Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

Access to clinically indicated genetic tests for pediatric patients with Medicaid: Evidence from outpatient genetics clinics in Texas.

PURPOSE: Little is known about how Medicaid coverage policies affect access to genetic tests for pediatric patients. Building upon and extending a previous analysis of prior authorization requests (PARs), we describe expected coverage of genetic tests submitted to Texas Medicaid and the PAR and diagnostic outcomes of those tests. METHODS: We retrospectively reviewed genetic tests ordered at 3 pediatric outpatient genetics clinics in Texas. We compared Current Procedural Terminology (CPT) codes with the Texas Medicaid fee-for-service schedule (FFSS) to determine whether tests were expected to be covered by Medicaid. We assessed completion and diagnostic yield of commonly ordered tests. RESULTS: Among the 3388 total tests submitted to Texas Medicaid, 68.9% (n = 2336) used at least 1 CPT code that was not on the FFSS and 80.7% (n = 2735) received a favorable PAR outcome. Of the tests with a CPT code not on the FFSS, 60.0% (n = 1400) received a favorable PAR outcome and were completed and 20.5% (n = 287) were diagnostic. The diagnostic yield of all tests with a favorable PAR outcome that were completed was 18.7% (n = 380/2029). CONCLUSION: Most PARs submitted to Texas Medicaid used a CPT code for which reimbursement from Texas Medicaid was not guaranteed. The frequency with which clinically indicated genetic tests were not listed on the Texas Medicaid FFSS suggests misalignment between genetic testing needs and coverage policies. Our findings can inform updates to Medicaid policies to reduce coverage uncertainty and expand access to genetic tests with high diagnostic utility.

Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment.

Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle-associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop-gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off-label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment.

An additional case of Néstor-Guillermo progeria syndrome diagnosed in early childhood.

Néstor-Guillermo progeria syndrome (NGPS; OMIM 614008) is characterized by early onset and slow progression of symptoms including poor growth, lipoatrophy, pseudosenile facial appearance, and normal cognitive development. In contrast to other progeria syndromes, NGPS is associated with a longer lifespan and higher risk for developing severe skeletal abnormalities. It is an autosomal recessive condition caused by biallelic pathogenic variants in BANF1. There are two previously reported patients with NGPS, both Spanish with molecular diagnoses made in adulthood and having the same homozygous pathogenic variant c.34G > A; p.Ala12Thr. Presented here is a 2 year, 8 month old girl with short stature, poor weight gain, sparse hair, and dysmorphic facial features reminiscent of premature aging. Whole exome sequencing identified the same c.34G > A homozygous pathogenic variant in BANF1 as reported in the previous patients. This is the first reported case of a child and is supporting evidence for this recurrent loss of function variant.

An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism.

Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.

Warfarin-induced tissue necrosis: a case study.

Warfarin-induced tissue necrosis is a rare and serious side effect associated with warfarin treatment. A case study of a patient with warfarin-induced tissue necrosis taken from clinical practice illustrates the importance of timely diagnosis and treatment to avoid the devastating consequences of this adverse drug reaction. Nurse prescribers must be alert to and aware of potential adverse drug reactions that may be caused by any prescribing decision, and should be able to take appropriate action when such an event occurs.

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

Warfarin-induced tissue necrosis: a case study.

Warfarin-induced tissue necrosis is a rare and serious side effect associated with warfarin treatment. A case study of a patient with warfarin-induced tissue necrosis taken from clinical practice illustrates the importance of timely diagnosis and treatment to avoid the devastating consequences of this adverse drug reaction. Nurse prescribers must be alert to and aware of potential adverse drug reactions that may be caused by any prescribing decision, and should be able to take appropriate action when such an event occurs.