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Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases that contribute to nonimmune hydrops fetalis (NIHF). Our objective was to review the pooled exome sequencing (ES) diagnostic yield of LSD in NIHF cases. We expanded our previous meta-analysis and updated our search strategy of prenatal ES studies from 1/1/2000 to 8/1/2024. Cases with LSD gene variants were reviewed. Variants were curated based on the current American College of Medical Genetics and Genomics and ClinGen guidelines. Forty-one ES studies met our inclusion criteria. A total of 207/558 NIHF cases yielded a positive diagnosis by ES. LSD cases represented 27/558 (5%) of all clinically diagnosed NIHF cases that had ES. Rate of LSD among NIHF cases with positive genetic diagnosis by ES was 27/207 (13%). The 27 diagnostic variants and 4 additional variants of uncertain significance (VUS) were identified in 9 different LSD genes. All variants were inherited with a recurrence risk of 25%. Mucopolysaccharidosis type VII (MPS VII) was most prevalent (14/27, 52%). Also, the 4 cases with VUS were identified in the GUSB gene. Most cases (21/31, 68%) were isolated NIHF. Hydrops recurrence when reported was present in 75% (15/20) of cases. Consanguinity was reported in 57% (12/21) of cases. In conclusion, 5% of all NIHF cases received a genetic diagnosis of LSD by ES. Thirteen percent of NIHF cases that received a genetic diagnosis by ES were attributable to LSD, with MPS VII being the most prevalent condition. Pairing ES results with enzymatic studies can aid variant interpretation and could have potentially upgraded some of the 4 VUS cases, leading to a higher LSD diagnostic yield. Most cases of LSD presenting as NIHF manifest prenatally as isolated NIHF. High rate of NIHF recurrence and consanguinity highlight importance of genetic counseling and testing for LSD.

Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification. Using a new computational pipeline for identification of drug-selective transcriptomic responses and FAERS data, the authors identified potential pathways and genomic variants indicative of cancer drug cardiotoxicity in iPSC-derived cardiomyocytes.

Hereditary anemias are a cause of nonimmune hydrops fetalis (NIHF). Our objective was to review the spectrum of hereditary anemia genes in NIHF diagnosed by exome sequencing (ES). We performed a systematic review of ES studies in NIHF from January 1, 2000 to August 1, 2024 with emphasis on genes causing fetal anemia as a primary phenotype. Forty-one ES studies with 207 genetically diagnosed NIHF cases met our inclusion criteria; 6 cases within 6 studies involved NIHF and hereditary anemia. Among the six cases, five had definitive diagnosis or likely diagnosis supported by pathogenic or likely pathogenic variants, while one case harbored only variants of uncertain significance and was classified as a possible diagnosis. The six different hereditary anemia genes included SEC23B, SPTA1, KLF1, RPL11, UNC13D, and RFWD3. Overall, ES confirmed the etiology of hereditary anemia in 2.4% (5/207) of genetically diagnosed NIHF cases. Hereditary anemias, therefore, represent a distinct and clinically relevant subset of ES-diagnosed NIHF cases. ES should be considered first line in fetuses with NIHF, as common non-genetic causes such as fetomaternal hemorrhage, infectious etiologies, and alloimmunization are excluded. It is also indicated when fetal anemia is suspected, particularly in the setting of elevated MCA Dopplers with a negative evaluation for common hemoglobinopathies and nongenetic etiologies.

Virus-specific T cells (VST) from partially-HLA matched donors have been effective for treatment of refractory viral infections in immunocompromised patients in prior studies with a good safety profile, but rare adverse events have been described. Here we describe a unique and severe adverse event of VST therapy in an infant with severe combined immunodeficiency, who receives, as part of a clinical trial (NCT03475212), third party VSTs for treating cytomegalovirus viremia following bone marrow transplantation. At one-month post-VST infusion, rejection of graft and reversal of chimerism is observed, as is an expansion of T cells exclusively from the VST donor. Single-cell gene expression and T cell receptor profiling demonstrate a narrow repertoire of predominantly activated CD4 + T cells in the recipient at the time of rejection, with the repertoire overlapping more with that of peripheral blood from VST donor than the infused VST product. This case thus demonstrates a rare but serious side effect of VST therapy. Infusion of virus-specific T (VST) cells is used for treating drug-resistant viremia. Here the authors report, as part of the clinical trial, NCT03475212, a lethal case of unexpected bone marrow graft loss and chimerism reversal that is induced by the infusion of third-party VST intended to treat transplantation-related cytomegalovirus viremia.

Smith–Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1 , and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader–Willi Syndrome (PWS) region. This can help clarify NDN’s role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.

Purpose Four patients with Saul–Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype. Methods Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z -scores for height, weight, head circumference and body mass index were calculated at different ages. Results All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z -score between −4 and −8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod–cone dystrophy, and cystic macular changes. Conclusions Saul–Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.

Macrocephaly, defined as a large head size, has a very broad differential and sometimes can be challenging to differentiate as benign versus indicative of pathology. In this review, we outline a stepwise approach to improving diagnosis of neurogenetic disorders versus other causes using the example of PTEN (phosphatase and TENsin homolog) Hamartoma Tumor Syndrome (PHTS). PHTS is a multiple hamartoma syndrome with medical management implications including the need for tumor surveillance, but often cases are not diagnosed until later in adulthood. Our review emphasizes the utility of using head circumference z scores in combination with other features as a triage tool for genetic identification of disorders such as PHTS.

Hydrops fetalis (HF), accumulation of fluid in two or more fetal compartments, is life-threatening to the fetus. Genetic etiologies include many chromosomal and monogenic disorders. Despite this, the clinical workup typically evaluates limited genetic targets. To support broader molecular testing of pregnancies with HF, we cataloged the spectrum of monogenic disorders associated with nonimmune hydrops fetalis (NIHF). We performed a systematic literature review under PROSPERO tag CRD42018099495 of cases reporting NIHF meeting strict phenotypic criteria and well-defined genetic diagnosis. We ranked the evidence per gene based on number of reported cases, phenotype, and molecular/biochemical diagnosis. We identified 131 genes with strong evidence for an association with NIHF and 46 genes with emerging evidence spanning the spectrum of multisystem syndromes, cardiac disorders, hematologic disorders, and metabolic disorders. Several genes previously implicated with NIHF did not have any reported cases in the literature with both fetal hydrops and molecular diagnosis. Many genes with strong evidence for association with NIHF would not be detected using current sequencing panels. Nonimmune HF has many possible monogenic etiologies, several with treatment implications, but current diagnostic approaches are not exhaustive. Studies are needed to assess if broad sequencing approaches like exome sequencing are useful in clinical management of HF.

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. 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. 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). 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.

BackgroundCongenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model.MethodsFour hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections.ResultsLoss of function ROBO1 variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model.ConclusionOur findings identify Slit-Robo as a significant pathway in human heart development and CHD.