Prenatal Phenotype of Alkuraya-Kucinskas Syndrome: A Novel Case and Systematic Literature Review.

Alkuraya-Kucinskas syndrome (AKS) is an autosomal recessive multisystem disorder resulting from mutations in the BLTP1 gene, formerly known as KIAA1109. Primary manifestations include brain malformations, arthrogryposis, and clubfeet. Cardiac, renal, and ophthalmologic abnormalities may also be observed, while nonimmune hydrops is rare. We present a case of two novel BLTP1 canonical splice-site variants in a fetus with multiple congenital anomalies, including hydrops, a kinked brainstem, and joint contractures. A systematic literature review was conducted to describe the prenatal phenotype of AKS, which was inspired by our case. Our systematic literature review of the prenatal phenotype in 19 cases, including our additional case, demonstrated joint contractures in 90% (18/20), ventriculomegaly in 60% (12/20), brainstem dysgenesis in 50% (10/20), cerebellar hypoplasia in 50% (10/20), parenchymal thinning with lissencephalic aspect in 60% (12/20), and facial dysmorphism in 70% (14/20) of reported AKS cases. In addition to our case, hydrops was reported in two other families. AKS should be considered in fetal presentations with characteristic features, especially brainstem kinking and joint contractures. Exome sequencing, including coverage of canonical intronic splice-site variants, can clarify the diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT03911531.

Connecting the dots: Carrier screening and the Genetic Information Nondiscrimination Act in the United States.

OBJECTIVE: To highlight the possibility of genetic discrimination in the United States with respect to carrier screening under limitations of the Genetic Information Nondiscrimination Act (GINA) and to encourage providers to educate patients about this possibility during pretest counseling. METHODS: Review of current professional guidelines and practice resources regarding the necessary components of pretest counseling for carrier screening in the context of GINA's limitations and the potential impact of carrier screening results on life, long-term care and disability insurance. RESULTS: Current practice resources advise that patients in the United States should be informed that their employer or health insurance company generally cannot use their genetic information during the underwriting process. However, these resources do not elaborate on GINA's limitations or explain why there may be adverse consequences to patients regarding these limitations. Studies have demonstrated significant gaps in provider knowledge of GINA, especially for those without formal genetic training. CONCLUSION: Enhanced education and provision of GINA educational resources for providers and patients will help ensure that patients have the opportunity to prioritize their insurance needs prior to undergoing carrier screening.

Fetal pharmacogenomics: A promising addition to complex neonatal care.

OBJECTIVE: Pharmacogenomics (PGx) characterizes genetic variation in medication response. 85-95% of the population carries actionable PGx variants. No prior studies have demonstrated the application and feasibility of PGx in prenatal testing. We assessed parental desire for PGx findings from fetal exome sequencing (ES), evaluated PGx variants, and reviewed implications for medically complex neonates. METHODS: A prospective cohort undergoing ES for nonimmune hydrops fetalis were offered PGx results as a secondary finding. Seven pharmacogenes with Level A evidence, defined by Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, were tested and reported to patients and referring providers. Medication administration records were reviewed. RESULTS: Most participants (36/40, 90%) desired PGx testing. 32/36 (89%) had potentially actionable PGx diplotypes in six genes: CYP2C19 (20/36, 56%), CYP2C9 (16/36, 44%), CYP2D6 (10/36, 28%), SLCO1B1 (13/36, 36%), TPMT (6/36, 17%), UGT1A1 (4/36, 11%). 12/13 (92%) live births had PGx variants. Neonatal chart review indicated that three medications with CPIC Level A evidence were administered to four neonates. None of the patients received a medication that aligned with an actionable pharmacogenetic variant as defined by Level A CPIC guidance. CONCLUSION: Most participants opted to receive PGx results. 89% had actionable variants, consistent with population estimates. Obtaining fetal PGx data is feasible for medically complex neonates. Further studies are needed for broad clinical application of PGx in fetuses with major congenital abnormalities. Our study demonstrates the potential of PGx as useful preemptive clinical information that could be obtained at the time of fetal exome sequencing for other indications. CLINICALTRIALS: gov Registration: NCT03911531.

High diagnosis rate for nonimmune hydrops fetalis with prenatal clinical exome from the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) Study.

PURPOSE: Nonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic etiologies. We explored incremental diagnostic yield of testing with prenatal exome sequencing (ES) for NIHF following a negative standard NIHF workup. METHODS: Participants enrolled into the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study met a strict definition of NIHF and had negative standard-of-care workup. Clinical trio ES from fetal samples and parental blood was performed at a CLIA-certified reference laboratory with clinical reports returned by geneticists and genetic counselors. Negative exomes were reanalyzed with information from subsequent ultrasounds and records. RESULTS: Twenty-two fetal exomes reported 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases comprised seven de novodominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, and RRAS2), three musculoskeletal disorders (RYR1, AMER1, and BICD2), two metabolic disorders (sialidosis and multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1). CONCLUSION: The etiology of NIHF predicts postnatal prognosis and recurrence risk in future pregnancies. ES provides high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup.

Maternal outcomes of a cohort of pregnancies affected by non-immune hydrops fetalis.

OBJECTIVE: To describe the maternal outcomes of a prospective cohort of non-immune hydrops fetalis (NIHF) pregnancies with negative standard-of-care evaluations. METHODS: This study was a secondary analysis of a prospective cohort study of NIHF pregnancies with negative work-ups (infection, alloimmune anemia, fetomaternal hemorrhage, and chromosomal disorders). Outcomes were obstetric complications, including pre-eclampsia, mirror syndrome, preterm birth, polyhydramnios, postpartum hemorrhage, and maternal mental health. RESULTS: Forty pregnancies were included. Four patients developed pre-eclampsia (4/40, 10.0%); three occurred postpartum. None was diagnosed with mirror syndrome. Of the 31 continued pregnancies, 16 (51.6%) resulted in early fetal death or stillbirth and 15 (48.4%) resulted in live births. Of the 15 live births, 8 (53.3%) were delivered by primary cesarean delivery; 5 (62.5%) were for hydrops fetalis. Eleven live births (73.3%) were delivered preterm; 9 (81.8%) were indicated, most commonly for fetal indications (7/9, 77.8%). Polyhydramnios occurred in 14/40 (35.0%) cases. Where EBL was recorded (n=37), there were 5 (13.5%) cases of postpartum hemorrhage and an additional 3 (8.1%) had uterine atony without hemorrhage. Eighteen patients (18/40, 45.0%) had new-onset or exacerbated depression or anxiety symptoms. CONCLUSION: Our study identified several important adverse outcomes of pregnancies complicated by NIHF with negative standard-of-care evaluations, including a high rate of postpartum pre-eclampsia and worsened mental health. We identified a higher rate of cesarean delivery and preterm birth, both primarily for fetal indications. We also observed the known relationship between polyhydramnios, hemorrhage, and atony, but noted that this risk included pregnancies concluding in dilation and evacuation. Counseling after a diagnosis of NIHF should include these adverse outcomes.

Isolation of apoptosis-inducing stilbenoids from four members of the Orchidaceae family.

High-throughput natural product research produced a suite of anticancer hits among several species of the Orchidaceae family (Oncidium microchilum, O. isthmi, and Myrmecophila humboldtii). A commercial Oncidium sp. was also examined as a convenient source of additional material. Isolation and structure elucidation led to the identification of fifteen stilbenoids including a new phenanthraquinone and two new dihydrostilbenes. NMR data for structure elucidation and dereplication were acquired utilizing a Bruker BioSpin TCI 1.7-mm MicroCryoProbe or a 5-µL CapNMR capillary microcoil. Several compounds inhibited proliferation of NCI-H460 and M14 cancer cell lines. All compounds were also examined for their ability to induce apoptosis. Apoptosis induction was determined by measuring caspase 3/7 activation and LDH release in a NCI-H460 cell line. Based on these results, a portion of the extract from a commercially available Oncidium sp. was chemically modified in an attempt to obtain additional phenanthraquinones.

A Systematic Review of Reproductive Counseling in Cases of Parental Constitutional Reciprocal Translocation (9;22) Mimicking BCR-ABL1.

We aim to determine the spectrum of cytogenetic abnormalities and outcomes in unbalanced offspring of asymptomatic constitutional balanced t(9;22) carriers through a systematic literature review. We also include a case of a constitutional balanced t(9;22) carrier from our institution. Among the 16 balanced t(9;22) carriers in our review, 13 were maternal and 3 were paternal. Of the 15 unbalanced translocation cases identified, 13 were live births, one was a missed abortion, and one resulted in pregnancy termination. The spectrum of established syndromes reported among the live births was the following: trisomy 9p syndrome (6/13), dual trisomy 9p and DiGeorge syndrome (3/13), dual 9q subtelomere deletion syndrome and DiGeorge syndrome (1/13), 9q subtelomere deletion syndrome (1/13), and DiGeorge syndrome (1/13). One unbalanced case did not have a reported syndrome. The phenotype of the unbalanced cases included cardiac abnormalities (5/13), neurological findings (7/13), intellectual disability (6/10), urogenital anomalies (3/13), respiratory or immune dysfunction (3/13), and facial or skeletal dysmorphias (13/13). Any constitutional balanced reciprocal t(9;22) carrier should be counseled regarding the increased risk of having a child with an unbalanced translocation, the spectrum of possible cytogenetic abnormalities, and predicted clinical phenotype for the unbalanced derivative.

Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria.

BACKGROUND: Expanded carrier screening (ECS) utilizes high-throughput next-generation sequencing to evaluate an individual's carrier status for multiple conditions. Combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency is a rare inherited disease included in such screening panels. Some cases have been reported with metabolic symptoms in childhood yet other cases describe a benign clinical course, suggesting the clinical phenotype is not well defined. METHODS/CASE REPORT: Clinical and laboratory findings during the prenatal period were obtained retrospectively from medical records. RESULTS: A 37-year-old nulliparous woman and her partner were each identified as carriers of ACSF3 variants and presented at 9 weeks gestation for prenatal genetic consultation. The couple received extensive genetic counseling and proceeded with chorionic villus sampling at 11 weeks gestation. Subsequent analysis confirmed that the fetus inherited both parental ACSF variants. The couple was devastated by the results and after reviewing options of pregnancy continuation and termination, they decided to terminate the pregnancy. Following this decision, the patient was diagnosed with acute stress disorder. CONCLUSION: This case highlights how expanded carrier screening adds complexity to reproductive decision-making. Stronger guidelines and additional research are needed to direct and evaluate the timing, composition, and implementation of ECS panels.

Antibiofilm phenylethanoid glycosides from Penstemon centranthifolius.

Bioassay-guided fractionation of the antibacterial ethyl acetate-ethanol (50 : 50) extract obtained from the aerial parts of Penstemon centranthifolius led to the isolation of six phenylethanoid glycosides (1-6) and eleven iridoid glycosides (7-17). Their structures were determined on the basis of spectroscopic analysis and comparison with the literature. Among them, two phenylethanoid glycosides, 4'''-O-acetylverbascoside (1) and verbascoside (2), were found to show significant inhibition of the formation of bacterial biofilms by Escherichia coli UTI89. Compound 1 showed 77% biofilm inhibition at 2.5 microg/mL, and compound 2 showed 60% inhibition at 5 microg/mL.

Pregnancy management in a patient with stickler syndrome.

BACKGROUND: Stickler syndrome is a collagen disorder that can affect multiple organ systems. It is characterized by ocular abnormalities, hearing loss, midfacial hypoplasia, hypermobility, and joint abnormalities. The phenotypic expression of Stickler syndrome can vary among those affected. Since Stickler syndrome is a collagen disorder, it is possible to expect pregnancy complications similar to those reported in other collagen disorders. To our knowledge, there is only one case report in the literature on the management of pregnancy and delivery of a patient with Stickler syndrome. METHODS/CASE REPORT: A 37-year-old primigravid woman with a diagnosis of Stickler syndrome presented at 9 weeks gestation for prenatal genetic consultation. At 26, the patient had prophylactic laser therapy for lattice degeneration of the retina. At 32, she was found to be heterozygous for the c.1527 G>T variant in the COL2A1 gene, which is associated with ocular abnormalities and autosomal dominant form of Stickler syndrome. Subsequently, she desired to pursue prenatal diagnostic testing for the familial variant. The patient voiced that the results would impact pregnancy management. Amniocentesis was performed at 16 weeks gestation. Results were negative for the maternal COL2A1 variant. Karyotype was normal (46, XX). RESULTS: A multidisciplinary team using a patient-centered approach including obstetrics, ophthalmology, maternal-fetal medicine, and genetics determined that there were no contraindications for vaginal delivery. At 39 weeks, the patient underwent spontaneous vaginal delivery with no complications. CONCLUSION: There is a paucity of data available regarding the maternal outcomes of women affected with collagen disorders, especially Stickler Syndrome. This case highlights the importance of accurate genetic diagnosis in the prenatal period and provides information to physicians caring for patients with Stickler syndrome.

Dammarane-type triterpene glycosides from Oncoba manii active against methicillin-resistant Staphylococcus aureus.

Drug-resistant bacteria are becoming more prevalent both in the community and in hospitals. In a search for new antibiotic leads, we used a high-throughput natural products chemistry approach to isolate one new (1) and two known (2, 3) dammarane-type triterpenes with mass-limited material from the African plant Oncoba manii. The new compound was determined by spectroscopic methods to be 1beta,2alpha,3beta,20(R)-tetrahydroxydammar-24-ene 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranoside. Compounds 1 and 2 inhibited the growth of methicillin-resistant Staphylococcus aureus (MRSA).

Antibacterial chromene and chromane stilbenoids from Hymenocardia acida.

Six chromene stilbenoids and one chromane stilbenoid were isolated from the African tree Hymenocardia acida. Several were moderately active against methicillin-resistant Staphylococcus aureus clinical isolate MRSA-108, including hymenocardichromanic acid, which was active at 8 µg/ml. None had IC50 values <20 µM in antiproliferation assays against several human cancer cell lines.

Antibacterial activity of Taxodium ascendens diterpenes against methicillin-resistant Staphylococcus aureus.

One new and seven known diterpenes were identified from an antibacterial chromatographic fraction of Taxodium ascendens. Of these, demethylcryptojaponol (2), 6-hydroxysalvinolone (3), hydroxyferruginol (4), and hinokiol (5) demonstrated potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). These compounds represent a class of synthetically accessible compounds that could be further developed for treatment of drug-resistant bacterial infections.

Polyoxygenated cyclohexene derivatives from Monanthotaxis congoensis.

A phytochemical investigation of Monanthotaxis congoensis afforded eight polyoxygenated cyclohexenes as well as the known crotepoxide. Structures were determined using NMR, MS, and optical rotation analyses. One compound displayed moderate antiproliferative activity against NCI-H460 and M14 cancer cells.

Abronione, a rotenoid from the desert annual Abronia villosa.

A high-throughput phytochemical investigation of Abronia villosa afforded a new rotenoid designated abronione (1) along with the known compounds boeravinone C and lupeol. The structure of 1 was determined using NMR, MS, and optical analysis with < 400 µg of material. Compound 1 displayed moderate cytotoxicity against NCI-H460 and HL-60 human cancer cell lines with IC(50) values of 14 and 36 µM, respectively.

Antibacterial clerodane diterpenes from Goldenrod (Solidago virgaurea).

Nine clerodane diterpenes, solidagoic acids C-I (1-7), cleroda-3,13(14)-dien-16,15:18,19-diolide (8) and cleroda-3,13(14)-dien-15,16:18,19-diolide (9) were isolated and characterised from the ethanol-ethyl acetate (1:1) extract of Solidago virgaurea. The structures were determined by NMR spectroscopic analysis. Several displayed moderate antibacterial activity against Staphylococcus aureus.