Alzheimer\'s disease (AD) is the most prevalent and devastating neurodegenerative disease occurred in the elderly. One of the pathogenic hallmarks is senile plaques composed of amyloid-β (Aβ) fibrils. Single mutations resided in Aβ were found in familial AD (FAD) patients that have early onset of the disease. The molecular details and properties of each FAD Aβ variants are still elusive. Here, we employed collective spectroscopic techniques to examine the properties of various Aβ40 fibrils. We generated fibrils of wild type (WT) and three FAD mutants on residue E22 including E22G, E22K, and E22Q. We monitored fibril formation by thioflavin T (ThT) assay, examined secondary structure by Fourier transform infrared and far-UV circular dichroism spectroscopy, imaged fibril morphology by transmission electron microscopy, and evaluated ThT-binding kinetics. In the thermal experiments, we found E22K fibrils resisted to high temperature and retained significant β-sheet content than the others. E22K fibril seeds after high-temperature treatment still possess the seeding property, whereas WT fibril seeds are disturbed after the treatment. Therefore, in this study we demonstrated the mutation at E22K increases the thermal stability and seeding function of amyloid fibrils.

Variants in CAMK2-associated genes have recently been implicated in neurodevelopmental disorders and intellectual disability. The clinical manifestations reported in patients with mutations in these genes include intellectual disability (ranging from mild to severe), global developmental delay, seizures, delayed speech, behavioral abnormalities, hypotonia, episodic ataxia, progressive cerebellar atrophy, visual impairments, and gastrointestinal issues. Phenotypic heterogeneity has been postulated. We present a child with neurodevelopmental disorder caused by a pathogenic CAMK2B variant inherited from a healthy mother. A more mildly affected sib was determined to have the same variant. Monoallelic mutations in CAMK2B in patients have previously only been reported as de novo mutations. This report adds to the clinical phenotypic spectrum of the disease and demonstrates intrafamilial variability of expression of a CAMK2B mutation.

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Transgender individuals comprise a growing patient population in genetic counseling practice. The identification of a pathogenic variant in a cancer susceptibility gene may impact a transgender person\'s decisions regarding hormonal and/or surgical transition. Limited scientific literature exists on specific genetic counseling needs and medical management strategies for transgender individuals. In addition, most genetic counselors have had limited experience and training in conducting genetic counseling sessions with transgender patients. In this report, we describe three cases of transgender individuals who underwent genetic counseling and testing in our clinic. All were at ≥50% risk to carry a familial BRCA1 pathogenic variant. Case 1 is a 20-year-old transgender female initiating hormonal agents. Case 2 is a 19-year-old transgender male considering surgical decisions who has a BRCA1 pathogenic variant on both sides of the family. Case 3 is a 24-year-old transgender male who had previously undergone gender-affirming mastectomy (top surgery) and is taking androgen therapy. Unique aspects of genetic testing, psychosocial counseling, and medical management of transgender individuals have arisen in the course of their care. In this report, we discuss our experiences and practices of case preparation, case management, appropriate genetic testing, and medical management such as screening, surgical decisions, and coordination of care. There is a need for more research in this area and more transgender-specific training for genetic counselors.

Family health history (FHH) information is well established as a basis for assessing a patient\'s personal disease risk, but is underutilized for diagnosis and making medical recommendations. Epidemiological and genetic information have heightened the value of FHH to an individual\'s health. This has motivated the development of new FHH collection tools and strategies for family members, but will require greater awareness and knowledge by both patients and practitioners. FHH will be increasingly important as genomic data become a mainstay of medical diagnostics, since in many cases, a medically important FHH results from lineage-specific genetic variants. The impact of complementary FHH and genomic information will drive the pursuit of personalized and precise targeting of treatments and interventions aimed at maintaining patient health.

With the increasing use of clinical genomics to guide cancer treatment and management, there is a rise in the identification of germline cancer predisposition syndromes and a critical need for patients with germline findings to be referred for surveillance and care. The University of Chicago Hematopoietic Malignancies Cancer Risk Team has established a unique approach to patient care for individuals with hereditary hematologic malignancies through close communication and coordination between our pediatric and adult programs. Dedicated program members, including physicians, nurses, genetic counselors, and clinical research assistants, screen individuals for cancer predisposition at initial diagnosis through survivorship, in addition to testing individuals with an established family history of a cancer predisposition syndrome. Sample procurement, such as a skin biopsy at the time of bone marrow aspirate/biopsy in individuals with a positive screen, has facilitated timely identification of clinical germline findings or has served as a pipeline for translational research. Our integrated translational research program has led to the identification of novel syndromes in collaboration with other investigators, which have been incorporated iteratively into our clinical pipeline. Individuals are referred for clinical assessment based on personal and family history, identification of variants in susceptibility genes via molecular tumor testing, and during evaluation for matched related allogeneic stem cell transplantation. Upon referral, genetic counseling incorporates education with mindfulness of the psychosocial issues surrounding germline testing at different ages. The training and role of genetic counselors continues to grow, with the discovery of new predisposition syndromes, in the age of improved molecular diagnostics and new models for service delivery, such as telemedicine. With the identification of new syndromes that may predispose individuals to hematologic malignancies, surveillance guidelines will continue to evolve and may differ between children and adults. Thus, utilizing a collaborative approach between the pediatric and adult oncology programs facilitates care within families and optimizes the diagnosis and care of individuals with cancer predisposition syndromes.

The post-mortem brains of individuals with Parkinson\'s disease (PD) and other synucleinopathy disorders are characterized by the presence of aggregated forms of the presynaptic protein α-synuclein (aSyn). Understanding the molecular mechanism of aSyn aggregation is essential for the development of neuroprotective strategies to treat these diseases. In this study, we examined how interactions between aSyn and phospholipid vesicles influence the protein\'s aggregation and toxicity to dopaminergic neurons. Two-dimensional NMR data revealed that two familial aSyn mutants, A30P and G51D, populated an exposed, membrane-bound conformer in which the central hydrophobic region was dissociated from the bilayer to a greater extent than in the case of wild-type aSyn. A30P and G51D had a greater propensity to undergo membrane-induced aggregation and elicited greater toxicity to primary dopaminergic neurons compared to the wild-type protein. In contrast, the non-familial aSyn mutant A29E exhibited a weak propensity to aggregate in the presence of phospholipid vesicles or to elicit neurotoxicity, despite adopting a relatively exposed membrane-bound conformation. Our findings suggest that the aggregation of exposed, membrane-bound aSyn conformers plays a key role in the protein\'s neurotoxicity in PD and other synucleinopathy disorders.

Cantu syndrome is an autosomal dominant overgrowth syndrome associated with facial dysmorphism, congenital hypertrichosis, and cardiomegaly. Some affected individuals show bone undermodeling of variable severity. Recent investigations revealed that the disorder is caused by a mutation in ABCC9, encoding a regulatory SUR2 subunit of an ATP-sensitive potassium channel mainly expressed in cardiac and skeletal muscle as well as vascular smooth muscle. We report here on a Japanese family with this syndrome. An affected boy and his father had a novel missense mutation in ABCC9. Each patient had a coarse face and hypertrichosis. However, cardiomegaly was seen only in the boy, and macrosomia only in the father. Skeletal changes were not evident in either patient. Craniosynostosis in the boy and the development of aortic aneurysm in the father are previously undescribed associations with Cantu syndrome.