Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.

Protein-truncating variants (PTVs) near the 3' end of genes may escape nonsense-mediated decay (NMD). PTVs in the NMD-escape region (PTVescs) can cause Mendelian disease but are difficult to interpret given their varying impact on protein function. Previously, PTVesc burden was assessed in an epilepsy cohort, but no large-scale analysis has systematically evaluated these variants in rare disease. We performed a retrospective analysis of 29,031 neurodevelopmental disorder (NDD) parent-offspring trios referred for clinical exome sequencing to identify PTVesc de novo mutations (DNMs). We identified 1,376 PTVesc DNMs and 133 genes that were significantly enriched (binomial p < 0.001). The PTVesc-enriched genes included those with PTVescs previously described to cause dominant Mendelian disease (e.g., SEMA6B, PPM1D, and DAGLA). We annotated ClinVar variants for PTVescs and identified 948 genes with at least one high-confidence pathogenic variant. Twenty-two known Mendelian PTVesc-enriched genes had no prior evidence of PTVesc-associated disease. We found 22 additional PTVesc-enriched genes that are not well established to be associated with Mendelian disease, several of which showed phenotypic similarity between individuals harboring PTVesc variants in the same gene. Four individuals with PTVesc mutations in RAB1A had similar phenotypes including NDD and spasticity. PTVesc mutations in IRF2BP1 were found in two individuals who each had severe immunodeficiency manifesting in NDD. Three individuals with PTVesc mutations in LDB1 all had NDD and multiple congenital anomalies. Using a large-scale, systematic analysis of DNMs, we extend the mutation spectrum for known Mendelian disease-associated genes and identify potentially novel disease-associated genes.

An examination of the factors contributing to the expansion of subspecialty genetic counseling.

In recent years, genetic counselors have moved into increasingly varied areas of patient care. Yet limited information is known about how these genetic counselors transitioned from more general clinical practice to subspecialized practice. This study was designed to answer three research questions: (1) What common factors establish a need for a genetic counselor in a subspecialty setting? (2) How do genetic counselors in subspecialties establish their positions? (3) Once established, how do the positions of these genetic counselors evolve as the subspecialty expands? Phone interviews with subspecialized genetic counselors led to the development of an online survey distributed through the National Society of Genetic Counselors ListServ. Sixty-eight of the 144 initial participants met eligibility criteria for participation as subspecialty genetic counselors in a clinical role. Physician interest in hiring a genetic counselor, clinical need, genetic counselor interest in subspecialty area, and available genetic testing were commonly reported as contributing factors to position creation. Most subspecialty genetic counseling positions were created as new positions, rather than evolved from a previous position. Over time, subspecialty positions drew more departmental funding and included increased clinical coordination or administrative responsibilities. The results of this study can encourage genetic counselors to collaborate with their medical institutions to utilize their skill-set in diverse areas of patient care.

Outcome and life satisfaction of adults with myelomeningocele.

BACKGROUND: Myelomeningocele (MMC) commonly causes impairments in body structure and functions as well as cognitive disabilities that can have an adverse effect on adult life. Improved medical care has resulted in increased numbers of individuals with MMC surviving to adulthood, however little is known about the impact of MMC on the lives of adults age 25 years or older. OBJECTIVE: To gain a better understanding of outcomes in education, employment, relationships, reproduction and life satisfaction of adults with MMC. METHODS: A primarily quantitative multiple-choice questionnaire designed to capture outcomes in education, employment, relationships and reproduction, along with a previously validated life satisfaction checklist (LiSat-11), was completed by adults with MMC. Relationships between demographic variables, outcomes and life satisfaction were determined using cross tabulation analysis, logistic regression and linear regression. RESULTS: Ninety adults with MMC, age 25-85 years (median age 32), reported a diverse range of outcomes in education, employment, relationships and reproduction. The most consistent variable associated with difficulty attaining adult milestones was hydrocephalus, the presence of which reduced the likelihood of living independently (p ≤ 0.001), having a partner (p = 0.003) and reproducing (p ≤ 0.001), but did not contribute to reduced life satisfaction. CONCLUSIONS: Adults with MMC, especially those without hydrocephalus, can obtain gainful employment, live independently, form partner relationships and have children, and these achievements contribute to life satisfaction. While MMC does not affect overall reported life satisfaction for adults, attention should be paid to specific domains with less reported satisfaction.

Influence of genetic risk information on parental role identity in adolescent girls and young women from families with fragile X syndrome.

Using a multi-group cross-sectional design, we explored self-concept related to parental role salience and enactment in 53 young women (14 to 24 years) with knowledge they were either carriers, non-carriers, or could be a carrier of fragile X syndrome (FXS). Parental role salience included the participants' desire "to be a mother" and the importance they placed on this role. Enactment focused on the participants' views regarding ways to become a mother (reproductive options), parenting a child affected by FXS, and the development of partner relationships (marriage). Participants completed the FXS Adolescent Interview and the FX-Visual Analog Scale. Participants' knowledge of their genetic risk status appears to have influenced both salience and enactment of the parental role, and the effect varied based on carrier status. For many, knowledge of genetic risk appears to have led to reappraisal, redefinition, and re-engagement with the goal of becoming a parent. This process was prominent in those who were carriers and less so in those who were at-risk, and it did not typically occur in those who were non-carriers. Findings offer valuable insight into the impact of genetic risk information on developing perceptions of the parental role and offer new directions for genetic counseling with adolescents and young women with a family history of FXS.

Communication of genetic risk information to daughters in families with fragile X syndrome: the parent's perspective.

Parental approaches to communicating information about genetic disorders to their children may be an important determinant in how the children manage stress as well as their adjustment and adaptation to that information. We explored communication patterns through structured interviews with 46 parents of daughters who learned about their genetic risk status as minors. Three different levels of knowledge about fragile X syndrome were explored: 1) informing that it has been diagnosed in the family and is an inherited disorder, 2) informing about the possibility of a daughter being a carrier, and 3) if testing had been done, informing the daughter of her actual carrier status. Additionally, parental perceptions of their daughter's understanding of the information were explored along with frequency of discussions. We found that communication about genetic risk was initiated by the parents. Five disclosure patterns were identified with variations in style, content, and frequency of communication related to the information that was being disclosed. Aspects of resilient communication were present for all levels of disclosure; however, as the information became more personally relevant for the daughter such as disclosure about the possibility of "being a carrier" for fragile X syndrome and there was uncertainty regarding potential outcomes, the conversations included fewer resilient characteristics. Uncertainty about what and how to present information may negatively affect a parent's ability to include elements of resilient communication when disclosing genetic risk information.

When to tell and test for genetic carrier status: perspectives of adolescents and young adults from fragile X families.

We report here on our findings from adolescent and young adult females (ages 14-25) with a family history of fragile X syndrome regarding their perceptions of the optimal ages for (1) learning fragile X is inherited, (2) learning one could be a carrier for fragile X, and (3) offering carrier testing for fragile X. Three groups were enrolled: those who knew they were carriers or noncarriers and those who knew only they were at-risk to be a carrier. Only 2 of the 53 participants felt that offering carrier testing should be delayed until the age of 18 years. Participants who knew only that they were at-risk to be a carrier provided older optimal ages for offering carrier testing than those who knew their actual carrier status. Participants did not express regret or negative emotions about the timing of the disclosure of genetic risk information regarding their own experiences. Participants' reasoning behind reported ages for informing about genetic risk and offering carrier testing varied depending on what type of information was being disclosed, which carrier status group the participant belonged to, and the preferred age for learning the information. Study findings suggest that decisions regarding the timing to inform about genetic risk and offer testing should be tailored to the individual needs of the child and his/her family.

Genetic risk communication: experiences of adolescent girls and young women from families with fragile X syndrome.

Little is known about how and what genetic risk information parents communicate to their children and even less is known about what children hear and remember. To address this void, we explored how genetic risk information was learned, what information was given and who primarily provided information to adolescent girls and young adult women in families with fragile X syndrome. We explored three levels of risk knowledge: learning that fragile X syndrome was an inherited disorder, that they could be a carrier, and for those who had been tested, actual carrier status. These data were collected as part of a study that also explored adolescent self concept and age preferences about when to inform about genetic risk. Those findings have been presented separately. The purpose of this paper is to present the communication data. Using a multi-group cross-sectional design this study focused on girls ages 14-25 years from families previously diagnosed with fragile X syndrome, 1) who knew they were carriers (n = 20), 2) noncarriers (n = 18), or 3) at-risk to be carriers (n = 15). For all three stages of information the majority of the study participants were informed by a family member. We identified three different communication styles: open, sought information, and indirect. The content of the remembered conversations varied based on the stage of genetic risk information being disclosed as well as the girls' knowledge of her own carrier status. Girls who had been tested and knew their actual carrier status were more likely to report an open communication pattern than girls who knew only that they were at-risk.