Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations.

BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.

Workforce survey of PAs' genetic-genomic knowledge, attitudes, and application in practice.

OBJECTIVE: This study surveyed practicing physician associates/assistants (PAs) about their genetics-genomics knowledge, attitudes, and application in practice. METHODS: A 25-question electronic survey was emailed to each constituent organization of the American Academy of Physician Associates (AAPA) with a description of the study and a request to forward to their members. Additionally, a posting was displayed in the bulletin board section of the online AAPA Huddle. RESULTS: Of the 420 PAs who completed the survey, few are knowledgeable (25%) about or confident (13%) in applying a genomic approach to patient care, although most (61%) think genetics-genomics is important to delivering high-quality care. Remarkably, 97% of PAs surveyed are interested in genetics-genomics continuing medical education. CONCLUSIONS: PAs lack knowledge and confidence in integrating genetics-genomics into patient care; however, they have a positive attitude toward genetics-genomics and want to improve their knowledge and confidence through education.

Large Chromosome 2p Duplication-Associated Mechanisms and Clinical Presentations.

Chromosome 2p (chr2p) duplication, also known as trisomy 2p, is a rare chromosome abnormality associated with developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Most of the reported cases involving trisomy 2p include additional copy number variants (CNVs) in other regions of the genome and are usually small in size. Little is known about the clinical outcomes of large duplications of chr2p as the sole cytogenetic abnormality. In this study, 193 samples at the Greenwood Genetic Center (GGC) with CNVs involving chr2p were evaluated, out of which 86 had chr2p duplications. Among them, 8 patients were identified with large chr2p duplications ranging in size from 9.3 Mb to 89 Mb, and no deletions or duplications involving other chromosomes were identified in those patients. These duplications were associated with inverted duplication, tandem duplication, and duplication as the result of translocation, with no additional CNVs identified by microarray analysis. Confirmation by conventional cytogenetics was performed in 7 of the 8 patients, and the translocations were confirmed by fluorescence in situ hybridization. Interestingly, 1 patient was found to have mosaic complete trisomy 2p as the result of an unbalanced de novo (X;2) chromosomal translocation. X-inactivation was skewed toward the derivative X chromosome, yet it did not appear to extend into the chromosome 2 material. Various shared clinical manifestations were observed in the individuals in this study, including developmental delay, hemifacial hypoplasia, cleft palate, and short stature, and they also have distinct features such as hypotonia, cerebellar hypogenesis, and corpus callosum agenesis, which might result from a gene dosage effect of the duplication. In conclusion, single-event large chr2p duplications can result from different mechanisms, including inverted or tandem duplications within chromosome 2, or translocations involving chromosome 2 and other chromosomes. Partial or complete trisomy 2p is commonly associated with developmental delay, and additional clinical features may be related to gene dosage effects.

The State of Genetics and Genomics Education in US Physician Assistant Programs.

PURPOSE: This study aimed to assess the current landscape of genetics-genomics education in physician assistant (PA) student training. METHODS: A 25-question electronic survey was emailed to program directors of the 273 accredited PA programs. Questions represented PA program demographics and 4 domains: curricular characteristics and perceived adequacy; content; curricular approaches and instructional methods; and intent, barriers, and perceived needs for an optimal curriculum. RESULTS: A total of 115 PA program representatives (42%) returned the survey. More than two-thirds of responding programs do not require a prerequisite genetics course for matriculation. Most programs (48%) include 1 to 10 contact hours of genetics-genomics content and use various content delivery methods and approaches. Most programs (67%) use PA program faculty to teach genetics-genomics as part of one course or many courses throughout the curriculum (85%) using didactic lectures (97%). The most significant barrier to developing an optimal curriculum is an already overloaded curriculum (71%). Physician assistant educators welcome supportive resources, such as genetic case studies (96%). CONCLUSIONS: The study findings elucidate the current state of genetics-genomics education in PA programs. Every responding program reports that genetics-genomics is integrated into their curriculum; however, no standardization exists between programs. Although medical genetics-genomics has changed and advanced rapidly since a similar survey was conducted 14 years ago, the number of contact hours is unchanged, and genetics-genomics content is less dispersed throughout PA curricula. To create genetic-competent and genomic-competent PAs, education must evolve to stay current with ongoing advancements in genomic science.

The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Genetics and Genomics Education for Physician Assistant Students: A Review of the Literature.

INTRODUCTION: The purpose of this study was to critically review the literature and determine what is known about genetics-genomics education for physician assistants (PAs). METHODS: A rapid review method was used to search CINAHL, MEDLINE, PubMed, and Web of Science databases. The review is presented historically to describe the development of genetics-genomics education in PA programs. RESULTS: Of 594 publications retrieved, 11 articles met inclusion criteria. Retained articles include an assessment of PA programs, genetics-genomics competencies, educational efforts developed by PA programs regarding genetics-genomics, and continuing education programs for PAs. DISCUSSION: A paucity of published literature regarding genetics-genomics education for PAs was found. The few studies retrieved describe content being taught in PA programs, the number of genetics-genomics contact hours that PA students receive, and recommendations for continuing education programs. Most of the available literature is outdated, leaving a need for more current information to inform the education of genetic- and genomic-competent PAs. Recommendations for future research include assessment of PA programs regarding genetics-genomics education; development and validation of an assessment tool to measure genetics-genomics knowledge; and utilization of the RISE2 Genomics standards to plan, implement, evaluate, and report educational interventions. These recommendations are necessary to build an evidence base regarding genomics education for PA students and practicing PAs.

Clinical and functional characterization of germline PIK3CA variants in patients with PIK3CA-related overgrowth spectrum disorders.

Mosaic variants in the PIK3CA gene, encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), produce constitutive PI3K activation, which causes PIK3CA-related overgrowth spectrum disorders. To date, fewer than 20 patients have been described with germline alterations in PIK3CA. In this study, we describe three unrelated individuals with overgrowth and germline PIK3CA variants. These variants were discovered through whole-exome sequencing and confirmed as germline by testing multiple tissue types, when available. Functional analysis using Patient 1's fibroblast cell line and two previously reported patients' cell lines showed increased phosphorylation of AKT during cellular starvation revealing constitutive activation of the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway. Alternatively, stimulation of the cells by fetal bovine serum produced a reduced response, indicating an activated status of the PI3K complex reducing the pathway response to further external stimulation. Additional studies utilizing Biolog Phenotype Microarray technology indicated reduced energy production when cells were exposed to growth factors stimulating the PI3K/AKT/mTOR pathway, confirming the trend observed in the AKT phosphorylation test after stimulation. Furthermore, treatment with inhibitors of the PI3K/AKT/mTOR pathway rescued the normal energy response in the patients' cells. Collectively, these data demonstrate that disease-causing germline PIK3CA variants have a functional consequence, similar to mosaic variants in the PI3K/AKT/mTOR pathway.

The phenotypic spectrum and genotype-phenotype correlations in 106 patients with variants in major autism gene CHD8.

CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype-phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO). We identified 29 unique nonsense, 25 frameshift, 24 missense, and 12 splice site variants. Furthermore, two unique inframe deletions, one larger deletion (exons 26-28), and one translocation were observed. Methylation analysis was performed for 13 patients, 11 of which showed the previously established episignature for IDDAM (85%) associated with CHD8 haploinsufficiency, one analysis was inconclusive, and one showing a possible gain-of-function signature instead of the expected haploinsufficiency signature was observed. Consistent with previous studies, phenotypical abnormalities affected multiple organ systems. Many neurological abnormalities, like intellectual disability (68%) and hypotonia (29%) were observed, as well as a wide variety of behavioural abnormalities (88%). Most frequently observed behavioural problems included autism spectrum disorder (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%). Furthermore, abnormalities in the digestive (53%), musculoskeletal (79%) and genitourinary systems (18%) were noted. Although no significant difference in severity was observed between males and females, individuals with a missense variant were less severely affected. Our study provides an extensive review of all phenotypic abnormalities in patients with IDDAM and provides clinical recommendations, which will be of significant value to individuals with a pathogenic variant in CHD8, their families, and clinicians as it gives a more refined insight into the clinical and molecular spectrum of IDDAM, which is essential for accurate care and counselling.

DNA methylation episignature in Gabriele-de Vries syndrome.

PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance.

Syndromic Autism Revisited: Review of the Literature and Lessons Learned.

Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, stereotyped behaviors, restricted interests, and impaired social skills. The severity of the neurobehavioral phenotype is variable and historically has been distinguished based on the presence or absence of additional symptoms, termed syndromic and nonsyndromic or idiopathic autism, respectively. However, although the advancement in genetic molecular technologies has brought an increased understanding of the pathophysiology of autism, most of this success has been in the diagnosis of syndromic disease, whereas the etiology of nonsyndromic autism remains less understood. Here we review the common and rare genetic syndromes that feature autism, specifically highlighting deletion and duplication syndromes, chromosomal anomalies, and monogenic disorders. We show that the study of syndromic autism provides insight into the phenotypic and molecular heterogeneity of neurodevelopmental disease and suggests how study of these disorders can be helpful in understanding disease mechanisms implicated in nonsyndromic autism.