Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.

Complex genomic rearrangements (CGRs) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here, we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated, we observed localization and multiple copy number changes including deletions, duplications, and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism's life cycle.

Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.

An innovative medical school curriculum to enhance exposure to genetics and genomics: Updates and outcomes.

PURPOSE: In 2011, we introduced an innovative parallel curriculum at Baylor College of Medicine, formerly called the Genetics Track Curriculum and now called the Genetics and Genomics Pathway, aimed at providing an opportunity for an enriched educational experience throughout medical school. In this report, we describe our 10-year experience with the program and highlight growth in enrollment as well as academic achievements of graduating students. METHODS: We reviewed the data of students enrolled in this pathway, including retention, satisfaction, student-driven curriculum changes, scholarly outcomes, and career outcomes. RESULTS: From September 2011 to June 2021, 121 students were enrolled in the Genetics and Genomics Pathway program. In total, 64 students (64/121 = 53%) left the program before graduating (the majority, after their first year). Of the 57 remaining students, 29 graduated (29/57, approximately 51%), and 4 of the 29 students (4/29 = 14%) matched into a genetics training program. CONCLUSION: This novel program serves as a mechanism for garnering increased interest and competence in medical genetics. The longitudinal nature of the program fosters enthusiasm for genetics and provides ample opportunity to develop valuable research skills. Given the ongoing shortage of providers in this field, such programs are vital to increase the size of the workforce and broaden the knowledge of providers in diverse fields.

Pursuing genetic testing for children with autism spectrum disorders: What do parents think?

The American Academy of Pediatrics, the American College of Medical Genetics and Genomics, and the American Academy of Neurology recommend genetic testing, as a genetic evaluation tool, for children diagnosed with autism spectrum disorders (ASD). Despite the potential benefits, the utilization of genetic testing is low. We proposed an integrated theoretical framework to examine parents' intention and associated psychosocial factors in pursuing genetic testing for their children with ASD. Recruiting primarily from the Interactive Autism Network, a nationwide sample of 411 parents of children with ASD who had never pursued genetic testing for their children completed our theory-based online survey. Data were analyzed using structural equation modeling. About half of the parents were willing to pursue genetic testing for their children with ASD. Findings of the structural equation modeling suggested a good model fit between our integrated theoretical framework and survey data. Parents' intention was significantly and positively associated with their attitudes toward genetic testing, subjective norm, and self-efficacy in having their children tested. This study serves as an initial window to understand parental intention to pursue genetic testing for their children with ASD. Our findings can help physicians and genetic counselors understand, educate, counsel, and support parents' decision-making about having their children with ASD genetically tested. Furthermore, our study can also assist physicians and genetic counselors in developing theory- and evidence-based patient education materials to enhance genetic testing knowledge among parents of children with ASD.

Financial barriers in a county genetics clinic: Problems and solutions.

A genetic evaluation may lead to a clinical or molecular diagnosis, which helps clarify prognosis, tailor surveillance protocols based on risks associated with the genetic condition, and aid in assessment of risk to family members. However, individuals of low socioeconomic and/or minority status often have limited access to genetics services, which contributes to healthcare disparities (Journal of Community Genetics, 2018, 9, 233). Our county hospital system, dedicated to providing health care to the underserved, offers a unique opportunity to reduce healthcare inequalities in genetics. This retrospective chart review included 2,304 patients evaluated at an outpatient county hospital genetics clinic between January 1, 2013, and December 31, 2018, during which time genetic testing was recommended for most patients (58.5%) for a total of 1,429 recommended genetic tests. Most tests were obtained through non-hospital financial resources (56.5%), and loss to follow-up during the phlebotomy stage was the most common reason for tests not to be ordered (41.9%) and not to be completed (36.4%). The experience in our clinic suggests that identifying financial avenues, such as commercial laboratory financial assistance programs in addition to county hospital funds, can support obtaining genetic testing and allow healthcare providers to overcome financial barriers to genetic testing.

Development and evaluation of a genomics training program for community health workers in Texas.

PURPOSE: Genomics services have the potential to reduce incidence and mortality of diseases by providing individualized, family health history (FHH)-based prevention strategies to clients. These services may benefit from the involvement of community health workers (CHWs) in the provision of FHH-based genomics education and services, as CHWs are frontline public health workers and lay health educators, who share similar ethnicities, languages, socioeconomic statuses, and life experiences with the communities they serve. We developed, implemented, and evaluated the FHH-based genomics training program for CHWs. METHODS: This theory- and evidence-based FHH-focused genomics curriculum was developed by an interdisciplinary team. Full-day workshops in English and Spanish were delivered to 145 Texas CHWs (91.6% were Hispanic/black). Preworkshop, postworkshop, and 3-month follow-up data were collected. RESULTS: CHWs significantly improved their attitudes, intention, self-efficacy, and knowledge regarding adopting FHH-based genomics into their practice after the workshops. At 3-month follow-up, these scores remained higher, and there was a significant increase in CHWs' genomics practices. CONCLUSION: This FHH-based genomics training successfully educated Texas CHWs, and the outcomes were promising. Dissemination of training to CHWs in and outside of Texas is needed to promote better access to and delivery of personalized genomics services for the lay and underserved communities.

Autism genetic testing: a qualitative study of awareness, attitudes, and experiences among parents of children with autism spectrum disorders.

PURPOSE: The goal of this first-of-its-kind qualitative study was to examine the awareness, attitudes, and experiences among parents of autistic children regarding autism genetic testing. METHODS: We conducted in-depth, individual, and semistructured interviews with 42 parents of autistic children with diverse racial/ethnic backgrounds. All interviews were audio-taped, transcribed, and coded into major themes and subthemes. RESULTS: Approximately one-quarter of participants had two or more autistic children, and about half of them were ethnic/racial minorities. The majority of participants postulated favorable attitudes toward autism genetic testing for three main reasons: early intervention and treatment, identifying the etiology of autism, and informed family planning. Nevertheless, among parents who had taken their children for genetic testing, some expressed frustration and questioned the competency of their providers in interpreting test results. Asian parents and those with a low socioeconomic status expressed lower awareness and tended to have more limited access to autism genetic testing. CONCLUSION: As health-care providers play a vital role in providing genetic services and education, these professionals should be educated and be sensitive to the needs of parents with autistic children. Further quantitative research is required to examine the effects of socio-demographic factors on parents' awareness, attitudes, and experiences regarding autism genetic testing.

The practice of adult genetics: a 7-year experience from a single center.

The purpose of our study is to familiarize the reader with genetic disorders commonly seen in adults and identify challenges and barriers that limit provision of services. We conducted a retrospective chart analysis of patients seen in the adult Genetics clinics from January 2004 to December 2010 in a metropolitan medical center consisting of an academic private clinic and a county hospital clinic. During the study period, a total of 1,552 patients (n = 1,108 private clinic patients; n = 444 county clinic patients) were evaluated and managed. Of these, 790 and 280 were new patient visits at the private clinic and county clinic, respectively. Approximately 35% (374/1,070) of new patients were seen for cancer-related indications, while neurological indications accounted for approximately 14% (153/1,070) in both clinics. Cardiology-related indications accounted for approximately 13% (145/1,070) of patients, followed closely by chromosomal and syndromic indications for which almost 9% (96/1,070) of new patients were seen. Approximately 8% (90/1,070) of new patients were seen for musculoskeletal indications. We saw increased clinic growth during the study period and found that the most common indications for referral are: (1) Personal/family history of cancer (2) neurological (3) cardiovascular (CV) (4) chromosomal/syndromic and (5) musculoskeletal. A number of challenges were identified, including coordination of services, feasibility of testing, and an overall higher complexity of care with increased clinic scheduling time requirements. Through this review, we demonstrate the demand for adult genetics services and propose some guidelines to address the challenges of management in the adult genetics patient population.

Prevalence of pathogenic germline variants in adult-type diffuse glioma.

Background: No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma. Methods: A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected. Results: We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, and 1p/19q co-deleted patients. Pathogenic variants in BRCA2, MUTYH, and CHEK2 were most common (3/15, 20% each). BRCA1 variants occurred in 2/15 (13%) patients, with variants in NF1, ATM, MSH2, and MSH3 occurring in one patient (7%) each. Prior cancer diagnosis was found in 5/15 patients (33%). Second-hit somatic variants were seen in 3/15 patients (20%) in NF1, MUTYH, and MSH2. Referral to genetics was performed in 6/15 (40%) patients with pathogenic germline variants. 14/15 (93%) of patients discovered their pathogenic variant as a result of their paired glioma sequencing. Conclusions: These findings suggest a possible overlooked opportunity for determination of hereditary cancer syndromes with impact on surveillance as well as potential broader treatment options. Further studies that can determine the role of variants in gliomagenesis and confirm the occurrence and types of pathogenic germline variants in patients with IDH wild type compared to IDH mutant tumors are necessary.

Enhancing exposure to genetics and genomics through an innovative medical school curriculum.

PURPOSE: Physicians entering medical practice in the 21st century will require more than a basic understanding of human genetics because of rapid progress in the field of genetics and genomics. The current undergraduate medical curriculum at most institutions is not adequate to prepare medical students for these challenges. Enhancing exposure to genetics throughout the medical school curriculum should help prepare the next generation of physicians to use genetic and genomic information for optimal patient care. METHODS: We have introduced a Genetics Track Curriculum to the undergraduate medical curriculum at Baylor College of Medicine. RESULTS: This track runs in parallel to the existing 4-year curriculum and includes didactic sessions, small group discussions, longitudinal clinical experiences, clinical and laboratory rotations, community outreach, and scholarly projects related to genetics. It also provides the students a means to network and discuss topics and career paths in medical genetics. CONCLUSION: We have developed a novel curriculum that enhances genomic education for medical students with the ultimate goal of enabling our graduates to deliver more effective and personalized medical care. We believe that the Genetics Track Curriculum at Baylor College of Medicine can serve as a prototype for other medical schools across the country and abroad.

WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype.

Sensenbrenner syndrome and unclassified short rib-polydactyly conditions are ciliopathies with overlapping phenotypes and genetic heterogeneity. Mutations in WDR35 were identified recently in a sub-group of patients with Sensenbrenner syndrome and in a single family that presented with an unclassified form of short-rib polydactyly (SRP) syndrome. We report on siblings with an unusual combination of phenotypes: narrow thorax, short stature, minor anomalies, developmental delay, and severe hepatic fibrosis leading to liver failure and early death in two of the children. Both parents were unaffected suggesting autosomal recessive inheritance. The family and their affected children were followed over a decade. Exome sequencing was performed in one affected individual. It showed a homozygous missense mutation in a highly conserved position of the WDR35 gene. This family represents a WDR35-ciliopathy with a complex clinical presentation that includes significant overlap of the phenotypes described in Sensenbrenner syndrome and the unclassified SRPs. The accurate molecular diagnosis of this family exemplifies the power of exome sequencing in the diagnosis of Mendelian disorders and enabled us to broaden and refine our understanding of Sensenbrenner syndrome and SRP. Detailed genotype-phenotype information is provided as well as discussion of previously reported cases.

Genetic testing and cancer risk management recommendations by physicians for at-risk relatives.

PURPOSE: Sequence-based cancer susceptibility testing results are described as negative, deleterious mutation or variant of uncertain significance. We studied the impact of different types of test results on clinical decision making. METHODS: Practicing physicians from five specialties in Texas completed an online case-based survey (n = 225). Respondents were asked to make genetic testing and management recommendations for healthy at-risk relatives of patients with cancer. RESULTS: When the patient carried a deleterious BRCA1 mutation or variant of uncertain significance, 98% and 82% of physicians, respectively, recommended testing of at-risk relatives (P < 0.0001). In both situations, comprehensive BRCA1/2 analysis was selected most with a corresponding 9-fold increase in unnecessary genetic testing costs. There was no difference in physicians with (n = 81) or without (n = 144) prior BRCA1/2 testing experience (P = 0.3869). Cancer risk management recommendations were most intense for the relative with a deleterious mutation compared with variant of uncertain significance, negative, or no testing with 63%, 13%, 5%, and 2%, respectively, recommending oophorectomy (P < 0.0001). CONCLUSIONS: Independent of experience, or specialty, physicians chose more comprehensive testing for healthy relatives than current guidelines recommend. In contrast, management decisions demonstrated the uncertainty associated with a variant of uncertain significance. Utilization of genetic professionals and education of physicians on family-centered genetic testing may improve efficacy and substantially reduce costs.

Psychometric Properties of the POAGTS: A Tool for Understanding Parents' Perceptions Regarding Autism Spectrum Disorder Genetic Testing.

Due to the increased prevalence of Autism Spectrum Disorder (ASD), more children with ASD may be referred for genetic testing. It is important to develop a tool to help parents consider the benefits and drawbacks of genetic testing for ASD before pursuing genetic testing for children with ASD. We developed the first theory-based survey-Perceptions of ASD Genetic Testing Survey (POAGTS), as a tool to assist healthcare providers to better understand parents' perceptions and concerns regarding ASD genetic testing. The psychometric properties of POAGTS were first pre-tested and then formally tested with 308 parents of children with ASD who had not decided whether to pursue genetic testing for their children diagnosed with ASD. Findings suggest that the eight scales of the POAGTS were psychometrically sound, and had acceptable data reliability and validity. Additional research with various samples, such as parents of children with ASD who belong to diverse racial/ethnic and socioeconomic groups, is warranted in the future to determine whether the POAGTS is applicable to these particular groups. Condensing and refining this tool to a shorter, more user-friendly version is also recommended for future research.

Texas health educators' practice in basic genomics education and services.

Background: Health educators (HEs), who are specialized in health education, can provide basic genomics education/services to the public. Such practice of HEs is unknown. We examined HEs' genomics knowledge and practice, intention, attitudes, self-efficacy and perceived barriers in providing basic genomics education/services. Materials & methods: Texas HEs (n = 662) were invited to complete the survey that was developed based on theoretical constructs (i.e., practice/behavior, intention, attitudes, self-efficacy, knowledge and perceived barriers) from various health behavior theories. Results: Among 182 HEs completed the survey, most had never/seldom provided basic genomics education/services. Participants' practice was positively associated with their intention in performing basic genomics education/services and previous genomics training. Intention to offer such education/services was positively related to HEs' self-efficacy and attitudes, which were correlated to previous genomics training. Conclusion: Texas HEs lacked basic genomics education/services practice. As previous genomics training was associated with HEs' practice, providing continuing education may enhance their practice.

Family Health History-Based Cancer Prevention Training for Community Health Workers.

Cancer is the second leading cause of death in the U.S. Utilizing family health history in cancer prevention holds promise in lessening the burden of cancer. Nevertheless, family health history is underutilized in public health and preventive medicine. Community health workers, also known as lay health educators, are ideal candidates to offer basic cancer family history-based education and services to the general public. The authors developed the first cancer family history-based genomics training program in cancer prevention tailored for community health workers. This paper details the development and pilot testing findings of the training. Specifically, a multidisciplinary research team of geneticists, genetic counselors, health educators, community health workers, and community health worker instructors developed a 7-module, 6-hour, bilingual (English and Spanish) cancer family history-based training focusing on cancer family history-based risk assessment, lifestyle recommendations, and genetic evaluation and testing. The curriculum was based on an integrated theoretical framework, the National Comprehensive Cancer Network guidelines, the community health worker core competencies, and the 4MAT instructional model. The Texas Department of State Health Services approved and certified the curriculum with 2 delivery formats: in-person/face-to-face workshops and online training. A total of 34 community health workers completed the pilot training in person (n=17) and online (n=17) in 2018 and 2019. Participating community health workers' knowledge, attitudes, self-efficacy, and intention in delivering basic cancer family history-based genomics education and services significantly increased on the immediate post-test measures compared with their pretest data. Positive ratings and feedback were also reported by the community health workers. Findings from this pilot study suggest that wider training is warranted for educating more community health workers in the U.S.

Cranio-meta-diaphyseal dysplasia: 25 year follow-up and review of literature.

We report here on a 25-year follow-up of cranio-meta-diaphyseal dysplasia in a 31-year-old Caucasian male, who was reported in the literature at the age of 8 years [Langer et al. (1991); Skeletal Radiol 20:37-41]. He has hyperostotic craniofacial features with protruding lower jaw and midface hypoplasia. He has the typical radiographic features of wide long tubular bones without normal metaphyseal flaring and wide short tubular bones without normal diaphyseal constriction. We describe here his clinical and radiological findings and compare his case with those published in the literature. He is the oldest reported patient with this disorder giving some insight into the natural history of this rare skeletal dysplasia.

Implementation of a Medical School Elective Course Incorporating Case-Based Learning: a Pilot Study.

INTRODUCTION: Case-based learning (CBL) is a pedagogical method using clinical case studies to reinforce learning topics. A pilot elective course incorporating CBL was offered for first-year medical students. The purpose of this study is to (1) describe the logistics of implementing the course and (2) evaluate its reception among medical students on its efficacy in learning basic science class material. METHOD: An 8-week elective course was offered to medical students from 2012 to 2017. Specialists facilitated case discussions synthesizing material from didactic lectures with clinical scenarios. End-of-term surveys with multiple choice and free response questions were distributed to students and described using summary statistics. RESULTS: There were 13 cohorts of enrollees, and the average number of students enrolled per cohort was 45.6, out of an average class size of 186 (24.5%, range 36-60). One hundred ninety-eight (64.2%) students reported that the course considerably changed or greatly expanded knowledge. Three hundred two (89.1%) students felt it met a majority of or exceeded expectations. Two hundred eighty-seven (80.2%) responses indicated interest in taking the course again or recommending it to others. One hundred six responses (27.1%) indicated preference for CBL over traditional lectures, and 177 (45.3%) were interested to see CBL integrated into the curriculum. CONCLUSIONS: Overall, this CBL elective course was well-received and perceived as effective for better learning class material by students. Additionally, students were receptive to case-based learning and integrating this style of learning into a preclinical curriculum without entirely replacing didactic-based learning. These findings may encourage more medical schools to explore incorporating CBL in the curriculum.

Tetrasomy 13q mosaicism associated with phylloid hypomelanosis and precocious puberty.

Various forms of pigmentary dysplasias have been known to be associated with chromosomal mosaicism. One of these disorders, known as phylloid hypomelanosis, has been found to be predominantly associated with abnormalities in chromosome 13. Most of the reported literature involves mosaic trisomy 13 with clinical evidence of abnormal pigmentation in the form of leaf-like or oblong achromic macules following Blaschko's lines. Here, we report on an 8-year-old girl with phylloid hypomelanosis and precocious puberty who was found to have mosaicism for tetrasomy 13q in the form of inverted dup(13)(q21) on her skin fibroblasts as well as peripheral blood karyotype. A higher resolution (244K) chromosomal microarray was done on DNA from skin fibroblasts confirming the breakpoint and gain of distal 13q, which made her tetrasomic for 13q21-qter. This is the first-ever reported association of tetrasomy 13q with phylloid hypomelanosis and precocious puberty. Our report further emphasizes the need to exclude any type of abnormalities of chromosome 13 in patients with phylloid hypopigmentation.

Needs assessment in genetic testing education: A survey of parents of children with autism spectrum disorder in the united states.

Understanding parents' educational needs concerning genetic testing for their children with autism spectrum disorder (ASD) is important in developing tailored, evidence-based health education materials for clinical use. Since research is lacking in this area, to bridge the gap, we examined genetic testing education needs using a nationwide sample of parents of biological children with ASD in the United States. Prospective participants were recruited from the interactive autism network, and 552 parents of biological children with ASD completed the online survey. Most participants (73.7%) were interested in receiving health education about genetic testing. Yet, the majority of them (64.7%) reported that they did not receive the information needed from physicians. Parents who identified as racial/ethnic minorities (P = 0.029), who had an education degree below college (P = 0.002), or displayed low/no awareness of genetic testing (P = 0.003) were more interested in receiving health education regarding genetic testing. Parents' most desired topics for health education include the accuracy of genetic testing (88.4%), cost (85.9%), relevant benefits of such testing (83.8%), testing procedure (77.8%), eligibility to undergo genetic testing for their children with ASD (62.4%), potential harms caused by genetic testing (56.1%), previous use and experience among individuals affected by ASD (50.8%), and confidentiality issues (48.0%). Furthermore, web-based education was the preferable approach (85.4%). Our findings can help develop health education programs and/or materials regarding genetic testing for parents and physicians to facilitate better physician-parent communication and assist parents in making informed medical decisions regarding genetic testing. Autism Res 2019, 12: 1162-1170. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study examined educational needs on genetic testing among 552 American parents of children with autism spectrum disorder (ASD). Results showed that most parents expressed interests in receiving health education regarding genetic testing (73.7%) and favored online education resources (85.4%). Preferred topics included accuracy, cost, and testing benefits. Our findings can help develop genetic testing related health education programs and materials for parents of children with ASD.

Genetic Testing Experiences Among Parents of Children with Autism Spectrum Disorder in the United States.

This study examined the experiences of Autism Spectrum Disorder (ASD) genetic testing among parents of children with ASD. A nationwide sample of 552 parents of children with ASD completed an online survey. Nearly one-quarter (22.5%) of the parents reported that their affected children had undergone ASD genetic testing. The testing utilization was associated with awareness of ASD genetic testing and whether information was received from healthcare providers. Among parents whose children with ASD were tested, 37.6% had negative experiences, which mainly due to lack of perceived testing benefits to their affected children and unpleasant testing experiences with healthcare providers. To provide better healthcare services, it is critical to ensure parents understand the purposes, benefits, and results of ASD genetic testing.