Advancing Neuropediatric Rare Disease Diagnosis Through Clinical Genome Sequencing.

Background and Aim: The present study aimed to investigate the pathogenic ability of Cronobacter sakazakii in neonatal mice through the evaluation of its effect on liver tissue and the associated histopathological changes . Methods: Isolates of C. sakazakii were obtained from the Microbiology and Molecular Laboratory, College of Education for Pure Science (Ibn Al-Haitham), University of Baghdad, and were confirmed by 16S rRNA sequencing from samples of infant formula, spinal fluid, and blood. Forty-five neonatal mice aged between 10 and 16 days were obtained from the Iraqi Center for Cancer and Medical Genetics. The animals were divided into three experimental groups, the first group as a control and given only distilled water, the second and third group 10³ cells/ml , 10⁵ cells/ml administered of C. sakazakii (AIC) . Liver tissues were collected from the animals, processed for histopathological examination, sectioned, stained. Results: The results showed liver tissue was found represented by types of necrosis, including focal necrosis, hydropic and ballooning degeneration, swelling of liver cells vacuolated degeneration, congestion in blood vessels, extensive and diffuse hemorrhage , absent of normal structure of the liver cords, as well as The presence of many inflammatory cells in the liver is a sign of chronic inflammation . Conclusion: The study shows C. sakazakii causes severe liver damage in neonatal mice, linked to virulence factors OmpA and OmpX that aid adhesion and invasion. Though rare, infections are fatal in preterm infants. This model advances research on mechanisms, progression, and treatment.

Gene therapy acceptance in a high-consanguinity sickle cell disease population: bridging genetic literacy to therapeutic innovation in Saudi Arabia.

Children may be referred to genetic clinics following a cancer diagnosis or disclosure of family history and may or may not receive genetic testing for cancer predisposition syndromes depending on several factors. The current multi-method study explored psychological outcomes (distress, anxiety, and depression) of the genetic testing process and attitudes about genetic testing in caregivers of children who were recommended and not recommended for testing following genetic counseling. Ninety-four caregivers (≥18 years old) of children (<18 years old) were recruited at their first appointment at a genetic clinic at a large midwestern children's hospital. Caregivers completed standardized measures before their counseling visit (T1), 1 month (T2), and 2 months later (T3). Interested caregivers (n = 46) participated in qualitative interviews at T3. From T1 to T2, the proportion of caregivers with clinical levels of anxiety decreased for those recommended (39% to 15%) and increased for those not recommended (38% to 40%) (p = 0.03). From T2 to T3, the proportion of caregivers with clinical levels of distress increased for those recommended (31% to 65%) and decreased for those not recommended (48% to 39%) (p = 0.01). Qualitatively, caregivers of children who were not recommended endorsed feelings of relief and reassurance, while caregivers of children recommended endorsed no impact, sadness and guilt, empowerment, and anxiety followed by relief. Results indicate that while all caregivers may benefit from psychosocial support throughout the genetic testing process, additional support should be given to caregivers of children recommended for genetic testing.

Molecular findings have led to adeeper understanding of the pathophysiology of numerous diseases and now form the basis for targeted treatment. An example of this is chronic myeloid leukemia (CML). The identification of the BCR::ABL1 translocation enabled the development of specific tyrosine kinase inhibitors. While the median survival time used to be 4 years, CML is now often achronic disease with anear-normal life expectancy thanks to targeted treatment; however, most tumor diseases are more complex at the molecular level. Advances in genome analysis enable increasingly more refined molecular characterization. Common tumor diseases are thus divided into increasingly smaller molecularly distinct segments, which become rarer as individual entities but can also be treated in amore targeted and individualized manner. The concept of personalized medicine is manifested in molecular tumor boards. Asimilar approach can start from rare genetic syndromes. In this case, understanding the underlying pathophysiology does not necessarily lead to acausal treatment of the syndrome itself but it does enable new treatment options for frequent diseases. An example is thyroid hormone resistance (RTH)β. Findings on the effect of thyroid hormone receptorβ in the liver have contributed to the development of analogues that can now be used specifically to treat metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis and can possibly also have the potential to reduce the progression of liver cirrhosis. Overall, close cooperation between human genetics and internal medicine can substantially contribute to an improvement in treatment success. Abetter understanding of molecular disease mechanisms enables an increasingly more precise, individualized and effective treatment.

Clinical genetics in reproductive medicine has moved from cytogenetic assessment to integrated, genome-wide diagnostics that resolve both sequence-level and structural variation. For patients facing infertility, recurrent pregnancy loss, fetal structural anomalies, or early onset pediatric disease, contemporary care follows a reflexive pathway that links karyotyping, chromosomal microarray (CMA), and exome or genome sequencing (GS) with advanced structural platforms including optical genome mapping (OGM) and long-read sequencing. Karyotyping remains indispensable for aneuploidy and balanced rearrangements. CMA outperforms karyotyping for submicroscopic copy number variants and is guideline-endorsed in prenatal diagnosis. Trio exome or GS increases diagnostic yield and clinical utility in fetuses with anomalies and in children with neurodevelopmental disorders or other congenital anomalies. Professional societies now recommend exome or GS as first-tier test in many pediatric scenarios. Long-read sequencing resolves repeats and complex structural variants. OGM provides a single assay, genome wide structural view with strong multisite clinical concordance, including prenatal validations. We present a pragmatic algorithm that orders structure- and sequence-based tests to shorten time, reduce serial testing, and improve counseling and reproductive planning. Together, these modalities support precise diagnoses, tighter recurrence risk estimates, and alignment of care with patient values.

Genomic medicine enables early detection of treatable conditions and supports personalized care across all populations; however, evidence guiding its implementation in resource-constrained healthcare settings remains limited. Using a mixed-methods approach, this study evaluated the readiness of an Alabama Federally Qualified Health Center (FQHC) to implement genomic medicine as part of routine clinical care. Staff members (e.g., physicians, nurses, medical assistants, and administrators) completed surveys, individual interviews, a concept-mapping session, and a nominal group technique exercise. Study participants included 13 clinic members. Interviews and mapping revealed three dominant barriers: staffing shortages, financial constraints, and language obstacles. Facilitators included strong commitment to quality care, alignment with the clinic mission, and supportive leadership. Survey results (N = 12) revealed mean scores in the positive range for culture, learning climate, and leadership engagement, whereas scores for stress, available resources, and readiness for change were nearer to the neutral midpoint, suggesting potential practical constraints on genomic implementation. The use of the CFIR-ERIC Implementation Strategy Matching Tool allowed the team and participants to evaluate nine candidate strategies, prioritizing those with high feasibility and impact. The evaluation was visually developed into an impact matrix which placed patient and family involvement, tailored educational materials, educational meetings, and designated genomic-medicine leadership in the high-feasibility / high-impact quadrant. These strategies directly address identified barriers and fit existing clinic strengths, which is important for equitable precision-medicine adoption. Findings indicate that FQHCs can advance genomic services through culturally attuned patient engagement, structured provider training, and clear leadership roles.

Risk classification in B-cell acute lymphoblastic leukemia (B-ALL) remains challenging, even in the era of genomic precision medicine. Current molecular classifiers fail to fully explain the heterogeneity in patient outcomes, suggesting that key regulatory layers remain hidden. Here, we uncover a previously unexplored dimension of B-ALL biology by analyzing co-expression patterns between pseudogenes using single-sample co-expression networks (n = 1,416). Principal component analysis showed that these interactions explain a major component of variability among patients and contribute to patient stratification into clusters with distinct overall survival. After identifying interactions associated with these clusters, we used a LASSO-based feature selection pipeline to derive a three-interaction signature that predicted patient survival, with RPL7P10-RPS3AP36 emerging as the most robust biomarker. Our study shows that co-expression between pseudogenes represents a previously unrecognized layer of molecular heterogeneity in B-ALL, harboring promising molecular markers for future studies.

Triple X syndrome (TXS) is a relatively common but underdiagnosed sex chromosomal abnormality since incidence / prevelance of normal phenotype is not defined. Available literature largely highlights the congenital abnormalities and post-natal morbidities associated with this condition. There has been an apparent rise in cases of TXS with increasing use of pre-natal genetic testing. Counseling can be difficult for medical professionals in view of extreme variability of the phenotype especially in prenatal cases. We describe our experience with TXS at the Genetic and Perinatology clinic, Wadia hospital and also review the available literature.

Non-invasive prenatal testing (NIPT) has been gaining wider acceptance as the preferred screening test for detecting common fetal chromosomal aneuploidies. In addition, NIPT can also screen for sex chromosomal aneuploidies (SCAs), namely Turner syndrome (45,X), Klinefelter syndrome (47,XXY), Triple X syndrome (47,XXX), and Jacobs syndrome (47,XYY). Recently, the American College of Medical Genetics and Genomics 2022 guidelines recommend that NIPT should be offered to screen for SCAs in pregnant women with singleton pregnancies. In our experience, in 99.8% of pregnant women, the NIPT gave a conclusive result i.e. either low-risk or high-risk for SCAs. However, in the remaining 0.2%, an inconclusive result was released as the test parameters did not fall within the expected low-risk or high-risk score. In such cases, detailed ultrasound and further diagnostic testing with appropriate genetic counselling are recommended. In 30 of 183 samples with an inconclusive result, follow-up information from a diagnostic test was obtained. In most cases, i.e., in 40% (12/30), the diagnostic results did not reveal any abnormal findings. About 30% (9/30) of the cases presented with a history of vanishing twin. In about 10% (3/30) of the cases, the fetus had sex chromosomal abnormality (Monosomy X, 20% Mosaic XXX and XXY). In addition, in about 10% (3/30) of cases, the maternal biological background was confounding the NIPT result for the fetus, i.e., the pregnant woman was identified to have an SCA (2 XXX and Mosaic MX). Adverse outcomes such as intrauterine fetal demise and spontaneous miscarriage were observed in 6.7% (2/30) of cases (the reason for the adverse outcome could not be ascertained) and pregnancy was continued without any further investigations in 3.3% (1/30) of the cases. In conclusion, this study highlights the importance of careful analysis of NIPT results when reporting SCAs. While NIPT offers superior sensitivity (99.6%) and specificity (99.8%) for screening SCAs, it is critical that pregnant women receive appropriate pre-test and post-test counseling to understand the clinical implications of inconclusive results, and the importance of further investigations to determine the fetus’s chromosomal status and in some cases of the mother.

Genetic testing has become a routine part of clinical epilepsy care. Family history is an indication for genetic testing, but the diagnostic yield, predictors of a genetic diagnosis, and association with familial patterns are not well understood. This was a retrospective cohort study of genetic testing performed at pediatric and adult epilepsy genetics clinics. Eligible patients (probands) had epilepsy and one or more first-degree relatives or two or more other relatives with epilepsy. Genetic testing strategies were patient specific, reflecting real-world clinical practice. Familial patterns were classified based on affected relatives of the proband. Diagnostic variants were tested in the proband's parents when possible. We studied 484 probands and their families. A genetic diagnosis was identified in 99 of 484 (20%). Predictors of a genetic diagnosis were presence of neurodevelopmental disorder (X2(1) = 9.6, p = .002) and earlier age at seizure onset (Mann-Whitney U test, p < .001). The likelihood of a genetic diagnosis was not associated with epilepsy type, drug resistance, brain magnetic resonance imaging (MRI) findings, number of affected first-degree relatives, total number of affected relatives, or having an affected parent with epilepsy. Among those with genetic diagnoses, variant segregation matched the familial pattern of affected individuals in 79%. The other 21% of families had unexpected segregation, including de novo variants in patients with affected ancestors and inherited variants in patients with no known affected ancestors. Familial epilepsy has a substantial rate of genetic diagnosis and is an appropriate indication for genetic testing. Pedigree-related factors did not influence the likelihood of genetic diagnosis, suggesting that all families can be considered for genetic testing, independent of inheritance patterns and number of affected relatives. Familial patterns can help interpret genetic test results, while also revealing the complexities of incomplete penetrance and independent epilepsy etiologies in families.

Muscle biopsy has long been regarded as the cornerstone for diagnosing pediatric muscular disorders; however, it is invasive and may be limited by sampling error and inconclusive histopathological findings. This study aimed to evaluate whether whole-exome sequencing (WES) can effectively replace muscle biopsy as a first-line diagnostic approach in children with suspected neuromuscular disorders. Between January 2018 and December 2025, we prospectively enrolled 47 pediatric patients presenting with clinical features suggestive of muscular disorders at a tertiary medical center in Taiwan. The cohort included patients with suspected muscular dystrophies (n = 21), congenital myopathies (n = 23), and multiplex ligation-dependent probe amplification (MLPA)-negative Duchenne muscular dystrophy (DMD; n = 3). All patients underwent WES as the initial diagnostic test without prior muscle biopsy. Trio-based analysis using parental samples was performed in 29.8% of cases. Variant interpretation followed the American College of Medical Genetics and Genomics (ACMG) guidelines. WES identified a definitive molecular diagnosis in 72.3% of patients (34/47). Diagnostic yields varied by subgroup: 100% (3/3) in MLPA-negative DMD, 71.4% (15/21) in muscular dystrophies, and 69.6% (16/23) in congenital myopathies. Pathogenic or likely pathogenic variants were detected in 31 distinct genes, including COL6A1 and COL6A3, which are associated with Ullrich congenital muscular dystrophy. Notably, 58.8% of diagnosed patients (20/34) received molecular diagnoses that differed from their initial clinical impression, encompassing conditions such as ZSWIM6-associated neurodevelopmental disorders, GJB2-related hearing loss, OCRL-associated Lowe syndrome, and various metabolic or syndromic disorders. In all three MLPA-negative DMD cases, WES identified point mutations amenable to mutation-specific therapies. No patient required a muscle biopsy for diagnostic confirmation during the study period. First-tier WES demonstrates high diagnostic utility in pediatric muscular disorders while avoiding invasive muscle biopsy. The high rate of diagnostic reclassification underscores the substantial phenotypic overlap between primary neuromuscular diseases and other neurological or systemic conditions. These findings support the early implementation of genetic testing to enable accurate diagnosis and timely initiation of targeted therapies.

ABSTRACT KBG syndrome (KBGS, OMIM #148050) is a rare genetic disorder caused by heterozygous truncating or missense variants in the ANKRD11 gene or a deletion of 16q24.3 involving ANKRD11 . While truncating variants clearly disrupt protein function, the interpretation of missense variants is more challenging, as many remain variants of uncertain significance (VUS). To address this, we evaluated PhenoScore, an open‐source AI‐based phenomics framework integrating facial recognition and medical data analysis, for predicting the pathogenicity of ANKRD11 missense variants and providing supporting evidence for variant interpretation within the ACMG framework, specifically the PP4 criterion. PhenoScore was trained on 79 individuals with truncating variants in ANKRD11 and age‐, sex‐, and ethnicity‐matched controls with other neurodevelopmental disorders, and its performance was compared to AlphaMissense, REVEL, and the evaluation of a clinical geneticist. Six individuals with functionally confirmed pathogenic missense variants were used for testing. PhenoScore achieved high predictive accuracy with an area under the curve (AUC) of 0.95 and a Brier score of 0.089, and pathogenic missense variants in the test set received a mean prediction score of 0.94. PhenoScore significantly outperformed REVEL ( p &lt; 0.01), especially in cases supported by functional and clinical evidence, while no significant difference was observed compared to AlphaMissense ( p = 0.63); importantly, the two tools showed complementary strengths. These findings suggest that PhenoScore represents a promising tool for clinical variant interpretation, as it quantifies phenotypic concordance with KBGS and provides objective evidence that can strengthen the PP4 criterion within the ACMG framework. Combined with molecular prediction tools like AlphaMissense, PhenoScore may help reduce uncertainty surrounding VUS in ANKRD11 by complementing these scores.

Meeting abstracts from the Annual Conference "Clinical Genetics of Cancer 2024".

Medical genetics is one of the fields with the greatest advancements in medical knowledge. The discovery of genes that determine greater susceptibility to certain neoplasms has motivated a vast amount aimed at determining the best management of patients with these mutations. The use of hormones, both as contraception and during menopause, for these women is a subject of ongoing debate — given their involvement in the pathophysiology of breast neoplasia. This article, therefore, aims to review the available literature on the topic. Thirteen publications were selected for narrative review. Regarding contraception, individualized assessment of these patients is still paramount in indicating hormonal contraception, with no formal contraindication to its use for patients with high-penetrance mutations. Regarding hormone therapy (HT), there are also no absolute contraindications. Consideration is only given to patients who have not undergone mastectomy. In such cases, HT can be considered for short periods, ideally using micronized progesterone in patients with a uterus.

Background With increasing use of prenatal screening, sex chromosome aneuploidies (SCAs) are more frequently detected. Individuals with SCAs have variable physical and medical findings, and developmental and behavioural outcomes. Objective This retrospective study describes the growth, development and clinical features of individuals with SCAs seen at the Genetics clinic in KK Women’s and Children’s Hospital, Singapore, between January 2011 and July 2014. Results Forty-seven patients were included in this study, comprising six groups: 47, XXY (Klinefelter syndrome); 47, XXY/46, XY; 47, XYY; 47, XYY/46, XY; 47, XXX; and other rare SCAs. The majority (39 patients, 82.9%) were detected prenatally. A developmental assessment was available for 44/47 (93.6%). Of these, 28 (63.6%) were delayed in at least one domain, though the delay was mild in the majority (17 patients) with improvement documented on follow-up. Among eight individuals diagnosed postnatally, global developmental delay was reported in 4 (50%), compared to none among those diagnosed prenatally. Growth appeared unaffected in most, with 11.9% (5 patients) having tall stature. Conclusions While 63.6% of our patients had developmental delay in at least one domain, commonly affecting speech and language, the delay was mild in the majority. No prenatally diagnosed patient had global developmental delay. This information is valuable in genetic counselling, especially prenatally. (201 words).

This study presents the first complete chloroplast genome assembly of Calophyllum membranaceum Gander & Champ 1849, a species noted for its pharmacologically active metabolites. The chloroplast genome of C. membranaceum measures 160,820 bp in length and an overall GC content of about 36.4%. It contains a total of 131 genes, which consisted of 86 protein-coding genes, 37 tRNAs, and 8 rRNAs. The phylogenetic analysis based on chloroplast data from the Malpighiales order suggests a close relationship between C. membranaceum and C. brasiliense. Our results provide valuable genomic resource that support future research on genetic resources, conservation, and medicine.

Abstract Secondary findings (SF) identified in massive parallel sequencing raise important clinical and healthcare related questions. To get an overview on current practices of European healthcare providers (HCP), we conducted a cross-sectional survey study among 39 stakeholders—predominantly senior medical and laboratory geneticists—from 15 European countries participating in the European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS). Respondents reported considerable heterogeneity in SF management and reporting, even within countries. While 31% of responding HCP return findings from all 81 genes on the American College of Medical Genetics and Genomics (ACMG) recommended SF list version 3.2, 41% restrict SF disclosure, often excluding genes associated with cardiological or metabolic disorders or with limited clinical actionability. A further 26% do not report ACMG-listed SF at all. Notably, 70% of HCP also assess additional cancer-predisposition genes beyond the ACMG list, using in-house gene lists or national guidelines. Most HCP restrict reporting to (likely) pathogenic variants (90%) and find SF in less than 5% of genetic analyses (59%). Consent procedures and patient information practices varied, with most HCP employing opt-in consent models and genetic counselling primarily delivered by medical geneticists and genetic counsellors. Major institutional challenges raised by participants, include lack of harmonised guidelines, concerns about patient anxiety, and insufficient resources for follow-up care. The findings of this study highlight the need for robust, evidence-based European guidelines to ensure clinically relevant and patient-centred SF management.

This review aims to highlight the characteristic clinical features, pathophysiology, risk factors, genetics, diagnostic work-up, therapeutic management, and recent advances in the clinical setting and management of juvenile open-angle glaucoma (JOAG). A retrospective literature review of PubMed and Google was judiciously done to provide this update [2000-2025]. A diagnosis of JOAG is established on the basis of history and clinical examination, tonometry, angle evaluation by gonioscopy, central corneal thickness (CCT) evaluation, and slit lamp biomicroscopy for evaluation of optic disc changes and retinal nerve fiber layer (RNFL) loss. Structural [optical coherence tomography (OCT) and OCT angiography] and functional assessment [automated perimetry] is important in diagnosis and monitoring it. Juvenile open-angle glaucoma is a rare type of primary open-angle glaucoma affecting individuals between 3 and 40years of age. Classically described as having an early age of onset, high intraocular pressures, normal-appearing angles on gonioscopy, optic disc cupping, and visual field loss; other forms like juvenile ocular hypertension and juvenile normal tension glaucoma are also observed. Trabeculodysgenesis is the primary pathology hindering the normal egress of aqueous humor from the trabeculum; it is currently classified into four clinical subtypes on the basis of gonioscopic angle appearance. Male gender and myopia are risk factors. The MYOC gene mutations are commonly implicated in its pathogenesis. Medical therapy is the first-line management, but selective laser trabeculoplasty also yields favourable outcomes. Surgical management consensus is based on surgeon expertise and preference and is indicated for inadequate intraocular pressure control with non-invasive procedures. JOAG is a heterogeneous and challenging disease, and a multidisciplinary approach is required in its diagnosis and management. Screening of patients at risk or those with a family history or risk factors may allow for earlier diagnosis and prevent visual disability. Prognosis depends on the stage of diagnosis, patient compliance, and prompt appropriate management. Lifelong follow-up is necessary to prevent visual morbidity from this optic neurodegenerative disorder.

Cancer Predisposition Syndromes (CPS) are heritable genetic conditions associated with an increased risk of developing various cancers throughout life. While early identification and tumour surveillance can improve outcomes, CPS are often underdiagnosed in clinical practice. To evaluate clinicians' perspectives and identify barriers to CPS identification and care across Europe, we conducted the SCOPE study: a three-part cross-sectional survey of paediatric haematology/oncology professionals, followed by a modified Delphi consensus process with members of the SIOP Europe Host Genome Working Group. A total of 185 paediatric oncologists from 22 countries participated in the survey. More than 40% of participants reported low or uncertain confidence across different CPS-related tasks, particularly in counselling families (64.3%) and interpreting germline genetic findings (57.3%). Access to clinical geneticists and dedicated CPS clinics were predictors of higher confidence for some domains, while individual experience and institutional patient volume had limited influence. Regular use of universal CPS screening tools was low (42.3%), with most clinicians relying on personal judgement rather than structured criteria. The most cited barriers were lack of screening guidelines (57%) and difficulties in interpreting results (35.1%). Regular training and workshops, availability of genetic counsellors or educators for patient support, and patient-friendly education material were most cited as areas of improvement. The Delphi process led to three recommendations: (1) improve clinician training and communication strategies, (2) integrate CPS screening into standard treatment plans, and (3) develop accessible, patient-centred educational materials. These recommendations highlight opportunities to enhance CPS care through structured support, interdisciplinary collaboration, and systematic screening approaches.