Secondary findings of cancer patients who have undergone cancer precision medicine have been reported; however, cascade test outcomes have not yet been reported in Japan. This study aimed to evaluate the uptake of genetic medicine in cancer patients with germline pathogenic variants (GPVs) and cascade test in their relatives in Japan. Referral to genetic counseling, incidence of secondary findings [presumed GPVs (PGPVs) and GPVs], and uptake of confirmative germline testing and cascade test were retrospectively analyzed in 862 patients who underwent comprehensive genomic profiling testing in June 2019 and December 2023, using the institutional criteria of cascade test eligibility. Among the 852 patients who underwent tumor-only tests, 95 (11.2%) displayed PGPVs, 54 (6.3%) visited genetic counseling, 34 (4.0%) undertook germline testing, and 22 (2.6%) showed GPVs. One GPV was detected in 10 tumor/normal-paired tests. The 23 detected GPVs included BRCA2 [10], BRCA1 [6], APC [1], ATM [1], BAP1 [1], CDK4 [1], CDKN2A [1], MSH2 [1], and RAD51C [1]. The 23 patients with GPVs had 43 relatives eligible for cascade test and 22 non-eligible relatives (including 9 young relatives aged 14-34years). Cascade test was performed in 30 (69.8%) of the 43 eligible relatives, and GPVs were detected in 10 (33.3%). The median interval between GPV disclosure and cascade test was 50days (range: 6-304days). The uptake level of cascade test can be acceptable. Hospitals need to maintain contact with the young untested relatives until they have achieved sufficient growth to undertake cascade test.

Digital platforms hold promise to scale implementation of population screening. We tailored the Genetics Adviser platform to provide education, decision support, consent, and result return in a genomic newborn screening (gNBS) study, BabyScreen + . Participants were surveyed and interviewed on the usability and value of Genetics Adviser. Genetics Adviser was used by 1048 participants and 1007 (96%) provided feedback. The majority (96%, n = 963) found the platform easy to navigate, with 85% (n = 851) spending <20 min online. Participants demonstrated excellent understanding, over 80% answering at least 6/8 knowledge questions correctly. Only 7% (12/173) of participant-initiated contacts with the study team were for genetic counselling. Interview participants valued the online process. We demonstrate the successful use of a digital platform for a genomic screening program. This model is streamlined, providing consistent, user-friendly education to support decision-making with minimal input from healthcare practitioners. Further evaluation in diverse populations will be essential for future use.

Objectives: The objective of the study is to describe the distribution of hemoglobin (Hb) variants among patients referred for high-performance liquid chromatography (HPLC) screening at a tertiary care center in India. Hemoglobinopathies are among the most common inherited disorders in India. While population-based studies provide prevalence estimates, hospital-based data offer insights into the clinical burden in high-risk groups. This study presents a descriptive analysis of Hb variants among patients referred for HPLC testing at a tertiary referral center. Material and Methods: This retrospective study analyzed 3,052 patients referred for HPLC screening between October 2019 and October 2024. Patients were referred based on clinical suspicion of anemia or hemoglobinopathy. Hb variants were identified using HPLC, and demographic and laboratory data were retrieved from electronic medical records. Results: Abnormal Hb patterns were observed in 48.53% of referred patients. Beta thalassemia trait (36.39%) and HbE variants (Homozygous: 20.66%, Heterozygous: 14.44%) were most common, with regional clustering in West Bengal and Assam. Sickle cell variants were more prevalent in Odisha, Jharkhand, and Telangana. Conclusion: This referral center-based analysis highlights the regional burden of hemoglobinopathies and underscores the need for targeted screening and genetic counseling. Findings should be interpreted in the context of referral bias and the absence of confirmatory molecular testing.

Does DNAH14 deficiency impair sperm flagellar integrity and contribute to male infertility? Loss of DNAH14 leads to disrupted sperm annulus positioning, defective mitochondrial assembly, reduced sperm motility, and impaired male fertility in both humans and mice. Pathogenic variants in several axonemal dynein heavy chain (DNAH) genes have been implicated in male infertility and primary ciliary dyskinesia. DNAH14 remains the only member whose roles are undefined. Genetic analysis was performed on two unrelated Han Chinese infertile men. Functional studies were carried out in a CRISPR-Cas9 Dnah14 knockout (KO) mouse model, with phenotyping of males and their offspring. Whole-exome sequencing was applied to patient samples. Dnah14 KO mice were generated to assess reproductive phenotypes. Sperm morphology and motility were analyzed using Papanicolaou staining, scanning electron microscopy (SEM), transmission electron microscopy (TEM), immunofluorescence staining, and computer-assisted sperm analysis (CASA). Intracytoplasmic sperm injection (ICSI) was performed in both patients and KO mice, and offspring survival and growth were monitored. Biallelic DNAH14 variants were identified in two men with asthenoteratozoospermia. Patient HX-042 carried compound heterozygous variants c.1055T>C and c.9788T>C, whereas Patient HX-137 harbored compound heterozygous variants c.10434G>T and c.12512A>G. In both cases, sperm exhibited markedly reduced motility, disrupted annulus positioning and mitochondrial disorganization. DNAH14 was specifically localized to the midpiece of both human and mouse sperm. Dnah14 KO mice exhibited subfertility, characterized by reduced sperm motility, sperm mitochondrial sheath anomaly, annulus mislocalization, and midpiece bending, whereas ciliogenesis in non-reproductive tissues remained unaffected. ICSI achieved normal fertilization and embryonic development in both patients and KO mice. Offspring of KO males exhibited reduced survival and growth retardation. Not available. We have, for the first time, established genotype and phenotype associations of DNAH14/Dnah14 in humans and mice; however, mechanistic studies remain limited. Further in vivo investigations using animal models are necessary to elucidate the molecular mechanisms by which DNAH14 regulates the structural integrity of sperm flagella. In addition, potential epigenetic mechanisms underlying the role of DNAH14 in postnatal growth also warrant further clarification. These findings identify DNAH14 as a novel contributor to sperm flagellar architecture and male fertility, expanding the genetic spectrum of DNAH-related disorders. In particular, we identified a critical role of DNAH14 in the precise positioning of the sperm annulus, and further found that DNAH14 may regulate offspring growth and development through sperm epigenetic mechanisms, thereby revealing its important biological functions and providing new perspectives for genetic counselling in infertility. This work was supported by the National Natural Science Foundation of China (82471650), Sichuan Science and Technology Program (2024YFFK0267), and the National Key Research and Development Program of China (2023YFC2706402). The authors declare no conflict of interests. N/A.

Due to the challenges of identifying patients with hereditary cancer predispositions in oncology practice, we propose a comprehensive and practical tool intended for oncologists managing adult patients with malignant solid tumors and/or gastrointestinal polyps. This tool was developed based on a comprehensive review of international guidelines, GeneReviews, and recent literature. Key criteria for genetic referral were compiled and organized by organ site and tumor subtype. The resulting resource includes a primary reference table for genetic referral, a polyposis-specific table, two visual summary figures and curated lists of associated genes and syndromes to streamline the clinical decision-making process. This comprehensive tool aims to support oncologists in the timely identification of patients eligible for genetic counseling, thereby enhancing therapeutic decisions and improving familial risk assessment.

To investigate the prenatal manifestation and genetic basis for two fetuses suspected for Osteocraniostenosis (OCS). Two fetuses undergoing invasive prenatal diagnosis at Cangzhou People's Hospital in April and August 2021 for short long bones and abnormal skull morphology were selected as the study subjects. Clinical data were collected and analyzed. Genomic DNA was extracted from amniotic fluid and peripheral blood samples of the two couples. Candidate variants were validated by Sanger sequencing. Literature was retrieved from CNKI, Wanfang Data Knowledge Service Platform and PubMed using keywords including "FAM111A gene", "gracile bone dysplasia", "FAM111A" and "osteocraniostenosis" from January 1, 2000 to June 30, 2025. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: K2020-049). Fetus 1 was found to have short limbs, abnormal skull morphology and shallow cerebral sulci. Fetus 2 showed short limbs, irregular skull halo, prominent forehead and bilateral frontal narrowing. Trio-WES revealed that fetus 1 has carried a heterozygous missense variant c.1582G>C (p.Asp528His) in exon 4 of the FAM111A gene, which was unreported previously. Fetus 2 has harbored a heterozygous in-frame deletion c.1020_1022delTTC (p.Ser343del) in exon 6 of the FAM111A gene, which has been recorded as likely pathogenic by the ClinVar and HGMD databases. Sanger sequencing confirmed that the parents of both fetuses were wild-type for the variant sites. A total of 9 previously reported patients with FAM111A-related gracile bone dysplasia/OCS from 4 publications were retrieved. The main clinical features included intrauterine growth restriction, hypomineralized skull, gracile long bones with narrow medullary cavities and characteristic facial anomalies, which were in large in keeping with the prenatal features of the two fetuses. Both fetuses were diagnosed with FAM111A-related OCS based on the characteristic prenatal findings and identification of the FAM111A variants. Above finding expanded the phenotypic spectrum of FAM111A-associated disorders and provided clues for the prenatal diagnosis and genetic counseling.

Background: Diabetes mellitus is characterized by elevated blood sugar due to absolute or relative insulin deficiency. Diabetes is classified as type 1 (T1D) or type 2 diabetes (T2D), gestational diabetes, and other types, such as monogenic diabetes, exocrine pancreatic disorders, and medication-induced diabetes. Objectives: This review article provides an overview of diabetes genetics, covering polygenic, monogenic, and syndromic forms of the disorder with emphasis on aspects to help clinicians in diagnosis, management, and counseling, but also to foster valuable knowledge for diabetic researchers in identifying phenotypes that will help inform gene discovery. Key Findings: Most cases of T1D and T2D are polygenic with environmental triggers. T1D results from autoimmune destruction of pancreatic beta cells leading to absolute insulin deficiency. Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to T1D. Early studies showed a linkage between T1D and several human leukocyte antigen (HLA) susceptibility loci on chromosome 6. Genome-wide association studies (GWAS) have identified more than 100 HLA- and non-HLA loci that increase susceptibility to T1D. It has been well established that a substantial portion of the genetic risk for T1D is encoded in the HLA locus. The non-HLA loci INS, CTLA4, IL2RA, IFIH1, and PTPN22 make moderate contributions to T1D risk. Many other non-HLA loci have small effects to the phenotype and are relevant to autoimmunity, but they are yet to be identified. T2D, on the other hand, is associated with obesity and insulin resistance with relative insulin deficiency. Thousands of gene variants that are common and contribute small effects have also been identified through GWAS to contribute to T2D risk, but the rarer variants may confer significant risk to an individual’s risk. Common variants in the TCF7L2 locus consistently carry one of the largest risks associated with T2D with a reported 1.7-fold disease odds for homozygous carriers. The usefulness of individual variants for genetic counseling in the common forms of diabetes has been limited in clinical settings in the past. The development of polygenic risk scores (PRS) and partitioned polygenic risk scores (PPRS), statistics derived from GWAS, are being used to predict and classify diabetes. The performance of PRS and PPRS varies by ancestry and type of diabetes. The PRS performs better with T1D, with an area under the curve and receiver operating characteristics (AUC-ROC) ranging from 0.87 to 0.93, compared to 0.72–0.75 for T2D. The genetic architecture of T2D is markedly more polygenic than T1D, and the PPRS has been useful in assessing risk in that setting. Monogenic diabetes comprises several dysglycemic disorders that include neonatal diabetes, maturity-onset diabetes of the young (MODY), and other genetic syndromes that have diabetes either as an associated finding and/or as a complication. Some of the monogenic diabetes gene variants have incomplete penetrance and variable expressivity leading to different ages of onset and variable presentation even within the same family. Hence some patients with these conditions have been previously diagnosed as having T1D or T2D. Many monogenic disorders follow Mendelian inheritance patterns, so genetic counseling is relatively straightforward if pathogenic variants are found to be inherited from a parent. Counseling for forms of diabetes due to maternally inherited mitochondrial cytopathies, such as MELAS and Kearns–Sayres syndrome, is not straightforward due to the occurrence of two or more populations of genetically distinct mitochondrial DNAs in the cells (heteroplasmy); the higher the percent of pathogenic variants in a cell or tissue, the greater the chance for affectation of disorder. Implications: Early stages of diabetes may be asymptomatic, and improvement in methodologies to identify individuals at high risk is important so prevention strategies can be targeted to susceptible individuals to slow or obviate the onset of disease and to minimize complications. Conclusions: Diabetes is a heterogeneous disorder, and accurate definition of phenotypes in the setting of non-syndromic and syndromic forms, development of powerful statistical methodologies, use of next-generation sequencing applications to interrogate the genome, incorporation of epigenetic mechanisms in statistical modeling and accurate curation of gene variants, will help us to realize application of genomic medicine and to inform diabetes care.

To explore the genetic basis for a Chinese pedigree affected with Hereditary spastic paraplegia type 3A (SPG3A) and the genotype-phenotype correlation. A three-generation pedigree presented at Huantai Maternal and Child Health Care Hospital in March 2021 was selected as the study subject. Whole-exome sequencing (WES) and pedigree analysis was carried out. Candidate variant was validated by Sanger sequencing of the members from the pedigree. Haplotype analysis was used to trace the origin of the variant, and pathogenicity was rated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2025-12). A c.1024C>T (p.Pro342Ser) variant of the ATL1 was identified in the four affected members, including the proband, but none of the three unaffected relatives. Haplotype analysis suggested that the variant was derived from the proband's mother and has co-segregated with the disease phenotype. Based on the guidelines of the ACMG, it was classified as likely pathogenic. The ATL1 c.1024C>T (p.Pro342Ser) variant probably underlay the pathogenesis in this pedigree. Above finding has enriched the mutational spectrum of ATL1 and phenotypic spectrum of SPG3A in the Chinese population, and enabled genetic counseling for this pedigree.

Background Intellectual disorder, Type 98 (ID 98) is an X-linked disorder characterized by intellectual disability, epilepsy, and multisystem manifestations. This condition is caused by pathogenic variants in the NEXMIF gene through X-linked dominant inheritance. Case presentation We identified a novel hemizygous NEXMIF variant (c.1939_1942delinsAT, p.S647Ifs*3) in a 5-year-old male with severe intellectual disability via trio whole-exome sequencing. His mildly affected mother was a heterozygous carrier. Prenatal diagnosis for the mother’s subsequent pregnancy identified the same hemizygous variant in the male fetus. Following genetic counseling, the decision was made to terminate the pregnancy, thereby preventing the clinical manifestation of the disease in the offspring. Conclusion This report expands the NEXMIF mutational spectrum and underscores the critical role of genetic testing in achieving early diagnosis and informed reproductive counseling for families affected by this disorder.

Background Autosomal recessive polycystic kidney disease (ARPKD) is an inherited renal disorder characterized by multiple renal cysts. This study aimed to investigate the pathogenesis of PKHD1 gene variants in a Chinese ARPKD pedigree and elucidate the mechanisms underlying the phenotypic heterogeneity in patients with PKHD1 mutations. Methods Clinical data and blood samples were collected from the proband and family members. Whole-exome sequencing (WES) and Sanger sequencing were performed. Conservative analysis and local secondary structure prediction of the mutation site were performed to evaluate the pathogenicity. The genotype-phenotype correlation of PKHD1 mutations was analyzed in combination with this pedigree. Results A pediatric patient with ARPKD was identified. Ultrasonography revealed bilateral renal enlargement with multiple cysts, accompanied by hepatic fibrosis. WES identified a novel compound heterozygous variant in the PKHD1 gene (c.5850_5851insTTCAT; p.Gly1951Phefs*25 and c.8710G &amp;gt; A; p.Glu2904Lys). Conservation analysis confirmed that both mutations occurred in conserved regions, indicating potential pathogenicity. Secondary structure prediction revealed that the p.Gly1951Phefs*25 frameshift mutation resulted in protein truncation and conformational changes, whereas the p.Glu2904Lys missense mutation caused drastic changes in amino acid polarity, impairing protein stability and function. Genotype-phenotype analysis of 605 PKHD1 mutations revealed a trend suggesting that hepatobiliary manifestations might present with less severe mutational burden compared to renal phenotypes, and mild homozygous missense mutations or heterozygous states may attenuate or eliminate renal phenotypes. Conclusion This study uncovered novel PKHD1 mutations in an ARPKD patient, expanding the pathogenic gene spectrum of ARPKD and providing insights for genetic counseling and prenatal diagnosis. Our findings also contribute to the understanding of genotype-phenotype correlations in PKHD1 mutation carriers and generate hypotheses regarding potential organ-specific thresholds for disease manifestation.

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by variable degrees of inflammation and fibrosis affecting the pulmonary interstitium. Advances in molecular biology and genetics have greatly expanded our understanding of ILD pathogenesis, uncovering novel mechanisms and supporting precision medicine approaches. Genetic Insights: Genetic factors play a pivotal role in ILD heterogeneity, influencing disease onset, severity, and progression. To date, more than 30 genes with different inheritance patterns (autosomal dominant, recessive, or X-linked) have been associated with ILDs. These genes are primarily involved in surfactant metabolism, telomere maintenance, immune regulation, and epithelial repair. Emerging evidence also implicates genes encoding aminoacyl-tRNA synthetases. This review summarizes the main genetic alterations underlying ILD pathogenesis and discusses their impact on diagnostic and therapeutic approaches, highlighting how identification of disease-causing variants can improve diagnostic accuracy, refine prognostic assessment, and inform recurrence risk. Methods: A narrative review was conducted through targeted PubMed and Embase searches using disease- and gene-related keywords. Studies were prioritized based on predefined conceptual criteria, including clinical relevance, strength and replication of genetic associations, and availability of functional or translational evidence. Conclusions: This synthesis brings together the latest genetic insights into pediatric ILDs and their clinical implications. Integrating genomic data into clinical practice may enable earlier diagnosis, tailored follow-up, individualized therapeutic strategies, and more informed genetic counseling. However, important challenges remain, including incomplete genotype–phenotype correlations and limited functional validation for several disease-associated genes, which currently constrain full clinical translation.

Introduction Chromosomal abnormalities (CA) are a key genetic contributor to infertility, particularly in regions with high consanguinity. Despite growing utilization of assisted reproductive techniques (ART) in the Gulf region, large-scale cytogenetic data remain scarce. This study aimed to determine the prevalence and distribution of CA and chromosomal polymorphisms (CP) among infertile patients undergoing ART in the United Arab Emirates (UAE), providing region-specific evidence to support diagnostic decision-making and genetic counseling. Methods A retrospective cohort analysis was performed on 4,672 infertile patients (2,193 males and 2,479 females) who underwent conventional G-banded karyotyping between 2016 and 2024 at Al Ain Fertility Center. Semen parameters for all male participants were evaluated according to World Health Organization (WHO) standards. Cytogenetic findings were categorized into numerical abnormalities, structural abnormalities, and CP. Data were stratified by gender, infertility type, semen phenotype, and marital consanguinity (couple-level). Results A total of 305 patients (6.5%) showed CA or CP. The prevalence of abnormalities was higher in males, with sex-chromosome aneuploidies and autosomal structural rearrangements more frequently observed among azoospermic and severely oligozoospermic men. Consanguinity (marital relatedness) was descriptively compared across couple-level karyotype groups. The proportion of consanguineous couples was 39% (644/1,639) in the normal karyotype group, 34.6% (8/24) among couples with CA, and 45.1% (40/88) among couples with CP, with no statistically significant differences between groups. These findings reinforce the diagnostic value of karyotyping, particularly in males with severe sperm abnormalities. Discussion/conclusion This study represents the largest cytogenetic dataset on infertile patients in the UAE and the wider Gulf region, offering population-specific insights into chromosomal determinants of infertility. Routine karyotyping especially for azoospermic men remains essential for accurate diagnosis, informed counseling, and optimized ART planning. These findings provide UAE-specific prevalence data and support risk-stratified counseling; however, the consanguinity analysis reflects marital consanguinity within couples and does not assess parental consanguinity or causality.

Clonal hematopoiesis (CH) has emerged as a critical mediator of age-associated diseases, with far-reaching implications for hematologic malignancies, cardiovascular diseases, cancer therapy, autoimmune disorders, and other health conditions. This review synthesizes the current evidence supporting the integration of CH testing and monitoring into clinical practice, with a focus on translating scientific discoveries into actionable diagnostic and therapeutic strategies. We present a systematic framework for establishing and operating a dedicated CH program, drawing on institutional experience and evolving best practices. Our analysis encompasses risk stratification approaches, surveillance protocols, and intervention timing for various CH-associated conditions. Special attention is given to the challenges and opportunities in implementing CH screening within existing clinical workflows, including considerations for genetic counseling, interdisciplinary coordination, and patient education. By providing practical insights and evidence-based recommendations, this review aims to serve as a roadmap for healthcare institutions looking to develop comprehensive CH management programs that bridge the gap between molecular discoveries and clinical care delivery.

The escalating prevalence of infertility on a global scale represents a critical public concern, with over 50% cases attributed to male-related factors. Y chromosome microdeletion, within the azoospermia factor region, has emerged as a significant genetic contributor to male infertility, with its occurrence varying from 2% to 24% based on the geographic location and genetic background. The prevalence of such microdeletions in infertile individuals varies broadly, with AZFc being the most frequently reported deletion. The gr/gr partial deletion demonstrates a significant ethnic correlation, highlighting the genetic and demographic factors that may influence microdeletions in the AZF region. Reports also indicate significant geographical variation, with eastern and southern areas exhibiting higher prevalence, in contrast to Europe and Australia. In the Clinical aspect, the deletion is a reliable diagnostic tool for identifying infertility and its genetic causes, making it essential for accurate diagnosis and genetic counselling. Moreover, this review addresses challenges associated with the complex Y-Short Tandem Repeat profile interpretation, as well as their potential implication in forensic and medical genetics. The key focus is to investigate the uniparental inheritance of the Y chromosome, its importance in tracing the male lineage, identification of perpetrators in sexual assault cases, and in investigative genetic genealogy. However, the deletion results in an atypical profile pattern, thereby necessitating careful validation strategies to prevent interpretational errors in forensic and kinship analysis. In conclusion, establishing a standardised screening protocol, a unified testing threshold, and centralising the genetic database are essential for improving health management and forensic justice.

Metabolic renal cell carcinomas (RCC) deficient in succinate dehydrogenase (SDH) or fumarate hydratase (FH) are rare but clinically significant entities formalized in the last WHO classification. Their recognition typically starts from morphology and is corroborated by targeted immunohistochemistry (IHC) and, where appropriate, molecular and germline testing. In routine practice, however, implementation may be uneven. Hence, we conducted a nationwide, web-based survey (made by 25 items) among members of the Italian Study Group of Uropathology (GIUP) to map real-world awareness, diagnostic pathways, and test availability across Italian centers. Twenty-one pathologists responded; 18/21 (85.7%) reported dedicated uropathology practice with heterogeneous seniority (≤ 5years, 28.6%; 5-10years, 19.0%; 10-20years, 14.3%; > 20years, 38.1%). Despite substantial renal-tumor workloads (12/20, 57.1% handled > 100 cases in the previous 5 years), direct exposure to metabolic RCCs remained limited (FH-deficient ≥ 1 case, 11/21, 52.4%; SDH-deficient ≥ 1 case, 9/21, 42.9%). Suspicion was predominantly morphology-led: for SDH-deficient RCC, morphology ranked first in 16/21 (76.2%) with the commonest sequence morphology > age > number of lesions (76.2%); for FH-deficient RCC, morphology was top-ranked in 19/21 (90.5%). Key morphologic cues were mixed architectural patterns/papillary elements/macronucleoli for FH-deficient RCC, and eosinophilic cytoplasm with solid-alveolar architecture for SDH-deficient RCC. IHC mirrored these priorities (FH top for FH-deficient, 85.7%; SDHB top for SDH-deficient, 76.2%), whereas 2-succinocysteine (2SC) was rarely available (1/21, 4.8%). Critically, this FH-loss-only workflow can miss non-truncating FH variants (FH immunoreactive but enzymatically inactive) tumors, contributing to under-recognition. Molecular testing would be requested in all suspected cases by 12/21 (57.1%); among selective users, equivocal IHC was the leading trigger (6/8, 75%). Overall, metabolic RCC recognition in Italy is primarily morphology-driven but constrained by uneven access to confirmatory IHC, particularly 2SC, and to molecular assays. The findings argue for harmonized diagnostic algorithms, regional reference laboratory networks, and routine involvement of molecular tumor boards, supported by targeted educational initiatives (including curated digital slide repositories), to standardize practice and improve patient pathways from morphologic suspicion to genetic counselling and tailored surveillance.

Background: Hemoglobinopathies are a major public health issue in high-prevalence regions. They result from mutations affecting globin genes, causing qualitative abnormalities or quantitative defects. Phenotypic-based diagnosis often remains presumptive. Aim: This article highlights, through a case series, the importance of integrating gene sequencing into the diagnostic workflow of hemoglobinopathies. Methods: A prospective case series of patients was conducted over a three-month period in Mohammed VI National Laboratory of Medical Analyses (Casablanca-Morocco). Blood samples collected on EDTA tubes originated from private clinical laboratories. Hemoglobin electrophoresis was performed using capillary zone electrophoresis (CZE). Molecular analysis of the β-globin gene (HBB) was carried out by Sanger sequencing. Erythrocytes indices were obtained from the referring laboratories. Results: Electrophoresis’ conclusion was coherent with findings of HBB sequencing in 3 cases (Case 1, 3 and 5). Cases 3 and 4 having thalassemia confirmed by the finding of c.118C&gt;T heterozygous mutation; present elevated rates of HbA2. Case 4 appearing as homozygous hemoglobin S by electrophoresis was identified as compound heterozygous HbS/β⁰-thalassemia. For remaining cases, definitive conclusions have only been obtained after genetic molecular tests. Discussion: Phenotypic methods such as CZE coupled with red blood cells indices are effective when screening for hemoglobinopathies. However, they remain presumptive and have limitations in complex cases. Integrating genetic testing helps correct potential misinterpretations arising from phenotypic variability, solves complex cases and is crucial for genetic counseling as well as prevention strategies. Conclusion: Integration of molecular testing into hemoglobinopathies diagnostic algorithms can contribute to prevention in high-prevalence regions.

Fetal microcephaly (FMIC) is a neurodevelopmental disorder with heterogeneous etiologies and uncertain prenatal prognosis. Discrepancies between prenatal and postnatal head circumference (HC) measurements may confound ultrasound-based diagnosis, underscoring the need for genetic stratification to improve risk assessment. This prospective cohort study analyzed data from 301 fetuses with suspected FMIC collected between 2014 and 2022. Trio-prenatal exome sequencing (pES) was performed in 301 fetuses with suspected FMIC and normal results on karyotyping and chromosomal microarray analysis. Diagnostic yield, molecular spectrum, and pathway enrichment were analyzed. Clinical follow-up was conducted to correlate genetic findings with postnatal neurodevelopmental outcomes. Molecular diagnoses were achieved in 41 cases (13.6%). Diagnostic yield was significantly higher in complex FMIC compared with isolated FMIC (15.9% vs. 10.1%, p < 0.01), and peaked in cases with family history (26.7%). Our findings expand the prenatal phenotypic spectrum for six genes (TUBB2A, DUOX2, EBP, FAM111A, FGFR3, PEX1), indicating that microcephaly can be a primary presenting feature in the fetus for conditions where it was previously considered a secondary or postnatal finding. Pathogenic variants were enriched in neurogenesis and extracellular matrix-related pathways, implicating dysregulated cell cycle progression and synaptogenesis. Importantly, HC standard deviation (HC-SD) correlated with diagnostic yield and, as demonstrated by multivariable analysis, served as an independent predictor of postnatal prognosis (aOR: 2.1 per 1-SD decrease; 95% CI: 1.5-3.0), whereas fetal growth restriction appeared nonspecific. This prospective cohort study provides the largest prenatal genomic and prognostic analysis of FMIC to date, revealing potential genotype-phenotype associations, pathogenic pathways, and prognostic markers. These findings enhance understanding of FMIC mechanisms and provide essential evidence for prenatal genetic counseling and individualized risk assessment.

Introduction Inborn errors of immunity (IEI) are particularly prevalent in regions with high rates of consanguinity, yet the genetic profiles in these populations are underreported. This study aims to describe the clinical and molecular characteristics of IEI in a highly consanguineous population and investigate the impact of genetic diagnosis on patient management. Method This retrospective study included 52 patients with suspected IEI, as defined by the IUIS criteria. Clinical, immunological, and demographic data were recorded. Genetic analyses were performed primarily using next-generation sequencing (NGS) gene panels, and all pathogenic variants were confirmed by Sanger sequencing. Variants were interpreted in accordance with the ACMG guidelines. Results A total of 52 patients were included in the study, with 92% of the individuals born to consanguineous parents, comprising 28 females and 24 males. The mean age at diagnosis was 4.63 ± 2.5 years. The median duration of follow-up was three years. The overall incidence was 0.3% representing the proportion of patients diagnosed with IEI among those referred to our center during the study period. A high rate of consanguineous marriage was observed, reported in 92% of the cases. The most frequently represented category was Predominantly Antibody Deficiencies (PAD), accounting for 20 patients (38.5%), including 12 cases (23%) of transient hypogammaglobulinemia of infancy (THI) and 7 cases (13%) of selective IgA deficiency. Among the 52 patients, 3 (5.8%) were diagnosed with severe combined immunodeficiency (SCID): 1 patient had ADA deficiency, and two patients had DNA ligase IV deficiency (LIG4). Additionally, 14 patients (26%) were diagnosed with combined Immunodeficiencies (CID). Thirty patients were treated with IVIG, and 3 patients underwent HSCT. A molecular diagnosis was established in 33 patients (63%). Genetic findings influenced clinical management in 82% of variant-positive cases, including decisions regarding HSCT, targeted therapy, and genetic counseling. Conclusion This study highlights the distinctive genetic characteristics of IEI in a population with high consanguinity, emphasizing the need to incorporate molecular diagnostics into standard immunology practice, particularly in areas where recessive disorders are prevalent.

Genetic counseling and testing for dementia - A scoping review of patient and relatives experiences and outcomes.

Indications for germline genetic testing (GT) for hereditary cancer predispositions have increased; however, a critical shortage of genetic counselors (GCs) necessitates the implementation of alternative delivery models. Here, we present the design and implementation of a coordinator-based alternative GT delivery model, called Fast-Track, embedded in a comprehensive cancer genetics program with oversight by GCs. The Fast-Track Program includes visits with clinical genetics coordinators (GCCs) who are trained by GCs in cancer genetic pre-test education and testing. Referrals received to the Smilow Cancer Genetics and Prevention Program (SCGP) are reviewed and triaged by GCs; patients that meet National Comprehensive Cancer Network (NCCN) guidelines for GT are then assigned to the Fast-Track Program. Patients are shown an educational video, which was created by the SCGP and have GT coordinated by the GCC. All cases are reviewed by a GC after the initial visit, regardless of whether GT is completed, for appropriate medical management recommendations. All patients with pathogenic/likely pathogenic variants (PGVs) identified or with complicated results are scheduled with a GC for result disclosure, while remaining patients have disclosure by GCCs. The Fast-Track Program was implemented in June 2023, and this report includes data from 6/12/2023 to 3/29/2024. During this 9-month period, 415 patients were seen in the Fast-Track Program and 12.3% of patients tested had PGVs identified. Mean days from the referral date to the appointment date were significantly shorter for the FT program compared with the standard GC pipeline (21.92 and 90.14 days, respectively) (p < 0.001). A coordinator-based genetics delivery model has been successful in expediting GT visits and is expanding at our institution. Oversight by GCs is essential to ensure standard-of-care delivery for cancer GT in the precision medicine era. Future work evaluating additional quality-of-care outcomes, such as patient satisfaction, will be essential to fully contextualize this model's impact.