Somatic overgrowth and vascular anomalies are often present at birth but may only be clinically recognized later in life. Affected tissues commonly include veins and arteries, skin, adipose tissue, bone, and brain, resulting in a broad phenotypic spectrum encompassing vascular malformations, lipomatous and melanocytic nevus syndromes, skeletal abnormalities, and brain malformations. These conditions are typically caused by postzygotic variants present in a subset of cells due to mosaicism. The developmental timing and cell lineages involved determine the extent and distribution of affected tissues. While germline variants and their clinical consequences are well characterized, the impact of somatic mosaic variants remains less well understood. Because these variants are often absent or present at very low levels in blood, sensitive assays and analysis of affected tissues are required for detection. Advances in high-depth next-generation sequencing have enabled reliable identification of low-level mosaic variants and are central to the genetic diagnosis of these disorders. Numerous causative genes have been described, most notably activating variants in the PI3K-MTOR and RAS-MAPK pathways. Genetic testing provides diagnostic confirmation, informs prognosis and recurrence risk, and in some cases enables targeted therapy, such as alpelisib for PIK3CA-related overgrowth spectrum. However, testing strategies vary across laboratories in gene panel content, sequencing depth, and tissue requirements, leading to inconsistent diagnostic approaches. This review summarizes known causative genes, current testing methodologies, variant interpretation and reporting practices, major genomic alteration classes and recurrent hotspot variants, and highlights key knowledge gaps from clinical and laboratory perspectives.
PURPOSE:Protein-altering gene variants in SEPSECS disrupt the biosynthesis of selenoproteins, leading to a spectrum of neurological diseases. METHODS:We studied 27 individuals with biallelic SEPSECS variants, identifying 13 unreported gene variants. To better understand and diagnose the disorder, broad biochemical correlation of neurological symptoms, focused metabolomics, and structural and in vitro activity analyses were deployed. RESULTS:Our results suggest three general clinical courses: (i) severe early-onset with cerebellar or cerebral atrophy, (ii) milder early-onset with gradual deterioration, and (iii) late-onset, mild disease. SEPSECS variants primarily affect the brain. In only one individual out of eight, thyroid hormone measurements suggested a defect of T4 to T3 conversion. Accompanied increase in glutathione and sulfur metabolites in plasma indicates elevated oxidative stress. Variants mapping to conserved N- and C-termini and catalytic site elicit SEPSECS misfolding, aggregation, thermal instability, and loss of function, that could ultimately lead to ferroptosis of neurons and perhaps oligodendrocytes. For differential diagnosis and monitoring therapeutic attempts, we recommend measuring levels of plasma selenium, glutathione and sulfur metabolites, GPX activity, and SELENOP. Given the pontine involvement in less than half of the cases, we suggest renaming the syndrome from PCH2D to SEPSECS-related neurodevelopmental disorder. CONCLUSION:Our study expands the understanding of SEPSECS-related neurodevelopmental disorders, highlighting the need for updated diagnostic criteria and potential treatment strategies.
PURPOSE:The utility of rapid genome sequencing (RGS) has been evaluated in pediatric intensive care unit (ICU) settings, but few studies investigate its use in non-critically ill hospitalized children. Our study assesses the impact of RGS use in the non-ICU setting. METHODS:We analyzed RGS results obtained for hospitalized children from 2019-2023 and evaluated the impact on non-ICU patient care. Changes in management were determined via chart review of the first 30 days after testing. RESULTS:RGS was performed on 422 individuals: 339 ICU and 83 non-ICU. The diagnostic rate was 39% (32/83) in non-ICU and 35% (120/339) in ICU patients. Eighty-one percent of non-ICU diagnostic RGS had a management change within 30 days, and 56% (18/32) received a disease- targeted intervention including medication or diet change, listing for transplant, or connection with a clinical trial. Of the children who received these intervention changes, the most common disease categories were metabolic (61%, 11/18) and epilepsy (22%, 4/18). CONCLUSION:RGS is effective at identifying treatable diagnoses in the non-ICU setting, with most patients experiencing a change in their care, and over half receiving disease-focused interventions. Our results support the utility of RGS use in non-ICU hospitalized children and can impact providers' decision-making and payor coverage.
PURPOSE:Neurofibromatosis type 1 (NF1) is a common autosomal dominant tumor-predisposition syndromes (∼1:3,000 worldwide), involving pigmentary, skeletal, and neurodevelopmental features, and lifelong tumor risk. Although NF1 has been traditionally assumed to follow Mendelian transmission, our analyses reveal a consistent deviation from this expectation. METHODS:We analyzed transmission patterns in 322 NF1 families across four well-characterized cohorts, applying strict inclusion criteria to minimize ascertainment bias and exclude possible mosaic cases. Sub-sampling and large-scale random down-sampling analyses were used to assess whether cohort size or other confounders could account for the observed transmission pattern. RESULTS:Among 701 offspring, 61.1% were diagnosed with NF1, significantly exceeding the 50% expected under Mendelian inheritance (p = 5 × 10-9). This robust transmission ratio distortion was present in both female (62.8%) and male (58.5%) transmitters. We propose that this pattern is most consistent with a mechanism involving clonal selection of NF1-null cells within the early embryonic germline, a concept conceptually grounded in established NF1 tumor biology but not previously linked to inheritance pattern. CONCLUSION:Our findings uncover a previously unrecognized feature of NF1 genetics and suggest germline selection as a driver of transmission distortion, with implications for clinical practice, prenatal diagnostics and reproductive counseling.
PURPOSE:Consensus is lacking on how to define and measure the concept of personal utility in genomic medicine. The study objective was to develop and assess the validity of the Patient-reported Genetic testing Utility InDEx (P-GUIDE) for pediatric genetics. METHODS:Informed by the literature, experts, and patient partners, a 55-item first draft of P-GUIDE was developed. Interviews were conducted with parents of children who had undergone genetic testing to assess item clarity and relevance. Clinical experts assessed content validity. Two independent sequential samples of parents completed questionnaires. Item reduction was achieved using exploratory factor analysis and confirmatory factor analysis. The performance characteristics of the final tool were assessed. RESULTS:Interviewees (n = 22) found most items relevant but requiring modification. Clinical experts (n = 11) recommended further revisions. Exploratory factor analysis (n = 103) removed 9 items. Confirmatory factor analysis (n = 103) generated a final tool consisting of 19 items across 3 factors: understanding and decision-making, psychosocial benefit, and psychosocial concern. P-GUIDE scores were positively correlated with published measures of utility, knowledge, empowerment, and emotion, establishing construct validity. P-GUIDE demonstrated strong test-retest reliability. CONCLUSION:P-GUIDE is available for use in pediatric populations. Emerging adaptations of P-GUIDE contribute to a novel utility measurement system for genetic testing.
PURPOSE:Achondroplasia (ACH) is a monogenic skeletal dysplasia caused by gain-of-function variants in FGFR3, leading to impaired endochondral ossification and foramen magnum stenosis. Although vosoritide promotes endochondral ossification, its effects on foramen magnum development remain unclear. In this study, we evaluated the impact of early vosoritide administration on foramen magnum development in infants and young children with ACH, using longitudinal magnetic resonance imaging. METHODS:This retrospective, single-center case series included 9 patients who initiated vosoritide before age 3 years. Serial head magnetic resonance imaging scans were analyzed. The anteroposterior and transverse diameters of the foramen magnum were measured and compared with reference curves from untreated ACH cohorts. The severity of stenosis was assessed using the ACH foramen magnum score (AFMS). Correlations between changes in body height standard deviation score and foramen magnum dimensions were assessed. RESULTS:Vosoritide was initiated at a median age of 4 months, with a mean treatment duration of 2.5 years. Compared with untreated cohorts, steeper growth rates were observed in 8 of the 9 patients for the anteroposterior diameter and in all patients for the transverse diameter. Most patients remained at AFMS 1 or 2. One patient progressed to AFMS 3 and underwent decompression surgery at age 11 months. No significant correlation was identified between changes in body height standard deviation score and foramen magnum diameter. CONCLUSION:Early vosoritide administration may promote foramen magnum development in infants and young children with ACH, independently of systemic growth effects. Even when height improvement is limited, enhancement of foramen magnum growth may be clinically relevant.
PURPOSE:Indigenous Peoples' concerns about how researchers collect, store, and use biospecimens have limited their participation in biospecimen-based research. Researchers must improve biospecimen governance to address these concerns and advance ethical research and data practices. In this study, we seek to better understand Indigenous Peoples' perspectives on biobanking and biospecimen storage in Canada, Australia, New Zealand, and the United States. METHODS:PubMed, Embase, Nature Online, Scopus, Academic Search Complete (EBSCO), JSTOR, and Project Muse were searched using terms related to the peoples, populations, and topics of interest. A 2-stage screening process assessed relevance, followed by inductive content analysis to identify key themes. Articles were included if they reported on Indigenous Peoples' perspectives or governance approaches related to biobanking or genetic research. RESULTS:Seventy articles published between 1988 and 2023 met the inclusion criteria, with nearly 70% being led by Indigenous authors. Six themes emerged: informed consent, biospecimen stewardship, data-sharing policies and expectations, research benefits and risks, Indigenous participation in research, and community engagement. CONCLUSION:The review highlights perspectives and governance approaches that guide ethical research, protect community rights, and oversee the use of biospecimens and related data. Findings underscore the need for Indigenous-led governance frameworks that center on Indigenous sovereignty and community-defined values.
Purpose Classification of DNA sequence data requires the implementation of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Therefore, automated tools have been developed. However, these tools often lack robust and up-to-date methodologies. This study reports on the development of a new tool and examines its performance for diagnostic and research purposes. Methods The automated ACMG-based variant classifier (AAVC) presented here computationally analyzes sequence variants following the ACMG guidelines, the Clinical Genome Resource specifications and a novel framework by leveraging large public databases and in silico prediction tools. Results AAVC demonstrated high concordance (94.39%) with the Food and Drug Administration recognized variant classifications, outperforming currently available tools. It classified 55% of the variants of uncertain significance in clinical variation into clinically significant categories. We identified, in the Turkish Variome, 215 novel pathogenic, likely pathogenic, or variants of uncertain significance high variants in the secondary finding genes and revealed that 1 in 10 individuals carried an actionable genotype. Conclusion AAVC constitutes a robust framework for the accurate classification of human germline sequence diversity is available at https://aavc.bilkent.edu.tr/, offering a highly accurate, rapid, and up-to-date platform for clinical laboratories and research groups to automatically interpret sequence variants.
PURPOSE:To determine whether offering patients newly diagnosed with colorectal cancer (CRC) access to free, phone-based patient navigation increases rates of referral, counseling, and germline genetic testing relative to usual care. METHODS:We conducted a randomized controlled trial in an academic-affiliated health system with an established universal CRC tumor screening program. Over one year, all patients eligible for germline genetic testing were identified and randomized to usual care or an offer of patient navigation. Navigation was designed to address barriers to genetic counseling attendance identified through a needs assessment. We followed a Zelen design, where patients randomized to navigation could choose not to participate, and outcome data were collected passively from the electronic health record. Ad hoc analyses examined predictors of genetic services utilization in the usual care arm. RESULTS:A total of 85 patients (69 [81%] under age 50 years; 41 [48%] female; and 68 [80%] White) were included in the analyses. Thirty-three percent of participants who were offered patient navigation (n = 43) ever engaged with the intervention. At six months, 65 (76%) participants were referred to genetic counseling, 53 (62%) had participated in counseling, and 47 (55%) had received testing. Rates of genetic service utilization did not differ significantly by arm (Z = -0.45, P = .65; Z = .08, P = .93; Z = -0.34, P = .73, respectively). In usual care, female patients and patients who lived closer to the health system were more often referred to genetic services (χ2 = 8.81, P < .01; t = 2.39, P = .02, respectively). CONCLUSION:Offering phone-based patient navigation in addition to usual care did not significantly increase the use of genetic services among patients with newly diagnosed CRC in this setting, as only one-third of patients offered navigation pursued it. Low engagement may limit the effectiveness of navigation, supporting efforts to mainstream genetic test delivery after a cancer diagnosis.
PURPOSE:SET is a member of the inhibitor of histone acetyltransferases complex involved in transcriptional silencing and gene regulation. Pathogenic variants in SET are postulated to cause neurodevelopmental disorder (NDD) phenotypes, but as only a few individuals are described, detailed clinical information is scarce. Hence, currently, counseling on phenotypes and prognosis of this condition remains challenging. METHODS:Here, we describe the clinical phenotype and mutational spectrum of 23 unreported individuals harboring (likely) pathogenic variants in SET. RESULTS:Phenotypes include global developmental delay, often with pronounced hypotonia, delayed motor development, and speech and language delay, ultimately evolving into (mild) intellectual disability. Comorbidities include behavioral concerns, sleep disturbances, and variable nonspecific ocular problems. Next-generation computer-assisted phenotyping using GestaltMatcher showed limited overlapping facial features between affected individuals and differences compared with disorders caused by related chromatin-modifying genes in individuals. In addition, we generated a DNA methylation signature able to distinguish individuals carrying pathogenic variants in SET from individuals with other neurodevelopmental disorders and healthy controls. We used this DNA methylation signature to assess the pathogenicity of 2 variants of uncertain clinical significance in SET found in 2 additional individuals. CONCLUSION:Together, this expands the knowledge on SET-related disorders and provides novel approaches for their diagnosis.
PURPOSE:Biallelic variants in the minor spliceosomal gene RNU4ATAC were successively identified in Taybi-Linder/Microcephalic osteodysplastic primordial dwarfism type I, Roifman, and Lowry-Wood syndromes, which are characterized by variable microcephaly, short stature, neurodevelopmental impairment, skeletal dysplasia, and immunodeficiency. Two-thirds of the reported individuals present with Taybi-Linder syndrome, the first-described and most severe form. METHODS:We collected clinical and molecular data from individuals with biallelic RNU4ATAC variants through various French and European networks and clinics to refine the phenotypic spectrum of RNU4ATAC-opathies. RESULTS:We enrolled 69 participants and identified 18 new pathogenic variants. We report a significant proportion of attenuated or atypical presentations, novel rare symptoms, and, unexpectedly, a broad spectrum of autoimmune or inflammatory manifestations, affecting nearly half of the participants. Integrating our data with the 109 published cases, we propose a novel classification based on the main manifestations, immunodeficiency, and microcephalic primordial dwarfism. Using computer-assisted facial analysis, we also demonstrated the existence of a specific dysmorphic pattern in RNU4ATAC-opathies that is distinct among some sub-syndromes. CONCLUSION:We present a large cohort of individuals with RNU4ATAC-opathies and expand the phenotypic spectrum to paucisymptomatic forms, indicating that these diseases are likely to remain underdiagnosed.
PURPOSE:We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene. METHODS:Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals. RESULTS:We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature. CONCLUSION:This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.
PURPOSE:Early actionable metabolic conditions (EAMCs) are disorders that are often severe but have early interventions that can improve clinical outcomes. EAMCs are not universally included on newborn screening panels. We studied the clinical utility of detecting EAMC gene variants prenatally using reproductive carrier screening (RCS). METHODS:We identified EAMCs from the 113 ACMG-recommended carrier panel and a 275-gene carrier panel. The carrier status for these EAMCs was determined in a cohort of women who underwent RCS between 2022 and 2024. Observed carrier frequencies were used to calculate theoretical affected pregnancy rates. RESULTS:110 EAMCs were identified. Among 54,119 individuals, the carrier frequency for any EAMC was 1 in 6, using the 113-gene panel, and 1 in 4, using the 275-gene panel. Assuming random pairing, the theoretical affected pregnancy rates were 0.07% with the 113-gene panel and 0.08% with the 275-gene panel. The most prevalent EAMCs in this cohort were phenylketonuria (MIM:261600, 1 in 41), congenital adrenal hyperplasia (MIM:201910, 1 in 57), Wilson disease (MIM:201910, 1 in 63), Smith-Lemli-Opitz syndrome (MIM:270400, 1 in 75), and medium-chain acyl-CoA dehydrogenase deficiency (MIM:201450, 1 in 80). CONCLUSION:RCS facilitates detection and early intervention, which may reduce associated morbidity for certain metabolic disorders.
Purpose Polygenic embryo screening (PES) examines embryos for their genetic likelihood of developing complex conditions and traits. The commercialization of PES places reproductive endocrinologists and infertility specialists (REIs) as the primary decision-makers in its use, despite professional guidelines cautioning that PES is not ready for clinical use. Methods This survey examines how 152 US REIs perceive and approach potential clinical decision-making scenarios regarding the use of PES. Results REIs were more likely to offer PES for medical conditions (up to 62% for cancer) than for traits (eg, 0% for skin color, 10% for body mass index). When evaluating 11 potential criteria to assess condition severity, clinical burden (eg, high mortality [80%]) was rated significantly higher than contextual burden (eg, low lifestyle modifiability [28%]); however, 82% to 93% of respondents considered each criterion at least slightly important. In hypothetical scenarios where PES rankings conflicted with embryo ploidy or morphology, only 8% preferred PES over ploidy, and 30% preferred PES over morphology. Still, 47% supported patient choice in morphology-based cases, and 30% supported patient choice in ploidy-based cases. Conclusion These findings indicate skepticism toward PES, while underscoring the nuanced, context-dependent factors that influence its potential use.
