Novel CHRNA3 variants identified in a patient with bladder dysfunction, dysautonomia, and gastrointestinal dysmotility.

Congenital anomalies of the kidney and urinary tract (CAKUT) are estimated to be responsible for 20%-50% of congenital anomalies and are also a leading etiology of early-onset renal disease. Primary CAKUT are caused by genetic factors that impair proper in-utero genitourinary tract development and secondary CAKUT result from the influence of environmental factors. The CHRNA3 gene, which encodes the Alpha-3 subunit of the nicotinic acetylcholine receptor, is hypothesized to be associated with Megacystis-microcolon-intestinal hyperperistalsis syndrome. More recently, pathogenic variants in CHRNA3 have been identified in individuals with CAKUT as well as individuals with panautonomic failure. Here we present a patient with neurogenic bladder, vesicoureteral reflux, mydriasis, and gastrointestinal dysmotility found to have novel compound heterozygous variants in CHRNA3. These findings support the consideration of CHRNA3 disruption in the differential for CAKUT with dysautonomia and gastrointestinal dysmotility.

Quality of care metrics for patients with inborn errors of metabolism.

Despite recent calls to action and a heavy emphasis on timeliness of care in guidelines for common inborn errors of metabolism, there is a dearth of specific measurable quality metrics for these conditions and little to no electronic decision support for their management. We have developed a novel set of process-oriented metrics based on the aforementioned guidelines that can be calculated from data already contained in most major EHRs, which we believe are responsive to the needs of the metabolism community.

Further delineation of van den Ende-Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome.

Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.

Postnatal ethanol exposure simplifies the dendritic morphology of medium spiny neurons independently of adenylyl cyclase 1 and 8 activity in mice.

BACKGROUND: Fetal exposure to alcohol can have multiple deleterious effects, including learning disorders and behavioral and executive functioning abnormalities, collectively termed fetal alcohol spectrum disorders. Neonatal mice lacking both calcium-/calmodulin-stimulated adenylyl cyclases (ACs) 1 and 8 demonstrate increased vulnerability to ethanol (EtOH)-induced neurotoxicity in the striatum compared with wild-type (WT) controls. However, the developmental impact on surviving neurons is still unclear. METHODS: WT and AC1/8 double knockout (DKO) mice were administered 1 dose of EtOH (2.5 g/kg) between postnatal days 5 to 7 (P5-7). At P30, brains were removed and processed for Golgi-Cox staining. Medium spiny neurons (MSNs) from the caudate putamen were analyzed for changes in dendritic complexity; number of branches, branch points and terminals, total and average dendritic length; spine density and soma size. RESULTS: EtOH significantly reduced the dendritic complexity and soma size in surviving MSNs regardless of genotype without affecting spine density. In the absence of EtOH, genetic deletion of AC1/8 reduced the dendritic complexity, number of branch points, spine density, and soma size of MSNs compared with WT controls. CONCLUSIONS: These data indicate that neonatal exposure to a single dose of EtOH is sufficient to cause long-term alterations in the dendritic complexity of MSNs and that this outcome is not altered by the functional status of AC1 and AC8. Therefore, although deletion of AC1/8 demonstrates a role for the ACs in normal morphologic development and EtOH-induced neurodegeneration, loss of AC1/8 activity does not exacerbate the effects of EtOH on dendritic morphology or spine density.

Justice in CRISPR/Cas9 Research and Clinical Applications.

CRISPR/Cas9 is a rapidly developing gene editing technology that will soon have many clinical applications. As with many other new technologies, somatic gene editing with CRISPR/Cas9 raises concerns about equitable access to therapies by historically disenfranchised racial and ethnic minorities. We describe justice concerns related to CRISPR/Cas9, including its potential impact on historically mistreated populations through underrepresentation of minorities in genomic databases and the potential for disparate access to somatic gene therapies when they become clinically available. We then describe ongoing work that aims to address these justice concerns. We conclude by highlighting important considerations to ensure equitable access to therapies going forward, including enhancing diversity in genomic sequencing efforts, improving education and transparency, and building partnerships with underserved and socially disenfranchised communities.

Adenylyl cylases 1 and 8 mediate select striatal-dependent behaviors and sensitivity to ethanol stimulation in the adolescent period following acute neonatal ethanol exposure.

Neonatal alcohol exposure in rodents causes dramatic neurodegenerative effects throughout the developing nervous system, particularly in the striatum, acutely after exposure. These acute neurodegenerative effects are augmented in mice lacking adenylyl cyclases 1 and 8 (AC1/8) as neonatal mice with a genetic deletion of both AC isoforms (DKO) have increased vulnerability to ethanol-induced striatal neurotoxicity compared to wild type (WT) controls. While neonatal ethanol exposure is known to negatively impact cognitive behaviors, such as executive functioning and working memory in adolescent and adult animals, the threshold of ethanol exposure required to impinge upon developmental behaviors in mice has not been extensively examined. Therefore, the purpose of this study was to determine the behavioral effects of neonatal ethanol exposure using various striatal-dependent developmental benchmarks and to assess the impact of AC1/8 deletion on this developmental progression. WT and DKO mice were treated with 2.5 g/kg ethanol or saline on postnatal day (P)6 and later subjected to the wire suspension, negative geotaxis, postural reflex, grid hang, tail suspension and accelerating rotarod tests at various time points. At P30, mice were evaluated for their hypnotic responses to 4.0 g/kg ethanol by using the loss of righting reflex assay and ethanol-induced stimulation of locomotor activity after 2.0 g/kg ethanol. Ethanol exposure significantly impaired DKO performance in the negative geotaxis test while genetic deletion of AC1/8 alone increased grid hang time and decreased immobility time in the tail suspension test with a concomitant increase in hindlimb clasping behavior. Locomotor stimulation was significantly increased in animals that received ethanol as neonates, peaking significantly in ethanol-treated DKO mice compared to ethanol-treated WT controls, while sedation duration following high-dose ethanol challenge was unaffected. These data indicate that the maturational parameters examined in the current study may not be sensitive enough to detect effects of a single ethanol exposure during the brain growth spurt period. Genetic deletion of AC1/8 reveals a role for these cylases in attenuating ethanol-induced behavioral effects in the neonatally-exposed adolescent.