Heavy ion beam probe for Wendelstein 7-X measurement capabilities as projected through its design.

A heavy ion beam probe (HIBP) diagnostic is being developed for studies of plasma equilibrium and turbulence in the optimized Wendelstein 7-X (W7-X) stellarator. Operation of W7-X has experimentally demonstrated that its optimized magnetic field results in improved neoclassical particle confinement and, as a result, turbulence is the predominant cause of energy transport. The HIBP will have the unique ability to provide experimental data needed to complement models of both neoclassical and turbulent transport. It will acquire direct measurements in the W7-X plasma interior of the electric potential (needed for understanding ambipolar particle flux) and fluctuations of electron density and potential (needed for understanding turbulence). The HIBP for W7-X will inject singly charged ion beams with energies of up to 2 MeV and is designed to access the upper cross section of the W7-X plasma. We use trajectory simulations to illustrate the plasma coverage that the diagnostic can achieve in the reference magnetic configurations of W7-X. We calculate beam signal levels, discuss anticipated measurement sensitivity of broadband fluctuations of electron density and plasma potential, and show how they depend on plasma density. We also discuss the diagnostic sensitivity to equilibrium plasma potential.

Expanding Genetic Counselor Roles: A Model for Global Research Development.

PURPOSE: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs' evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. METHODS: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children's Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the "My Bibliography" tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. RESULTS: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. CONCLUSIONS: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important.

Computer-vision analysis of craniofacial dysmorphology in 22q11.2 deletion syndrome and psychosis spectrum disorders.

BACKGROUND: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders. METHODS: Here, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics-a semi-automated machine learning technique that localizes and measures facial features. RESULTS: F2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements. CONCLUSIONS: The extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development.

Risk of meningomyelocele mediated by the common 22q11.2 deletion.

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.

Remote assessment of the Penn computerised neurocognitive battery in individuals with 22q11.2 deletion syndrome.

BACKGROUND: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in-person assessment can be unavailable or burdensome. The current study compares in-person and remote assessments of the Penn computerised neurocognitive battery (CNB). METHODS: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in-person at a laboratory (n = 222) or remotely (n = 162). RESULTS: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. CONCLUSIONS: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains.

Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age.

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.

Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA.

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co-occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA-a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co-occur in individuals with Turner syndrome.

A case-control study of bleeding risk in children with 22q11.2 deletion syndrome undergoing cardiac surgery.

Previous research suggests that individuals with 22q11.2 deletion syndrome (DS) have an increased risk of bleeding following cardiac surgery. However, current guidelines for management of patients with 22q11.2DS do not provide specific recommendations for perioperative management. This study sought to identify specific risk factors for bleeding in this patient population. Examine the factors determining bleeding and transfusion requirements in patients with 22q11.2DS undergoing cardiac surgery. This was a single center review of patients who underwent cardiac surgery at the Children's Hospital of Philadelphia from 2000 to 2016. Data was extracted from the medical record. Frequency of bleeding events, laboratory values, and transfusion requirements were compared. We included 226 patients with 22q11.2DS and 506 controls. Bleeding events were identified in 13 patients with 22q11.2DS (5.8%) and 27 controls (5.3%). Platelet counts were lower among patients with 22q11.2DS than in control patients, but not statistically different comparing bleeding to not bleeding. Patients with 22q11.2DS received more transfusions (regardless of bleeding status). However, multivariate analysis showed only procedure type was associated with increased risk of bleeding (p = .012). The overall risk of bleeding when undergoing cardiac surgery is not different in patients with 22q11.2DS compared to non-deleted patients. Though platelet counts were lower in patients with 22q11.2DS, only procedure type was significantly associated with an increased risk of bleeding.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

Psychosis spectrum features, neurocognition and functioning in a longitudinal study of youth with 22q11.2 deletion syndrome.

BACKGROUND: Neuropsychiatric disorders are common in 22q11.2 Deletion Syndrome (22q11DS) with about 25% of affected individuals developing schizophrenia spectrum disorders by young adulthood. Longitudinal evaluation of psychosis spectrum features and neurocognition can establish developmental trajectories and impact on functional outcome. METHODS: 157 youth with 22q11DS were assessed longitudinally for psychopathology focusing on psychosis spectrum symptoms, neurocognitive performance and global functioning. We contrasted the pattern of positive and negative psychosis spectrum symptoms and neurocognitive performance differentiating those with more prominent Psychosis Spectrum symptoms (PS+) to those without prominent psychosis symptoms (PS-). RESULTS: We identified differences in the trajectories of psychosis symptoms and neurocognitive performance between the groups. The PS+ group showed age associated increase in symptom severity, especially negative symptoms and general nonspecific symptoms. Correspondingly, their level of functioning was worse and deteriorated more steeply than the PS- group. Neurocognitive performance was generally comparable in PS+ and PS- groups and demonstrated a similar age-related trajectory. However, worsening executive functioning distinguished the PS+ group from PS- counterparts. Notably, of the three executive function measures examined, only working memory showed a significant difference between the groups in rate of change. Finally, structural equation modeling showed that neurocognitive decline drove the clinical change. CONCLUSIONS: Youth with 22q11DS and more prominent psychosis features show worsening of symptoms and functional decline driven by neurocognitive decline, most related to executive functions and specifically working memory. The results underscore the importance of working memory in the developmental progression of psychosis.

Coexisting Conditions Modifying Phenotypes of Patients with 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome.

Language Profiles of School-Aged Children with 22q11.2 Copy Number Variants.

Although it is known that copy number variants (CNVs) on chromosome 22, such as 22q11.2 deletion (22q11.2DS) and 22q11.2 duplication (22q11.2Dup) syndromes, are associated with higher risk for neurodevelopmental issues, few studies have examined the language skills across 22q11.2Dup nor compared them with the 22q11.2DS. The current study aims to characterize language abilities in school-aged children with 22q11.2Dup (n = 29), compared to age-matched children with 22q11.2DS (n = 29). Standardized language tests were administered, assessing receptive and expressive language skills across different language domains. Results indicate that children with 22q11.2Dup demonstrate significantly more language problems compared to the general population. Mean language skills were not significantly different among children with 22q11.2 CNVs in this cohort. While children with 22q11.2DS demonstrated language difficulties starting at the word level, the most common language problems in children with 22q11.2Dup started at the sentence level. Importantly, both expressive and receptive language as well as lexico-semantic and morphosyntactic domains were impaired in children with 22q11.2 CNVs. Early identification, therapeutic intervention, and follow-up of language impairments in children with 22q11.2Dup are recommended to support language development and to reduce longitudinal impact of language and communicative deficits.

Immunologic, Molecular, and Clinical Profile of Patients with Chromosome 22q11.2 Duplications.

PURPOSE: Duplication of chromosome 22q11.2 due to meiotic non-allelic homologous recombination results in a distinct syndrome, chromosome 22q11.2 duplication syndrome that has some overlapping phenotypic features with the corresponding 22q11.2 deletion syndrome. Literature on immunologic aspects of the duplication syndrome is limited. We conducted a retrospective study of 216 patients with this syndrome to better define the key features of the duplication syndrome. METHODS: Single-center retrospective record review was performed. Data regarding demographics, clinical details, and immunological tests were compiled, extracted into a predetermined data collection form, and analyzed. RESULTS: This cohort comprised 113 (52.3%) males and 103 (47.7%) females. The majority (54.6%) of mapped duplications were between low copy repeat regions A-D (LCR22A to -D). Though T cell subsets were relatively preserved, switched memory B cells, immunoglobulins, and specific antibodies were each found to be decreased in a subset of the cohort. One-fifth (17/79, 21.5%) of patients had at least 2 low immunoglobulin values, and panhypogammaglobulinemia was found in 11.7% (9/79) cases. Four children were on regular immunoglobulin replacement therapy. Asthma and eczema were the predominant atopic symptoms in our cohort. CONCLUSION: Significant immunodeficiencies were observed in our cohort, particularly in B cells and antibodies. Our study expands the current clinical understanding and emphasizes the need of immunological studies and multidisciplinary approaches for these patients.

Gathering the Stakeholder's Perspective: Experiences and Opportunities in Rare Genetic Disease Research.

BACKGROUND: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders' (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation. METHODS: Modified validated surveys were used to assess stakeholders´ views across three domains: (1) Research Study Enrollment, Retainment, Withdrawal, and Future Participation; (2) Overall Research Experience, Burden, and Preparedness; (3) Research Priorities and Obstacles. Top box score analyses were performed. RESULTS: A total of 704 stakeholders´ responded from 29 countries representing 55 CNVs. The top reasons for initial participation in the research included reasons related to education and altruism. The top reasons for leaving a research study included treatment risks and side effects. The importance of sharing research findings and laboratory results with stakeholders was underscored by participants. Most stakeholders reported positive research experiences. CONCLUSIONS: This study provides important insight into how individuals and families affected with a rare CNV feel toward research participation and their overall experience in rare disease research. There are clear targets for areas of improvement for study teams, although many stakeholders reported positive research experiences. Key findings from this international survey may help advance collaborative research and improve the experience of participants, investigators, and other stakeholders moving forward.

Platelet findings in 22q11.2 deletion syndrome correlate with disease manifestations but do not correlate with GPIb surface expression.

Prior studies have demonstrated that patients with chromosome 22q11.2 deletion syndrome (22q11.2DS) have lower platelet counts (PC) compared to non-deleted populations. They also have an increased mean platelet volume. The mechanism for this has been postulated to be haploinsufficiency of the GPIBB gene. We examined platelet parameters, deletion size and factors known to influence counts, including status of thyroid hormone and congenital heart disease (CHD), in a population of 825 patients with 22q11.2DS. We also measured surface expression of GPIB-IX complex by flow cytometry. The major determinant of PC was deletion status of GP1BB, regardless of surface expression or other factors. Patients with nested distal chromosome 22q11.2 deletions (those with GP1BB present) had higher PCs than those with proximal deletions where GP1BB is deleted. Patients with 22q11.2DS also demonstrated an accelerated PC decrease with age, occurring in childhood. These data demonstrate that genes within the proximal deletion segment drive PC differences in 22q11.2DS and suggest that PC reference ranges may need to be adjusted for age and deletion size in 22q11.2DS populations. Bleeding did not correlate with either platelet count or GPIb expression. Further studies into drivers of expression of GPIb and associations with severe thrombocytopenia and immune thrombocytopenia are needed to inform clinical care.

A Comprehensive Analysis of Cerebellar Volumes in the 22q11.2 Deletion Syndrome.

BACKGROUND: The presence of a 22q11.2 microdeletion (22q11.2 deletion syndrome [22q11DS]) ranks among the greatest known genetic risk factors for the development of psychotic disorders. There is emerging evidence that the cerebellum is important in the pathophysiology of psychosis. However, there is currently limited information on cerebellar neuroanatomy in 22q11DS specifically. METHODS: High-resolution 3T magnetic resonance imaging was acquired in 79 individuals with 22q11DS and 70 typically developing control subjects (N = 149). Lobar and lobule-level cerebellar volumes were estimated using validated automated segmentation algorithms, and subsequently group differences were compared. Hierarchical clustering, principal component analysis, and graph theoretical models were used to explore intercerebellar relationships. Cerebrocerebellar structural connectivity with cortical thickness was examined via linear regression models. RESULTS: Individuals with 22q11DS had, on average, 17.3% smaller total cerebellar volumes relative to typically developing subjects (p < .0001). The lobules of the superior posterior cerebellum (e.g., VII and VIII) were particularly affected in 22q11DS. However, all cerebellar lobules were significantly smaller, even after adjusting for total brain volumes (all cerebellar lobules p < .0002). The superior posterior lobule was disproportionately associated with cortical thickness in the frontal lobes and cingulate cortex, brain regions known be affected in 22q11DS. Exploratory analyses suggested that the superior posterior lobule, particularly Crus I, may be associated with psychotic symptoms in 22q11DS. CONCLUSIONS: The cerebellum is a critical but understudied component of the 22q11DS neuroendophenotype.

Conceptual design of a heavy ion beam probe diagnostic for the Wendelstein 7-X Stellarator.

This article describes the current state of the design of the heavy ion beam probe (HIBP) for Wendelstein 7-X (W7-X). It will be the first HIBP diagnostic on an optimized stellarator and is designed to study electric fields and ion scale turbulence in all W7-X reference magnetic configurations. The use of an existing 2 MV accelerator, located outside of the torus hall, results in the need for a circuitous primary beamline. This increases the complexity of the ion optics design to deliver a focused beam to the plasma. To access most of the magnetic configuration space of W7-X, the secondary beamline and an energy analyzer are designed to pivot, thereby redirecting a wider range of secondary beam trajectories. Signal level estimates indicate that the equilibrium potential can be measured at all radii and that the radial coverage for potential and density fluctuations measurements depends on the plasma density.

Influence of Parent-of-Origin on Intellectual Outcomes in the Chromosome 22q11.2 Deletion Syndrome.

Learning and intellectual disabilities are hallmark features of 22q11.2 deletion syndrome. Data are limited, however, regarding influences on full-scale IQ (FSIQ). Here, we investigated possible 22q11.2 deletion parent-of-origin effects. In 535 individuals, we compared FSIQ (≥50), 481 with de novo and 54 with inherited 22q11.2 deletions. In the subsets with data available, we examined parent-of-origin effects on FSIQ. We used linear regression models to account for covariates. Median FSIQ was significantly higher in de novo vs. inherited deletions (77; range 50−116 vs. 67; range 50−96, p < 0.0001). Results remained significant using a regression model accounting for age at IQ testing, sex and cohort site. No significant parent-of-origin differences in FSIQ were observed for de novo deletions (n = 81, 63.0% maternal; p = 0.6882). However, median FSIQ was significantly lower in maternally than in paternally inherited familial deletions (65, range 50−86 vs. 71.5, range 58−96, respectively, p = 0.0350), with the regression model indicating an ~8 point decrement in FSIQ for this variable (p = 0.0061). FSIQ is higher on average in de novo than in inherited 22q11.2 deletions, regardless of parental origin. However, parent-of-origin appears relevant in inherited deletions. The results have potential clinical implications with further research needed to delineate possible actionable mechanisms.

A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome.

The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, it is not well represented in the human reference genome. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo, hemizygous deletion approximately 3 Mbp in size occurring by non-allelic homologous recombination (NAHR) mediated by the LCR22s. The ability to fully delineate an individual's 22q11.2 regional structure will likely be important for studies designed to assess an unaffected individual's risk for generating rearrangements in germ cells, potentially leading to offspring with 22q11.2DS. Towards understanding these risk factors, optical mapping has been previously employed to successfully elucidate the structure and variation of LCR22s across 30 families affected by 22q11.2DS. The father in one of these families carries a t(11;22)(q23;q11) translocation. Surprisingly, it was determined that he is the parent-of-deletion-origin. NAHR, which occurred between his der(22) and intact chromosome 22, led to a 22q11.2 deletion in his affected child. The unaffected sibling of the proband with 22q11.2DS inherited the father's normal chromosome 22, which did not aberrantly recombine. This unexpected observation definitively shows that haplotypes that engage in NAHR can also be inherited intact. This study is the first to identify all structures involving a rearranged chromosome 22 that also participates in NAHR leading to a 22q11.2 deletion.

The experience of one pediatric geneticist with telemedicine-based clinical diagnosis.

Telemedicine has long been considered as an attractive alternative methodology in clinical genetics to improve patient access and convenience. Given the importance of the dysmorphology physical examination and anthropometric measurement in clinical genetics, many have wondered if lost information would hamper diagnosis. We previously addressed this question by analyzing thousands of diagnostic encounters in a single practice involving multiple practitioners and found no evidence for a difference in new molecular diagnosis rates. However, our previous study design resulted in variability in providers between in-person and telemedicine evaluation groups. To address this in our present study, we expanded our analysis to 1104 new patient evaluations seen by one highly experienced clinical geneticist across two 10-month periods before and after the start of the COVID-19 pandemic. Comparing patients seen in-person to those seen by telemedicine, we found significant differences in race and ethnicity, preferred language, and home zip code median income. The clinical geneticist intended to send more genetic testing for those patients seen by telemedicine, but due to issues with test authorization and sample collection, there was no difference in ultimate completion rate between groups. We found no significant difference in new molecular diagnosis rate. Overall, we find telemedicine to be an acceptable alternative to in-person evaluation for routine pediatric clinical genetics care.