individuals considering reproduction and all pregnant reproductive pairs, as ECS presents an ethnicity‐based carrier screening alternative which does not rely on race‐based medicine. The final decision to pursue carrier screening should be directed by shared decision‐making, which takes into account specific features of patients as well as their preferences and values. As a periconceptional reproductive risk assessment tool, ECS is superior compared to ethnicity‐based carrier screening in that it both identifies more carriers of AR and XL conditions as well as eliminates a single race‐based medical practice. ECS should be offered to all who are currently pregnant, considering pregnancy, or might otherwise biologically contribute to pregnancy. Barriers to the broad implementation of and access to ECS should be identified and addressed so that test performance for carrier screening will not depend on social constructs such as race. [ABSTRACT FROM AUTHOR]

This Position Statement provides guidelines to assist all health professionals who receive requests for carrier testing and laboratory staff conducting the tests. In this Statement, the term 'carrier testing' refers to genetic testing in an individual to determine whether they have inherited a pathogenic variant associated with an autosomal or X-linked recessive condition previously identified in a blood relative. Carrier testing recommendations: (1) Carrier testing should only be performed with the individual's knowledge and consent; (2) An individual considering (for themselves, or on behalf of another) whether to have a carrier test should be supported to make an informed decision; (3) The mode of inheritance, the individual's personal experience with the condition, and the healthcare setting in which the test is being performed should be considered when determining whether carrier testing should be offered by a genetic health professional. Regarding children and young people: Unless there is direct medical benefit in the immediate future, the default position should be to postpone carrier testing until the child or young person can be supported to make an informed decision. There may be some specific situations where it is appropriate to facilitate carrier testing in children and young people (see section in this article). In such cases, testing should only be offered with pre- and post-test genetic counseling in which genetic health professionals and parents/guardians should explore the rationale for testing and the interests of the child and the family. [ABSTRACT FROM AUTHOR]

Decision‐making regarding prenatal screening and diagnostic testing has become more complex as the number of options has increased, with pregnant patients having access to more information about their pregnancies than ever before. Genetic counselors have extensive training in prenatal genetic screening and testing options, but personal decision‐making in this well‐informed population remains largely unstudied. This study describes the prenatal testing decisions genetic counselors made during their own pregnancies, and the factors identified as important when making those decisions. A web‐based, mixed‐methods survey was distributed to members of multiple professional societies for genetic counselors. A total of 318 genetic counselors across numerous specialties in the United States and Canada participated in this study. The satisfaction with decision scale was modified and applied to measure participants' decisional satisfaction. In their most recent pregnancies, most genetic counselors pursued carrier screening (77%) and aneuploidy and/or open neural tube defect screening (88%). A minority of genetic counselors (15%) utilized diagnostic testing. Common factors considered when making testing decisions included wanting information that could impact future decisions, test specifics (e.g., accuracy, methodology, and content), and knowledge gained from participants' genetic counseling background. The uptake of diagnostic testing among prenatal genetic counselors was significantly greater (p < 0.05) than the uptake among genetic counselors in other specialties. This informed study population largely self‐directed their own prenatal care, leading to high satisfaction with their decisions. Data in this study provide evidence for promoting participation in prenatal screening and testing decision‐making to maximize decisional satisfaction. [ABSTRACT FROM AUTHOR]

Reproductive genetic carrier screening (RGCS) allows to identify couples who have an increased likelihood of conceiving a child affected with an autosomal recessive or X‐linked monogenic condition. Multiple studies have reported on a wide and fragmented set of reasons to accept or decline RGCS. Only a few studies have been performed to assess the uptake of RGCS. Nonpregnant women visiting their gynecologist were invited to complete a questionnaire assessing perceived susceptibility, the acceptability of offering RGCS, attitudes, the intention to participate in RGCS, reasons to accept or decline RGCS, and sociodemographic characteristics. Women who showed the intention to have RGCS were asked to consider a free RGCS offer. Most women (n = 127) were between 25 and 34 years old (60%), in a relationship (91%), and wanted to have children (65%). Study participants had positive attitudes towards RGCS and the intention to consider RGCS in the future. Reasons to accept RGCS were being able to share genetic information with children or relatives (n = 104/127, 82%), to prevent the birth of a child affected with a hereditary condition (n = 103/127, 81%), and/or to know the chance of conceiving a child with a hereditary condition (n = 102/127, 80%). Reasons for declining RGCS were the possible concerns that could arise when receiving test results (n = 27/127, 21%), having no family history of hereditary disorders (n = 19/127, 15%), and not wanting to take action based on test results (n = 13/127, 10%). Among test intenders that met the inclusion criteria, 53% decided to participate in RGCS together with their male reproductive partner. More in‐depth research on the decision‐making process behind the choice to accept or decline an RGCS offer would be highly valuable to make sure couples are making informed reproductive choices. [ABSTRACT FROM AUTHOR]

The goal of this study was to assess the feasibility of using exome (ES) and genome sequencing (GS) in guiding preconception genetic screening (PCGS) for couples who are planning to conceive by creating a workflow for identifying risk alleles for autosomal recessive (AR) and X-linked (XL) disorders without the constraints of a predetermined, targeted gene panel. There were several limitations and challenges related to reporting and the technical aspects of ES and GS, which are listed in the discussion. We selected 150 couples from a cohort of families (trios) enrolled in a research protocol where the goal was to define the genetic etiology of disease in an affected child. Pre-existing, de-identified parental sequencing data were analyzed to define variants that would place the couple at risk of having a child affected by an AR or XL disorder. We identified 17 families who would be selected for counseling about risk alleles. We noted that only 3 of these at-risk couples would be identified if we limited ourselves to the current ACMG-recommended expanded carrier screening gene panel. ES and GS successfully identified couples who are at risk of having a child with a rare AR or XL disorder that would have been missed by the current recommended guidelines. Current limitations of this approach include ethical concerns, difficulties in reporting results including variant calling due to the rare nature of some of the variants, determining which disorders to report, as well as technical difficulties in detecting certain variants such as repeat expansions., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

There has been considerable debate over whether adolescents should have the opportunity to learn genetic information about adult‐onset disease risk and carrier status without a clinical indication. Adolescents face increasing opportunities to learn more about such genetic risks through the return of secondary findings from clinical genomic testing, direct‐to‐consumer genetic testing, and research opportunities. However, little is known about the perspectives of adolescents who have received genomic screening results. We conducted separate qualitative interviews with 15 adolescents and their parents who enrolled in a research protocol where they decided which genomic screening results to receive for the adolescent for up to 32 conditions informed by 84 genes. The goal of these interviews was to explore the impact of adolescents learning genomic results without a clinical indication for screening. Of the participating dyads, four received positive results for a pathogenic/likely pathogenic (P/LP) variant for an autosomal dominant (AD) condition, five received carrier results for a heterozygous P/LP variant for an autosomal recessive (AR) condition, and six received negative results. An interpretive descriptive qualitative approach was used. Interview transcripts were coded using a guide developed by the study team based on themes that emerged from the interviews. Degree of recall and description of results, actionability, and emotional responses differed according to the types of results received. However, all participants were satisfied with their decision to learn results, and most did not report any lasting psychological harms. Participants adapted to genomic information about themselves, even after learning about unexpected increased risk for future health problems. Our findings support the position that, whenever possible, perspectives and wishes of adolescents should be strongly considered and respected in the decision‐making process regarding genetic testing. [ABSTRACT FROM AUTHOR]

Expanded carrier screening (ECS) is used to identify individuals and couples at risk for having children with recessive or X‐linked genetic conditions; however, personal health risks (PHR) can also be identified through this testing. There is limited data on how genetic counseling regarding PHR from ECS is perceived by the individual, or how they use this information. This study quantitatively surveyed individuals identified with these risks between September 2013 and March 2020. The 30‐item survey included the validated Genomics Outcome Scale Short Form, the validated Genetic Counseling Satisfaction Scale, and original questions. Survey topics included pre‐test knowledge of the possibility of discovering PHR through testing, satisfaction with pre‐test education that addresses potential risks, perceived severity of PHR, empowerment by and understanding of information, anxiety levels related to their PHR, perceived genetic counseling support, and satisfaction with telehealth. A total of 416 completed surveys were analyzed using descriptive statistics, and linear and logistic regressions. The majority of participants were satisfied or extremely satisfied with pre‐test education (n = 328; 78.8%) and telehealth (n = 329; 79.1%). However, more participants who were aware of the possibility of identifying PHR through ECS prior to testing were satisfied with pre‐test education compared to those who were not aware. Additionally, a lack of prior awareness of PHR was associated with lower empowerment scores (p =.004). Those who were highly satisfied with genetic counseling were more likely to feel empowered and understand the information presented (p =.001). The majority of individuals used their PHR information following their results appointment (n = 391; 94.0%). The results of this study suggest that receiving PHR information was useful and was positively influenced by both pre‐test education and the genetic counseling process. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease characterized by muscle weakness and atrophy with usually typical cognition. The first disease‐modifying therapy for SMA, nusinersen, was approved by the United States Food and Drug Administration (FDA) in 2016 and leads to improved outcomes, especially when administered presymptomatically. Population‐wide carrier screening and newborn screening (NBS) are now recommended by several professional organizations to promote reproductive autonomy, early diagnosis, and treatment. Prenatal genetic counselors (GCs) are important providers of the SMA screening and diagnosis process, but the possible impact of nusinersen on their practice has not been explored. A survey of 182 prenatal GCs in the United States (US) assessed baseline knowledge of nusinersen and likelihood of discussing this option with prospective parents. The majority of GCs (94.5%) were aware of this drug, and almost all (87.3%) felt that this information would affect pregnancy management decisions. However, less than half of GCs (49.2%) felt confident discussing nusinersen, 45.1% were unaware if this treatment was available in their practice setting, and one in five (19.3%) did not know where to find information about SMA treatments. Participants were more confident and knowledgeable about NBS for SMA, and several indicated that NBS would reduce their emphasis on carrier screening and diagnostic testing, not recognizing that an early prenatal diagnosis can enable preparations for complex, time‐sensitive treatment. Only 5.0% of participants felt that a prenatal GC should discuss nusinersen with prospective parents. However, encouragingly, nearly all GCs who felt confident discussing this treatment option (86.4%) reported using this information weekly in their real‐world practice. These data highlight an opportunity to provide up‐to‐date education about SMA treatments, as well as the significant impacts of early diagnosis. Additionally, interdisciplinary communication and care may be appropriate to clarify healthcare resources available and support a variety of patient needs. Increasing awareness and confidence about available options can help prenatal GCs empower patient autonomy and shared decision‐making in the new era of disease‐modifying treatment for SMA. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by biallelic inactivation of the survival motor neuron 1 (SMN1) gene. With a prevalence of ~1 in 11,000 live births (carrier frequency of ~1:50), SMA is one of the most common severe childhood‐onset diseases; therefore, current guidelines recommend pan‐ethnic carrier screening for SMA before or during pregnancy. Routine SMN1 copy number assessment detects ~96% of all SMA carriers, but not the remaining 4% who harbor two copies of SMN1 arrayed in ‐cis [2 + 0]. The c.*3+80T>G risk‐modifying SNP positively correlates with this chromosomal configuration and may be used to modify the residual risk of being a carrier for SMA. Methods: One year after incorporating the detection of the c.*3+80>G risk‐modifying SNP into our routine SMA carrier screen, we perform a retrospective chart review to evaluate its frequency and utilization in the prenatal clinic. Results: In comparison with classic carriers for SMA, study data show that individuals with two copies of SMN1 and the risk modifier were counseled less frequently about their increased risk of being a carrier for SMA. Conclusion: Incorporating the c.*3+80T>G risk‐modifying SNP is important for detecting carriers for SMA with a higher clinical sensitivity. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the level of interest in preconception carrier screening among reproductive‐aged persons presenting for gynecologic care and to identify demographic factors predictive of pursuing screening. Patients aged 18–40 who were presenting for gynecologic care at a single U.S. academic medical center were provided with information about current options for preconception carrier screening and were offered genetic counseling referral with the possibility to undergo screening. Outcomes of interest were desire for genetic counseling referral and attendance at genetic counseling visit. Statistical analyses were performed as appropriate using R version 3.6.1 with variables significant at 0.1 included in a multivariable logistic regression. Of 193 participants, 79 (41%) desired genetic counseling referral. Participants aged 25–34 (OR 3.39, 95% CI 1.47–8.10) and nulliparas (OR 2.69, 95% CI 1.23–6.03) were more likely to desire referral. Thirty‐five participants (44.3% of those who desired referral) attended a visit with genetic counseling. Having an advanced degree (OR 3.27, 95% CI 1.06–10.4) was associated with visit attendance. Thirteen participants underwent screening, and five were found to be a carrier of at least one X‐linked or autosomal recessive condition. Surprisingly, presenting for a gynecologic visit directly related to planning a pregnancy was not associated with increased interest in preconception carrier screening. Nulliparas and those aged 25–34 likely expressed greater interest in referral due to high potential for future childbearing in these groups. The increased level of visit attendance in participants with advanced degrees is likely confounded by the high level of health literacy and financial resources in this group. [ABSTRACT FROM AUTHOR]

Anna Kiseleva,1,* Marina Klimushina,1,* Evgeniia Sotnikova,1,* Olga Skirko,1 Mikhail Divashuk,1,2 Olga Kurilova,1 Alexandra Ershova,1 Eleonora Khlebus,1 Anastasia Zharikova,1,3,4 Irina Efimova,1 Maria Pokrovskaya,1 Petr A Slominsky,5 Svetlana Shalnova,1 Alexey Meshkov,1,* Oxana Drapkina1,* 1Federal State Institution «National Medical Research Center for Therapy and Preventive Medicine» of the Ministry of Healthcare of the Russian Federation, Moscow, 101000, Russia; 2Kurchatov Genomics Center-ARRIAB, All-Russia Research Institute of Agricultural Biotechnology, Moscow 127550, Russia; 3Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119991, Russia; 4Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127051, Russia; 5Institute of Molecular Genetics, Russian Academy of Sciences, Moscow 123182, Russia*These authors contributed equally to this workCorrespondence: Anna Kiseleva Email sanyutabe@gmail.comPurpose: Cystic fibrosis (CF) is one of the most common monogenic diseases with an autosomal recessive inheritance. Carrier screening leads to a reduction in the number of children born with CF disease. The aim of this study was to develop the custom panel for the diagnosis of heterozygous carriage of polymorphic variants in the CFTR gene and to establish their allelic frequencies (AF) in one of the Russian regions where ethnic Russians predominate.Patients and Methods: The diagnostic panel was designed on the basis of data from the register of CF patients in Russia for 2017 and validated on 22 blood samples of patients with previously genetically established CF. The study participants (n=642) for CF variants estimation were randomly selected from the population-based cohort study ESSE-Vologda. Genotypes were determined by real-time PCR on the QuantStudio 12K Flex Real-Time PCR System. Data processing was performed using the TaqMan Genotyper Software.Results: The proposed diagnostic panel allowed simultaneous analysis of 60 variants of the CFTR gene. A total of 23 carriers of the following variants were identified among 642 participants: F508del (rs113993960) with a frequency of 2.02%, L138ins (rs397508686) and 394delTT (rs121908769) – 0.47%, CFTRdele2.3 (c.54– 5940_273+10250del21080; p.S18Rfs*16) – 0.31%, R117H (rs78655421), and G542X (rs113993959) – 0.16%. The frequency of heterozygotes in the Russian population was 3.58% or 1:28 (CI95%: 2.28– 5.33% by Clopper–Pearson exact method).Conclusion: High frequency of heterozygous CFTR variants carriers and availability of highly productive diagnostic panel for detection of CFTR variants suggest the prospect of carrier screening for some common CF variants among Russian population.Keywords: cystic fibrosis, CFTR, genetic analysis, carrier screening, carrier testing

Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by biallelic inactivation of the survival motor neuron 1 (SMN1) gene. With a prevalence of ~1 in 11,000 live births (carrier frequency of ~1:50), SMA is one of the most common severe childhood‐onset diseases; therefore, current guidelines recommend pan‐ethnic carrier screening for SMA before or during pregnancy. Routine SMN1 copy number assessment detects ~96% of all SMA carriers, but not the remaining 4% who harbor two copies of SMN1 arrayed in ‐cis [2 + 0]. The c.*3+80T>G risk‐modifying SNP positively correlates with this chromosomal configuration and may be used to modify the residual risk of being a carrier for SMA. Methods One year after incorporating the detection of the c.*3+80>G risk‐modifying SNP into our routine SMA carrier screen, we perform a retrospective chart review to evaluate its frequency and utilization in the prenatal clinic. Results In comparison with classic carriers for SMA, study data show that individuals with two copies of SMN1 and the risk modifier were counseled less frequently about their increased risk of being a carrier for SMA. Conclusion Incorporating the c.*3+80T>G risk‐modifying SNP is important for detecting carriers for SMA with a higher clinical sensitivity.

An estimated 7% of the world's population are carriers for a hemoglobin disorder. Current guidelines recommend carrier screening by complete blood count, with follow‐up hemoglobin electrophoresis or fractionation based on abnormal result or ethnicity. Advances in molecular genetic testing are thought to increase carrier detection. This study compares carrier screening methodologies in a multi‐ethnic sperm donor population. A retrospective analysis was conducted using data from a US sperm bank. All men underwent carrier screening for hemoglobin disorders via complete blood count, hemoglobin fractionation, and molecular testing. Results were compared using counts and percentages. McNemar's exact test was used to examine differences in the marginal probabilities of screening methodologies. Of the 438 tested, 25 (5.7%) were identified as carriers of at least one hemoglobin disorder by molecular testing. Seventeen (68%) of those carriers were missed by recommended methods. No identified carriers were detected by recommended methods but missed by molecular testing. The difference between these discordant pairs was significant (p‐value < 0.001). The majority (44%) of carriers were mixed ethnicity, followed by 36% White. Results indicate that molecular screening methodologies have a greater ability to detect carriers of hemoglobin disorders compared to currently recommended methods in a multi‐ethnic population. [ABSTRACT FROM AUTHOR]

Pheochromocytoma and paraganglioma are frequently hereditary tumors commonly associated with succinate dehydrogenase (SDHx) pathogenic variants (PV). Genetic testing is recommended to relatives of patients carrying SDHx PV. This study aims to explore the experiences associated with genetic testing for this hereditary condition. Semi‐structured interviews with 38 SDHx PV (tumor‐affected and non‐affected) carriers were transcribed and content‐analyzed. Four ways of living with this genetic alteration emerged from the interviews: 'living as if not knowing', 'preventing others from going through this', 'feeling privileged', and 'still suffering'. Within each, negative, neutral, and positive reactions to the actual test result emerged initially, in addition to blame and guilt. Recognition of the importance of the genetic test and of the follow‐up occurred in all four, but views on fecundity were divided between having and not having children. Consideration for the four different meanings of carrying an SDHx PV can improve participants' experiences and clinical practice. [ABSTRACT FROM AUTHOR]

The benefits and harms of identifying carriers in childhood have long been debated with European Guidelines advising against this practice. Yet over a thousand carriers are identified via newborn bloodspot screening per year in the United Kingdom alone. One of the concerns about identification is the impact it has on an individual's identity. This, in part, will be determined by how parents and peers view carriers, particularly during young adulthood. To address the paucity of research looking at how carriers are perceived by peers, this study sought to explore the views of young adults, who themselves are not carriers, toward carriers. As the narratives around COVID-19 increased, the salience of the term "carrier", the impact of such narratives on perceptions, was also explored. Twenty-five 18-25 year olds participated in a diary-interview study in the United Kingdom during 2021 to explore their perceptions of carriers via hypothetical scenarios. Data were analyzed using thematic analysis. Interviewees believed carriers would experience stigma-including societal and self-stigma. This was because people used existing illness beliefs to make sense of carrier status about which they had low levels of understanding. Interviewees believed carriers would experience challenges in familial and romantic relationships due to others' judgments. They also believed parents of carriers would experience a burden around making reproductive decisions, with clear views on what society would view as acceptable choices. Importantly interviewees felt knowledge of ones' own carrier status conferred complex communication challenges within relationships. These findings suggest an urgent need for more research and support for young adults entering a key stage in life for identity formation who have knowledge of their carrier status. The results suggest that support targeted toward the carrier regarding navigating complex communication and targeted more broadly to avoid stigma based on misunderstanding should be researched and developed., (© 2024 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Rapidly evolving genomic technologies have made genetic expanded carrier screening (ECS) possible for couples considering a pregnancy. The aim of ECS is to identify couples at risk of having a child affected with a severe disorder and to facilitate their reproductive decision-making process. The ECS test we offer at our center, called BeGECS (Belgian Genetic ECS), consists of 1268 autosomal recessive (AR) and X-linked pathogenic genes, including severe childhood-onset disorders. However, thus far data are scarce regarding the actual uptake of preconception ECS in a clinical setting. Therefore, our aim was to describe the characteristics of 407 couples to whom ECS was offered at the Center for Medical Genetics of the University Hospital Ghent (CMGG). In addition, we aimed to identify their reasons for accepting or declining BeGECS. Between October 2019 and January 2023, 407 preconception couples were offered BeGECS and were asked to fill in a questionnaire after their decision. Of the 407 couples participating in the survey, 270 (66%) decided to take the test and 137 (34%) declined. We observed that age, highest education level as well as indication for consultation were statistically different between the group that accepted to take the test and the group that declined (p = 0.037). In particular, age and education level were substantially higher in the group that accepted the test. Major reasons for taking BeGECS include prevention, wishing to obtain all information possible, helping preparing their future reproductive decision and increasing their sense of control by being informed. However, couples that do not chose to take BeGECS stated that too much information would make them anxious, that the result would not change their decision to have children, that they do not want to spend money on something that will not happen and that they do not worry about their family history. These findings show that the majority of preconception couples that were offered ECS, accepted the test., (© 2024 National Society of Genetic Counselors.)

We sought to determine the costs of genetic testing and compliance with published guidelines and clinical best practices at our institution. A cost analysis was performed comparing the costs of ordered tests to the cost of the recommended testing. This was an approved quality improvement project at a tertiary teaching hospital in California. We identified charts associated with the genetic testing billing codes for common genetic tests through our contracted laboratory (cystic fibrosis genotyping, Breast cancer susceptibility gene (BRCA 1&2), Methylenetetrahydrofolate reductase (MTHFR), factor V Leiden (FVL), prothrombin gene pathogenic variant, alpha‐thalassemia, hemochromatosis, and cell‐free fetal DNA). Charts were reviewed retrospectively by a licensed, certified genetic counselor to assess the compliance with published clinical practice guidelines identified on GeneReviews and the American College of Obstetricians and Gynecologists (ACOG). Tests were classified as: appropriate, misordered/not indicated, misordered/false reassurance, and misordered/inadequate. We performed a cost analysis for the recommended test changes. We reviewed 114 charts over a three‐month period. Forty‐four (38.6%) of the tests were misordered based on published clinical practice guidelines: 24 (21%) were misordered/not indicated, 8 (7%) were misordered/false reassurance, and 12 (10.5%) were misordered/inadequate. Costs of ordered testing ($75,177) were compared to recommended testing after review ($54,265), with a total cost savings of $20,912. In clinical practice, over one‐third of genetic tests reviewed were misordered. As these tests are a small fraction of all genetic tests at our institution, future studies should broaden the scope of testing evaluated to understand the magnitude of this problem and potential cost savings. Genetic counselor review and involvement in genetic test ordering can decrease inappropriate healthcare expenditures and improve patient care. [ABSTRACT FROM AUTHOR]

Tay‐Sachs disease (TSD) is a hereditary neurodegenerative condition inherited through an autosomal recessive pattern. The incidence and carrier frequency of infantile TSD were found to be increased among French Canadians in specific areas of the province of Quebec or calculated from New England populations with French‐Canadian heritage. No accurate infantile TSD carrier frequency for the whole French‐Canadian population in Quebec has been published. In this study, we estimate the incidence and carrier frequency of infantile TSD in the Quebec French‐Canadian population. The number of TSD cases was ascertained during the 1992–2015 period, as well as the number of births to mothers whose language of use is French. Seven cases of TSD have been diagnosed in Quebec during the period of ascertainment. This corresponds to an incidence of 1/218,144, which in turn corresponds to a carrier frequency of 1/234. In the same 24‐year period, there are two French‐Canadian couples who had a fetus prenatally diagnosed with TSD. If these cases are included, the incidence of TSD in the French‐Canadian population of Quebec is 1/169,668 and the carrier frequency 1/206. These findings can be used for genetic counseling and policy decisions regarding carrier screening for TSD in populations of French‐Canadian descent. [ABSTRACT FROM AUTHOR]

As population‐level carrier screening panels for reprogenetic information emerge globally, conditions to be included, and the timing of implementation is widely debated. Thalassemia is the only condition for which population‐based prenatal carrier screening is offered in the UK. However, little is known about the views and experiences of the UK thalassemia‐affected community toward this screening or other forms of genetic screening for thalassemia (newborn, preconception), despite the range of direct consequences of screening programmes for this group. Using a mixed‐methods integrative analysis (qualitative interviews n = 20 and quantitative survey n = 80), this study outlines the experiences and attitudes of adults with thalassemia, their family members, and screen‐identified thalassemia carriers toward preconception, prenatal, and newborn screening for thalassemia. The majority of participants described thalassemia as a burdensome condition with a range of negative impacts, which contributed to their strong support for screening in all its potential formats. However, the data also highlight the challenges of each screening mode for this group, reflected in the high level of value conflict in participants' accounts and decisions. Cultural, social, and (to a lesser extent) religious factors were found to mitigate against the advantages of early screens, particularly within faith communities. Social stigma emerged as key to this process, informing the way that thalassemia severity was not only perceived, but also experienced by affected adults, which ultimately influenced screening uptake and outcomes. These findings suggest that cultural and social sensitivity is as important as the mode of screening delivery itself, if the iatrogenic and unintended harms of screening—particularly the social/psychological burden of value conflict—are to be adequately addressed and minimized. [ABSTRACT FROM AUTHOR]

How individuals perceive uncertainties in sequencing results may affect their clinical utility. The purpose of this study was to explore perceptions of uncertainties in carrier results and how they relate to psychological well-being and health behavior. Post-reproductive adults (N = 462) were randomized to receive carrier results from sequencing through either a web platform or a genetic counselor. On average, participants received two results. Group differences in affective, evaluative, and clinical uncertainties were assessed from baseline to 1 and 6 months; associations with test-specific distress and communication of results were assessed at 6 months. Reductions in affective uncertainty (∆x̅ = 0.78, 95% CI: 0.53, 1.02) and evaluative uncertainty (∆x̅ = 0.69, 95% CI: 0.51, 0.87) followed receipt of results regardless of randomization arm at 1 month. Participants in the web platform arm reported greater clinical uncertainty than those in the genetic counselor arm at 1 and 6 months; this was corroborated by the 1,230 questions asked of the genetic counselor and residual questions reported by those randomized to the web platform. Evaluative uncertainty was associated with a lower likelihood of communicating results to health care providers. Clinical uncertainty was associated with a lower likelihood of communicating results to children. Learning one's carrier results may reduce perceptions of uncertainties, though web-based return may lead to less reduction in clinical uncertainty in the short term. These findings warrant reinforcement of clinical implications to minimize residual questions and promote appropriate health behavior (communicating results to at-risk relatives in the case of carrier results), especially when testing alternative delivery models. [ABSTRACT FROM AUTHOR]

The intent of carrier screening is to identify individuals at risk for having a child with a genetic disorder. American College of Medical Genetics and Genomics (ACMG) guidelines currently recommend that individuals of Ashkenazi Jewish (AJ) descent be screened for carrier status for nine disorders. However, a joint statement from five professional organizations acknowledges benefits of expanded carrier screening and this is becoming common practice. To better understand the impact of expanded carrier screening for the AJ population, we performed a retrospective analysis comparing detection rates for AJ individuals screened by two targeted panels: a pan‐ethnic panel comprising 87 disorders and an AJ panel comprising an 18‐disorder subset of the pan‐ethnic panel. We also extrapolated the detection rates for the 18 AJ disorders from the pan‐ethnic panel data and for the nine ACMG‐recommended disorders using data from both panels. We found that with the pan‐ethnic panel 431/1150 (37.5%) individuals were carriers of at least one disorder, compared to 319/1248 (25.6%) individuals with the AJ panel. If the pan‐ethnic panel cohort were tested in the AJ panel or for the nine ACMG‐recommended disorders, the detection rates would have been 280/1150 (24.3%) and 207/1150 (18.0%) respectively. Therefore, the pan‐ethnic expanded carrier screening panel of 87 disorders increased the carrier detection rate in AJ individuals by approximately 50% and 100%, respectively, compared with a panel of 18 disorders considered relevant to the AJ population and the ACMG‐recommended disorders. Twenty disorders accounted for the difference in carrier detection rates between the pan‐ethnic and AJ panels. Of these, three were among the 10 most commonly identified disorders. Our findings reinforce published data that targeted AJ panels are less effective than a pan‐ethnic panel in carrier detection among AJ individuals and provide metrics to address the impact of expanded carrier screening in this population. [ABSTRACT FROM AUTHOR]

Objective: To determine the appropriateness of using MCV/MCH as screening test for beta-thalassemia trait in the present population and also to find the most appropriate cutoff for optimum sensitivity of these indices. Methods: It was an analytical, observational and cross-sectional study. Complete blood count followed by high-performance liquid chromatography (HPLC) was performed. The MCV and MCH levels were noted in cases and controls. Results: Thalassemia trait was found in 66 out of 1300 antenatal women with anemia. The MCV and MCH were significantly low in cases (p = 0.0001). MCV had a better AUC (0.650) than MCH (0.635). The most suitable cutoff value of MCV was calculated as 72 fl (sensitivity—63.7%, specificity—68.3%, PPV—9.7%, LR—2.0) and that for MCH was 24 pg (sensitivity—63.6%, specificity—59.4%, PPV—7.7%, LR—1.5) using Youden's index. When MCH (cutoff of 28 pg) and MCV were combined (cutoff of 74 fl), the sensitivity and specificity were 95% and 16%, respectively. Conclusion: The sensitivity and specificity of MCV and MCH alone had low detection rate when used in combination had high sensitivity but the specificity was low; therefore, HPLC should be the preferred screening test for beta-thalassemia in Indian women. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) has been reported in both Amish and Mennonite (Plain) communities, and a higher incidence has been observed in certain Mennonite communities compared to the general population. There are several therapies for SMA, but all are most effective in pre-symptomatic newborns. To identify couples from the Wisconsin Plain community who are most likely to have a child with SMA, carrier screening is offered via mailed kits with at-home specimen collection. Our survey data about Plain families' perspectives on genetic testing suggest educational materials are needed for individuals providing informed consent with at-home specimen collection. We therefore developed a Plain population-specific educational trifold brochure about SMA carrier screening by incorporating existing medical education strategies and feedback from Plain community members and their health care providers. Along with the brochure, surveys were included in the kits to assess baseline knowledge about SMA carrier screening ("pre-education") as well as improvement in knowledge after reviewing the brochure and cultural appropriateness of the brochure ("post-education"). Fifty-five testing kits were distributed, and 26 survey pairs (pre- and post-education) were returned and analyzed (response rate 47%). Respondents had high baseline knowledge with an average of 5 of 7 questions (71%) answered correctly on the pre-education survey. Knowledge improved after reviewing the brochure as the average score increased to 6.5 of 7 questions (93%) answered correctly. Questions about risks of having an affected child after positive or negative carrier screening showed the most improvement from the pre-education to post-education surveys. Most respondents indicated the brochure was helpful, was easy to understand, and contained the right amount of information. Overall, incorporating elements of existing medical education strategies with feedback from the target population and stakeholders about appropriate language seems to be an effective method for creating beneficial, culturally responsive educational materials for the Plain population., (© 2024 National Society of Genetic Counselors.)

Aims: The pathogenic variant, p.GLY428Asp (c.1283G-A), in the epidermal growth factor receptor ( EGFR ) gene causes neonatal inflammatory skin and bowel disease 2, a disorder that is lethal during infancy due to skin infections and sepsis. This variant seems to be restricted to people of Roma origin with the majority of patients thus far reported being from Slovakia or the Czech Republic. The aim of this study was to establish the frequency of this variant in the Roma population in Slovakia. Methods: A population sample of 1321 unrelated healthy individuals of Roma origin from Slovakia was tested for the p.GLY428Asp variant in EGFR gene by real-time PCR. Results: The carrier frequency in the Roma ethnic group was 2.65%. Conclusions: This is the first report of the frequency of this variant. A high frequency of carriers together with a significant number of patients reported previously proves the p.GLY428Asp variant in the EGFR gene is a major health concern of the Roma populations in Slovakia and neighboring regions.

Nail‐Patella syndrome (NPS) is a genetic disorder generating physical malformations and, in approximately one in three cases, ocular and renal damage. The present research aimed to deeply understand patients' subjective experience with NPS, particularly the aspects of the syndrome that affect patients' adaptation and to propose interventions that can improve genetic and psychological counseling and help patients cope with their condition. Semi‐structured interviews of nine people diagnosed with NPS were analyzed using interpretative phenomenological analysis. Results highlighted attempts to look like a person without disabilities by hiding malformations and not telling the truth about symptoms' genetic origin because of patients' poor self‐esteem, negative self‐cognition, and social isolation experienced from childhood to adulthood. Difficulties of adaptation to physical limits and pain were also identified. The majority of participants who were not diagnosed at birth tended to consider physical symptoms as "birth malformations" without imagining other potential implications until receiving a diagnosis. Despite the diagnosis, the majority continued to minimize the potential complications by considering NPS as a "physical difference" and not adhering to medical surveillance. [ABSTRACT FROM AUTHOR]

Consanguinity, the union between two individuals who are related as second cousins or closer, is a long‐standing and respected tradition in many communities. Although there are social and economic benefits of consanguineous unions, offspring are at increased risk of having an inherited genetic condition or congenital anomaly. Genetic counseling services for consanguinity are available to couples at many centers. However, little is known about patient expectations of and experiences with genetic counseling for this indication, or their perspectives on genetic screening relevant to family planning, such as expanded carrier screening (ECS). This exploratory qualitative study involved interviews with 13 individuals who had recently received preconception or prenatal genetic counseling for consanguinity at a single center. We sought to gain insight into their expectations for the genetic counseling session, experiences discussing family history and reproductive risks with the genetic counselor, and views on ECS. Interview transcripts were analyzed using an interpretive descriptive approach. Data analysis revealed three main themes: (a) anticipation balances apprehension before the appointment; (b) genetic counseling reduces anxiety and empowers; and (c) the need for wider information dissemination about consanguinity‐related risks and genetic services. Our findings support the personal utility of genetic counseling for consanguinity and demonstrate the need for increased visibility and access to genetics information, counseling, and testing relevant to this patient population. [ABSTRACT FROM AUTHOR]

When a genetic disease‐causing variant causing autosomal dominant diseases is identified, predictive DNA testing is possible for at‐risk relatives to investigate whether they are carrying the familial variant. In current practice, the proband is asked to inform at‐risk relatives, often supported by a family letter. This review summarizes the literature on preferences of probands and relatives regarding how and by whom at‐risk relatives should be informed. A search involving digital databases (Pubmed, Medline, and PsycInfo) focusing on patient attitudes toward informing relatives at risk of autosomal dominant onco‐, cardio‐, or neurogenetic disease, resulted in 1,431 screened records, of which 117 full‐text papers were assessed. Eventually, 32 studies were selected. This review shows that a majority of participants was in favor of someone in the family to inform their at‐risk relatives, with participants generally feeling responsible for informing relatives at risk themselves. However, variation in patient preferences regarding who should inform was observed. Face‐to‐face disclosure by the proband with additional information material for relatives provided by HCPs was most appreciated. Actively offered support of healthcare professionals was desired. In conclusion, although the family‐mediated approach was appreciated by a majority of participants, support by healthcare professionals was desired. By taking patient attitudes into account, the approach used to inform at‐risk relatives could be improved. Subsequently, more relatives will be informed and enabled to attend genetic counseling and make an informed decision regarding predictive DNA testing. Further research on patient attitudes, specifying for disease type and cultural background, is needed. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive degenerative muscular conditions. Carrier testing is available to at-risk females. Though carrier testing is often offered to adolescent females, it raises ethical issues related to autonomy. This study aimed to address the impact of DMD/BMD carrier testing during adolescence, to elucidate what motivates adolescents to seek testing, and to assess the carrier testing experience. Retrospective semi-structured telephone interviews were conducted with 12 women out of 28 initially contacted. Data were coded using thematic analysis. For most (8/12) participants, discovering their carrier status during adolescence appeared to have helped alleviate uncertainty. The majority (9/12) of participants felt that they had made an autonomous decision and most (10/12) seemed to have adjusted well to their test result. Reproductive factors were framed as having been a key motivator prior to testing. However, following testing, participants’ views on prenatal diagnosis seemed more closely linked to their lived experience than to their test result. Just over half (7/12) the participants reported having not had the opportunity for genetic counseling prior to testing and after receiving their result, an issue that warrants further consideration. [ABSTRACT FROM AUTHOR]

Background: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X‐linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed. Methods: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project‐specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects. Results: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results. Conclusion: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources. The clinical sequencing exploratory research (CSER) consortium sought to understand the variability in approaches to identifying and disclosing carrier results. The broad range of experiences across 11 of the CSER projects allowed us to distill key considerations important for guiding future translational genomics research projects that will inform decisions regarding whether and how to disclose carrier results. This research may in turn help to guide policy decisions about clinical services. [ABSTRACT FROM AUTHOR]

Hemophilia involves a lifelong burden from the perspective of the patient and the entire healthcare system. Advances in genetic testing provide valuable information to hemophilia-affected families for family planning. The aim of this study was to analyze the cost-effectiveness of carrier and prenatal genetic testing in the health-economic framework in Taiwan. Methods: A questionnaire was developed to assess the attitudes towards genetic testing for hemophilia. We modeled clinical outcomes of the proposed testing scheme by using the decision tree method. Incremental cost-effectiveness analysis was conducted, based on data from the National Health Insurance (NHI) database and a questionnaire survey. Results: From the NHI database, 1111 hemophilic patients were identified and required an average medical expenditure of approximately New Taiwan (NT) $2.1 million per patient-year in 2009. By using the decision tree model, we estimated that 26 potential carriers need to be tested to prevent one case of hemophilia. At a screening rate of 79%, carrier and prenatal genetic testing would cost NT $85.9 million, which would be offset by an incremental saving of NT $203 million per year by preventing 96 cases of hemophilia. Assuming that the life expectancy for hemophilic patients is 70 years, genetic testing could further save NT $14.2 billion. Higher screening rates would increase the savings for healthcare resources. Conclusion: Carrier and prenatal genetic testing for hemophilia is a cost-effective investment in healthcare allocation. A case management system should be integrated in the current practice to facilitate patient care (e.g., collecting family pedigrees and providing genetic counseling).

When a boy is diagnosed with an X-linked condition such as Duchenne or Becker muscular dystrophy (D/BMD), the mother learns not only of her own potential carrier risk but also that of her daughters. Before the daughters are seen in the Genetics Clinic, responsibility for disclosing carrier risk information falls mainly to their mothers. We know little about if when and how these daughters are being told about their risk, and how mothers find the experience. Should we be doing more to help and support them? Using qualitative methods, six mothers known to the Manchester Centre for Genomic Medicine were interviewed about the disclosure of D/BMD carrier risk information to their daughters. The four key themes that arose are presented: communication process, facilitators of disclosure, barriers to disclosure and support and information. Despite the participants’ endeavours to be open and honest with their daughters and their belief that they had fully disclosed, key information was often withheld. Major barriers to discussion of the future, including reproductive options, were apparent. These were partly overcome by the involvement of genetic counsellors (GCs). The participants suggested a greater involvement of GCs, proactively sending appointments and written information, and offering carrier testing more flexibly. [ABSTRACT FROM AUTHOR]

Advances in technology and the promise of personalized health care are driving greater use of genome sequencing (GS) for a variety of clinical scenarios. As health systems consider adopting GS, they need to understand the impact of GS on the organization and cost of care. While research has documented a dramatic decrease in the cost of sequencing and interpreting GS, few studies have examined how GS impacts genetic counseling workloads. This study examined the time needed to provide genetic counseling for GS in the context of preconception carrier screening. Genetic counselors prospectively reported on the time spent in the results disclosure process with 107 study participants who were part of the NextGen study. We found that the median time for results disclosure was 64 min (ranged from 5 to 229 min). Preparation work was the most time-consuming activity. Qualitative data from journal entries, debrief interviews with genetic counselors, and detailed case conference notes provided information on factors influencing time for results disclosure and implications for practice. Results suggest that expanded carrier screening could require significant increases in genetic counseling time, unless we are able to generate new resources to reduce preparation work or develop other strategies such as the creation of new models to deliver this type of service. [ABSTRACT FROM AUTHOR]

Risk information and communication of health risks play a large role in medicine. With the growing importance of genetics and genomics in medicine, the importance of risk communication will even increase in the future. This paper starts with a discussion on the concept of medical risk information and then focusses on genetic risk information. Three examples of genetic risk information are discussed (carrier testing, susceptibility testing and pharmacogenomics testing) in order to exemplify the broad variety of types of risk information and their specific challenges for medical counselling. [ABSTRACT FROM AUTHOR]

As expanded genome‐scale carrier screening becomes increasingly prevalent, patients will face decisions about whether to receive results about a vast number of genetic conditions. Understanding patient preferences is important to meaningfully demonstrate the ethical goal of respect and support patient autonomy. We explore one possible way to elicit preferences by sorting conditions into categories, which may support patient decision making, but the extent to which categories are helpful is unknown. In the context of a randomized trial of genome sequencing for preconception carrier screening compared to usual care (single disease carrier testing), we interviewed 41 participants who had genome sequencing about their experience using a taxonomy of conditions to select categories of results to receive. We then conducted interviews with an additional 10 participants who were not randomized to genome sequencing, asking them about the taxonomy, their reasons for selecting categories, and alternative ways of presenting information about potential results to receive. Participants in both groups found the categories helpful and valued having a meaningful opportunity to choose which results to receive, regardless of whether they opted to receive all or only certain categories of results. Additionally, participants who received usual care highlighted preparedness as a primary motivation for receiving results, and they indicated that being presented with possible reasons for receiving or declining results for each category could be helpful. Our findings can be used to develop approaches, including the use of categories, to support patient choices in expanded carrier screening. Further research should evaluate and optimize these approaches. [ABSTRACT FROM AUTHOR]

X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy with a birth incidence of 1:14,700 live births. The disease is caused by mutations in ABCD1 and characterized by very long-chain fatty acids (VLCFA) accumulation. In childhood, male patients are at high-risk to develop adrenal insufficiency and/or cerebral demyelination. Timely diagnosis is essential. Untreated adrenal insufficiency can be life-threatening and hematopoietic stem cell transplantation is curative for cerebral ALD provided the procedure is performed in an early stage of the disease. For this reason, ALD is being added to an increasing number of newborn screening programs. ALD newborn screening involves the quantification of C26:0-lysoPC in dried blood spots which requires a dedicated method. C26:0-carnitine, that was recently identified as a potential new biomarker for ALD, has the advantage that it can be added as one more analyte to the routine analysis of amino acids and acylcarnitines already in use. The first objective of this study was a comparison of the sensitivity of C26:0-carnitine and C26:0-lysoPC in dried blood spots from control and ALD newborns both in a case-control study and in newborns included in the New York State screening program. While C26:0-lysoPC was elevated in all ALD newborns, C26:0-carnitine was elevated only in 83%. Therefore, C26:0-carnitine is not a suitable biomarker to use in ALD newborn screen. In women with ALD, plasma VLCFA analysis results in a false negative result in approximately 15–20% of cases. The second objective of this study was to compare plasma VLCFA analysis with C26:0-carnitine and C26:0-lysoPC in dried blood spots of women with ALD. Our results show that C26:0-lysoPC was elevated in dried blood spots from all women with ALD, including from those with normal plasma C26:0 levels. This shows that C26:0-lysoPC is a better and more accurate biomarker for ALD than plasma VLCFA levels. We recommend that C26:0-lysoPC be added to the routine biochemical array of diagnostic tests for peroxisomal disorders. [ABSTRACT FROM AUTHOR]

In the context of a child being diagnosed with a genetic condition, reports from both parents and health professionals suggest many genetic health professionals are reluctant to provide carrier testing for unaffected siblings, despite the lack of evidence of harm. We propose that genetic health professionals' understandings of why parents want to have their children tested may contribute to their reluctance to test. We draw on interviews with 17 genetic health professionals, reporting their beliefs about parents' motivations for testing and their intentions to communicate results to their children. Data were analyzed using inductive content analysis. Genetic health professionals reported attributions that contrasted with reasons parents actually report. These disparities fall into two categories: 1) attributing reasons that parents do not themselves report (i.e. for reassurance about their child's health), and 2) not recognizing the reasons that parents actually do report for wanting testing (i.e. to communicate the information to their child). By identifying that genetic health professionals may be misattributing reasons to parents for desiring their child's carrier status, they may be missing an opportunity to assist parents to make decisions that are in line with their values and the best interests of the family. [ABSTRACT FROM AUTHOR]

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Over 95% of SMA patients have homozygous deletions of the SMA-causative gene, SMN1 . Thus, SMA carriers are usually diagnosed based on SMN1 copy number, with one copy indicating SMA carrier status. However, two SMN1 copies do not always exclude carrier status. In this study, we identified SMA carriers with two SMN1 copies. Subjects and methods From 33 families, 65 parents of genetically confirmed SMA patients were tested to determine SMA carrier status. Molecular genetic analyses, including multiplex ligation-dependent probe amplification (MLPA) assay, were performed using blood samples from family members. Results Of the 65 parents, three parents from three families had two SMN1 copies. Accordingly, the frequency of carriers with two SMN1 copies was 4.6%. Two of these families were further studied. Patient 1 was homozygous for SMN1 deletion. Patient 1’s mother had two SMN1 copies on one chromosome, with deletion of SMN1 on the other chromosome ([2 + 0] genotype). Patient 1 inherited SMN1 -deleted chromosomes from both parents. Patient 2 was compound heterozygous for two SMN1 mutations: whole-gene deletion and intragenic missense mutation, c.826T > C (p.Tyr276His). Patient 2’s father had two SMN1 copies with the same intragenic mutation in one copy ([1 + 1 d ] genotype, d intragenic mutation). Patient 2 inherited the chromosome with an SMN1 mutation from the father and SMN1 -deleted chromosome from the mother. Conclusion SMA carriers with two SMN1 copies may be rare, but its possibility should be taken into consideration in carrier testing and counseling for SMA families or population-based carrier screening. [ABSTRACT FROM AUTHOR]