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GATA2 and ZNF148 have both been mapped to chromosome 3q. Pathogenic variants in GATA2 have been associated with immunodeficiency and high risk for myelodysplasia, acute myeloid leukemia, and chronic myelomonocytic leukemia. Gain-of-function variants in ZNF148 have previously been suggested as a mechanism for agenesis of the corpus callosum (ACC). Here, we report a novel 10.4 Mb interstitial deletion on 3q12.33q22.1 including GATA2 and ZNF148 in a child with developmental delay, agenesis of the corpus callosum, and vertebral segmentation defects. With this diagnosis, we were able to suggest preemptive referrals to hematology/oncology and allergy/immunology for close monitoring of early myelodysplasia. We also propose a possible link between ZNF148 loss of function variants and ACC., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

There are currently multiple disorders of aminoacyl-tRNA synthetases described, including KARS1-related disorder resulting from dysfunctional lysyl-tRNA synthetases. In this report, we describe four novel KARS1 variants in three affected individuals, two of whom displayed arthrogryposis-like phenotypes, suggestive of phenotypic expansion. We also highlight subjective clinical improvement in one subject following lysine supplementation in conjunction with a protein-fortified diet, suggesting its potential as a novel treatment modality for KARS1-related disorders. This report offers additional insight into the etiology and management of KARS1-related disorders and expands our ability to provide guidance to affected individuals and their families., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Noonan Syndrome is caused by variants in a variety of genes found in the RAS/MAPK pathway. As more causative genes for Noonan Syndrome have been identified, more phenotype variability has been found, particularly congenital heart defects. Here, we report a case of dilated coronary arteries in a pediatric patient with a RIT1 variant to add to the body of literature around this rare presentation of Noonan Syndrome.  CASE PRESENTATION: A 2-month-old female was admitted due to increasing coronary artery dilation and elevated inflammatory markers. Rapid whole genome sequencing was performed and a likely pathogenic RIT1 variant was detected. This gene has been associated with a rare form of Noonan Syndrome and associated heart defects. Diagnosis of the RIT1 variant also gave reassurance about the patient's cardiac findings and allowed for more timely discharge as she was discharged to home the following day.  CONCLUSIONS: This case highlights the importance of the association between dilated coronary arteries and Noonan syndrome and that careful cardiac screening should be advised in patients diagnosed with Noonan syndrome. In addition, this case emphasizes the importance of involvement of other subspecialities to determine a diagnosis. Through multidisciplinary medicine, the patient was able to return home in a timely manner with a diagnosis and the reassurance that despite her dilated coronary arteries and elevated inflammatory markers there was no immediate concern to her health., (© 2022. The Author(s).)

We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in LRP1 , in which segregation analysis helped dismiss additional variants of interest. LRP1 analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells., (© 2022 Mark et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10., Methods: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis., Results: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length., Conclusion: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis., Competing Interests: Conflict of Interest Several authors included on the manuscript are employees of GeneDx in Gaithursburg, MD (E.T., D.A.C., K.W., J.J., F.M., R.P., M.J.G.S., Y.S., and I.M.W.). B.K.B has received consulting fees and/or honoraria from Biomarin; Takeda; Alexion; Aeglea; Applied Therapeutics; Moderna, Inc; Denali, JCR Pharmaceuticals Co, Ltd; Horizon; SIO; Synlogic; and Ultragenyx and have conducted clinical trials funded by Biomarin; Takeda; Ultragenyx; Homology Medicines, Inc; and Sangamo. B.A.R. received royalties from UpToDate, Inc and is on the advisory boards for Teva Pharmaceuticals and Sanofi Genzyme. All other authors report no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Polyamine levels are intricately controlled by biosynthetic, catabolic enzymes and antizymes. The complexity suggests that minute alterations in levels lead to profound abnormalities. We described the therapeutic course for a rare syndrome diagnosed by whole exome sequencing caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC), characterized by neurological deficits and alopecia., Methods: N- acetylputrescine levels with other metabolites were measured using ultra-performance liquid chromatography paired with mass spectrometry and Z-scores established against a reference cohort of 866 children., Results: From previous studies and metabolic profiles, eflornithine was identified as potentially beneficial with therapy initiated on FDA approval. Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support., Conclusions: This work highlights the strategy of repurposing drugs to treat a rare disease., Funding: No external funding was received for this work., Competing Interests: SR, CB, AB Inventor on a pending US patent (US-2020215010-A1), methods for treating or preventing developmental disorders associated with mutations in the OCD1 gene. ML, AS, CR, JJ, EG, EV, YE, BW, JP No competing interests declared, (© 2021, Rajasekaran et al.)

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient's clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment., Competing Interests: JP performed a summer sabbatical in 2020 for AbbVie Inc, receiving hourly pay. RK, NA, BF, and LT were employees of Ambry Genetics during this study. NK is an advisory board member for Horizon pharmaceuticals and Pharming Healthcare. None of these listed conflicts were directly related to the current work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Prokop, Hartog, Chesla, Faber, Love, Karam, Abualkheir, Feldmann, Teng, McBride, Leimanis, English, Holsworth, Frisch, Bauss, Kalpage, Derbedrossian, Pinti, Hale, Mills, Eby, VanSickle, Pageau, Shankar, Chen, Carcillo, Sanfilippo, Olivero, Bupp and Rajasekaran.)

We present a male patient born at 38-wk gestation with rhizomelic shortening of extremities, hepatomegaly, ventriculomegaly, heart failure, severely depressed left ventricular function, biventricular hypertrophy, and biatrial enlargement. Additional physical findings included anteriorly displaced anus, vertebral anomalies, and brachydactyly. The patient's cardiac malformations led to persistent hypotension, sinus tachycardia, and multiorgan failure in the absence of arrhythmias. Rapid whole-exome sequencing was ordered on day of life (DOL) 8. The patient's family elected to withdraw supportive care, and he passed away that evening. Whole-exome sequencing returned posthumously and identified a variant in NAA10 , E100K. The genotype-phenotype was closest to Ogden syndrome or amino-terminal acetyltransferase deficiency. Typical features of this rare X-linked syndrome include progeroid appearance, failure to thrive, developmental delays, hypotonia, and cardiac arrhythmias. Other family members were tested and the patient's mother, who has a history of mild intellectual disability, as well as a daughter born later, were identified as carriers. All carriers showed no cardiac findings. The carrier sister has manifested developmental delay and cortical atrophy. Protein modeling, evolution, dynamics, population variant assessments, and immunoprecipitation depict the deleterious nature of the variant on the interactions of NAA10 with NAA15 These findings had subsequent implications for posthumous diagnosis of the index patient, for female carriers, and regarding family planning. We highlight how these rapid genetic tests and variant characterization can potentially lead to informed decision-making between health-care providers and family members of patients with critical or lethal conditions when treatment options are limited., (© 2020 Afrin et al.; Published by Cold Spring Harbor Laboratory Press.)

Estrogen receptor-alpha positive (ER(+)) breast cancers comprise the majority of human breast cancers, but molecular mechanisms underlying this subtype of breast cancers remain poorly understood. Here, we show that ER(+) mammary luminal tumors arising in Tip30(-/-)MMTV-Neu mice exhibited increased enrichment of luminal progenitor gene signature. Deletion of the Tip30 gene increased proportion of mammary stem and progenitor cell populations, and raised susceptibility to ER(+) mammary luminal tumors in female Balb/c mice. Moreover, Tip30(-/-) luminal progenitors displayed increases in propensity to differentiate to mature ER(+) luminal cells and FoxA1 expression. Knockdown of FoxA1 expression in Tip30(-/-) progenitors by shRNA specific for FoxA1 reduced their differentiation toward ER(+) mature luminal cells. Taken together, our results suggest that TIP30 is a key regulator for maintaining ER(+) and ER(-)luminal pools in the mammary luminal lineage, and loss of it promotes expansion of ER(+) luminal progenitors and mature cells and ER(+) mammary tumorigenesis.