A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome.

The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation.

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

The evolution of genetic counseling graduate education in New York City during the COVID-19 pandemic: In the eye of the storm.

The COVID-19 pandemic has ravaged the globe in the past year, demanding shifts in all aspects of life including health profession education. The New York City area was the first major United States epicenter and is home to four genetic counseling graduate programs. We set out to explore the multifaceted programmatic changes required from the four institutions in an early pandemic epicenter, providing the longest time horizon available for assessing the implications of this restructuring on graduate education in the profession. Using practitioner-based enquiry, our iterative reflections identified three phases of COVID-19 response within our programs from March through December 2020. The spring months were marked by significant upheaval and reactivity, with a focus on stabilizing our programs in an unstable environment that included a significant medical response required in our area. By summer, we were reinvesting time and energy into our programs and prioritizing best practices in online learning. Relative predictability returned in the fall with noticeable improvements in flexibility and proactive problem-solving within our new environment. We have begun to identify changes in both curricula and operations that are likely to become more permanent. Telehealth fieldwork, remote supervision, simulated cases with standardized clients, and virtual recruitment and admission events are some key examples. We explored early outcome measures, such as enrollment, retention, course evaluations, and student academic and fieldwork progress, all indicating little change from prior to the pandemic to date. Overall, we found our programs, and genetic counseling graduate education more broadly, to be much more resilient and flexible than we would ever have realized. The COVID-19 pandemic has awakened in us a desire to move ahead with reduced barriers to educational innovation.

De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.

Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

PURPOSE: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. METHODS: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. RESULTS: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. CONCLUSIONS: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Correction: Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

The original version of this Article contained an error in the undergraduate degree awarded to the author Ian Halim, which was incorrectly given as BS. This has now been corrected to BA in both the PDF and HTML versions of the Article.

The Lived Experience of MRKH: Sharing Health Information with Peers.

STUDY OBJECTIVE: To examine the process and emotional effect of disclosing a personal diagnosis of Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) to peers during adolescence and young adulthood. DESIGN AND SETTING: Qualitative study using semistructured telephone interviews. PARTICIPANTS: Nine women diagnosed with MRKH, aged 21-31 years, recruited via patient support groups. INTERVENTIONS AND MAIN OUTCOME MEASURES: Motivators and barriers to self-disclosure of a diagnosis of MRKH to peers and partners. RESULTS: Motivators to tell peers about a diagnosis included significant trust in the relationship (whether platonic or romantic), needing to unload the experienced burden of diagnosis, and a sense of responsibility to be forthcoming if a long-term romantic future was desired. The most common barrier to telling others was fear of rejection or being labeled a "freak." Although most participants did not receive guidance from a health care provider regarding approaches to sharing diagnostic information with others, almost all participants reported wishing they had received such counseling. CONCLUSION: A diagnosis of MRKH elicits recurring anxieties about disclosure and the effect on relationships that are inadequately addressed by health care providers. Guidance and support on disclosure to friends and romantic partners should be provided whenever possible.

Adverse events in cancer genetic testing: the third case series.

After repeated media attention in 2013 due to the Angelina Jolie disclosure and the Supreme Court decision to ban gene patents, the demand for cancer genetic counseling and testing services has never been greater. Debate has arisen regarding who should provide such services and the quality of genetics services being offered. In this ongoing case series, we document 35 new cases from 7 states (California, Connecticut, Florida, Georgia, Missouri, Pennsylvania, and Utah) and the District of Columbia of adverse outcomes in cancer genetic testing when performed without the involvement of a certified genetic counselor. We identified 3 major themes of errors: wrong genetic tests ordered, genetic test results misinterpreted, and inadequate genetic counseling. Patient morbidity and mortality were an issue in several of these cases. The complexity of cancer genetic testing and counseling has grown exponentially with the advent of multigene panels that include rare genes and the potential for more variants of uncertain significance. We conclude that genetic counseling and testing should be offered by certified genetics providers to minimize the risks, maximize the benefits, and utilize health care dollars most efficiently.