Genomic characterization using next-generation sequencing (NGS) has become a widely adopted tool in myeloid neoplasms (MN) and bone marrow failure (BMF) syndromes. It now supports diagnostic classification, prognostic stratification, and the identification of predictive and therapeutic biomarkers. However, the widespread NGS use increasingly reveals variants with interpretation challenges, highlighting the need appropriate tissue selection to distinguish somatic vs. germline variants.Within the GEMMA Project, a hematology–genetics outpatient program at Rome Policlinico Tor Vergata focused on identifying germline predisposition to BMF/MN, we analyzed samples from 81 individuals (03/2023-10/2025). These included 45 BMF/MN patients and 36 family members at risk. Control DNA was extracted from non-myeloid tissues in probands using CD3+ lymphocytes (n=31), fibroblasts (n=1), and nails (n=16). Peripheral blood mononuclear cell’s DNA was analyzed for family members.We confirmed the germline nature of variants in 13/45 patients. In 5 cases, germline origin was suspected based on variants with ~50% variant allele frequency (VAF) in myeloid panels for SH2B3 (n=3) and RUNX1 (n=2) variants, and was confirmed on DNA from nails. Germline confirmation derived from clinical exome sequencing in 8 cases, involving variants in GATA2, DDX41, TERC, SAMD9, and FANCA. Analysis of CD3+ T cells revealed a revertant mosaicism in a compound heterozygous FANCA-mutated patient. The recurrent identification of GATA2 and DDX41 variants prompted us to adopt a custom myeloid NGS panel from 30 to 51 genes as standard approach.Conversely, analysis of non-myeloid tissues excluded the germline nature of the variants in 7 acute myeloid leukemia cases (5 CEBPA-mutated, 2 TP53). This was further confirmed by therapy-dependent VAF fluctuations and was consistent with the recurrence of variants in these genes as somatic.The incidental finding of a MYD88 variant at 52% VAF in a primary myelofibrosis case, prompted nail DNA testing, which excluded the somatic origin and prevented misclassification of clonality.Accurate tissue selection is crucial for precision diagnostics in MN/BMF, not only to detect germline variants underlying disease predisposition, but also to exclude somatic mutations that could misdirect clinical management. While fibroblasts are the gold standard, nails (and CD3+ cells if chosen wisely) offer a rapid and minimally invasive alternative to distinguish somatic from germline variants. The traditional model of genetic testing management, where germline (hereditary) and somatic (cancer) results are handled through separate pathways and by different specialists, is fragmented, inefficient, and confusing for patients (10.1038/s41591-025-03686-8). We believe our experience supports a "patient-centered" scalable model (Fig 1) in which the two streams of information are integrated from the outset and presented to the patient in a unified manner.

Correspondence on “ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)” by Lee et al

Evaluation of CNV detection tools for prenatal diagnosis using amniotic fluid clinical whole-exome sequencing data.

Clinical Exome Sequencing: A Genetic Diagnostic Approach for Inherited Retinal Dystrophies.

ATP6V0A2-related cutis laxa is a rare autosomal recessive disorder characterized by connective tissue abnormalities, developmental delay, and neurological features. While multiple sequence variants have been reported, exon-level deletions are rarely documented, and their clinical significance remains largely unknown. This study aims to present the clinical and molecular characteristics of a novel frameshift variant and recurrent exon 16 deletions in the ATP6V0A2 gene, to investigate a potential founder effect in southeastern Türkiye, and to contribute to the expanding genotype-phenotype correlation in ATP6V0A2-related cutis laxa. Ten cases from six unrelated families were evaluated. Exome sequencing, clinical exome sequencing, long-range polymerase chain reaction, gel electrophoresis, and haplotype analysis were performed. Variant interpretation followed ACMG and ClinGen guidelines. Clinical features were assessed through physical examination, developmental history, and neuroimaging. A novel homozygous frameshift variant (c.235del, p.Leu79Phefs*13) associated with severe neurological regression was identified in one case. Nine individuals carried a recurrent homozygous 380 bp deletion spanning exon 16 (c.1936-147_2055+113del). In our study, neurological regression-a feature rarely reported in the literature-was noted in two older patients. Haplotype analysis revealed shared homozygous regions in three cases, suggesting a founder effect. This cohort represents the largest reported series of ATP6V0A2-CL cases with exon 16 deletion to date. This study expands the genotypic and phenotypic spectrum of ATP6V0A2-CL and underscores the importance of copy number variation detection in next-generation sequencing-based diagnostics. The identification of a recurrent exon 16 deletion and shared haplotypes provides evidence for a founder effect in southeastern Türkiye and supports the implementation of population-specific screening for this variant.

Dandy-Walker malformation (DWM) is a rare congenital abnormality of the posterior fossa and the cerebellum and has an incidence of 1 in 10 000 to 30 000 births. Although DWM can present in isolation, it is often associated with other central nervous system (CNS) abnormalities or extra-CNS anomalies (DWM+). A molecular cause is not identified in the majority of individuals with DWM+. This is due, in part, to uncertainty regarding optimal testing strategies and an incomplete understanding of the genetic causes of DWM+. In this study, we analyzed clinical exome sequencing (cES) data from 91 individuals with DWM+ to determine its diagnostic efficacy. A definitive or probable diagnosis was made for 32 individuals, yielding a diagnostic rate of 35.2% (32/91). Commercially available brain malformation panels would have detected only 24.2% (8/33) to 54.5% (18/33) of the diagnoses made by cES. We then used data from our cohort, published cases, and mouse models to identify nine phenotypic expansions involving DWM. Our results suggest that cES should be considered for all individuals with DWM+ for whom a molecular diagnosis has not been established and that additional testing to identify a genetic cause of DWM is likely not warranted in individuals with genetic syndromes caused by variants in ANKRD11, C2CD3, COL4A1, KMT2D, KRAS, OPHN1, SHOC2, SMARCB1, and WDR73.

BackgroundUp to 40% of neonatal seizures remain unexplained after standard evaluation, creating a diagnostic imperative. Distinguishing genetic etiologies is critical, as it enables the identification of treatable conditions and informs prognosis and family counseling. In this study, we aimed to define the genetic spectrum of unexplained neonatal seizures in a Chinese cohort.MethodsIn this single-center retrospective case series, we enrolled 40 neonates [2016–2024] admitted to the neonatal intensive care unit with video electroencephalography (vEEG)-confirmed seizures that were “unexplained” after a comprehensive evaluation including neuroimaging and metabolic screening. Exclusion criteria included identified causes such as hypoxic-ischemic encephalopathy or confirmed metabolic disorders. Genetic analysis involved whole-exome sequencing (WES), clinical exome sequencing (CES), WES of patient and parents (trio) (trio-WES), and mitochondrial DNA analysis.ResultsThe cohort included 29 male and 11 female neonates, with a median seizure onset at 1.5 days of life. Pathogenic or likely pathogenic variants were detected in 67.5% (27/40) of cases, including, but not limited to, variants in KCNQ2, ALDH7A1, and SUOX. A dual diagnosis was identified in one individual with compound heterozygous SUOX mutations and a de novoTUBG1 deletion. Additionally, nine of the 28 identified variants were novel. Although diagnostic yields varied among methodologies, the differences were not significant. Three patients with ALDH7A1 mutations achieved seizure freedom with vitamin B6 alone. All patients with SUOX nonsense/frameshift mutations had severe phenotypes and poor outcomes.ConclusionsOur findings demonstrate a high diagnostic yield of next-generation sequencing (NGS) in unexplained neonatal seizures and underscore its clinical utility in pinpointing treatable conditions and prognosticating severe disorders.

In genetic disease assessment centers, DNA sequencing can produce results irrelevant to the genetic examination's purpose. The American College of Medical Genetics and Genomics (ACMG) recommends evaluating and reporting 81 genes discovered using clinical genomic sequencing. While population studies on large cohorts can provide statistics on the prevalence of secondary findings (SFs), no studies have been published yet on large cohorts in Turkiye. We investigated ACMG SF by evaluating clinical exome sequencing data in 1600 individuals from different regions in Turkiye. We detected SF variants reported in ClinVar in 86 individuals (5.375%). Of the SFs, 30% were cardiovascular, 26% were cancer, 16% were neonatal metabolic disorders, and 28% were variants associated with various genetic diseases. In addition, we identified 212 different variants in 226 individuals and 45 different genes, which were not reported in ClinVar. When our results are compared with the Turkish National Genome and Bioinformatics Project database and studies in the literature, the studies vary in terms of participant characteristics, sequencing techniques, and versions of the ACMG SF list. Our findings highlight the importance of expanding and tailoring SF reporting guidelines in populations with high consanguinity and limited cohort-based data.

A woman in her late 20s presented with a 5-year history of progressive fatigue and generalised weakness. Examination revealed signs of premature ageing, anaemia, neuropathy and hepatosplenomegaly.Investigations showed pancytopenia, dimorphic anaemia, severe vitamin B12 deficiency, hepatic fibrosis and pulmonary fibrosis. Despite correction of nutritional deficiencies, the constellation of cytopenia, premature greying, osteoporosis, hepatic and pulmonary fibrosis raised suspicion of a genetic disorder. Clinical exome sequencing identified a monoallelic PARN missense variant (c.613T>C; p.Cys205Arg), classified as a Variant of Uncertain Significance. Germline pathogenic variants in PARN have been associated with dyskeratosis congenita, autosomal recessive 6 (DKCB6) and with telomere-related pulmonary fibrosis and/or bone marrow failure 4. The clinical-genetic correlation in this case supported a diagnosis of a telomere biology disorder (TBD). This case highlights the importance of considering TBDs in young adults with unexplained multisystem disease, even when classical mucocutaneous features are absent. Early recognition is crucial for guiding genetic counselling, surveillance and consideration of bone marrow transplantation in progressive cases.

Variants linked to the risk of ischemic stroke have been discovered through genome-wide association studies (GWASs). These variations frequently have little consequences that lack apparent biological significance. Hence, these findings demonstrate that exome sequencing can be highly relevant to stroke, even though stroke is a complex phenotype with various diseases and risk factors. In this case-control investigation, we used ARMS genotyping to investigate the distribution of polymorphic variations in genes associated with stroke susceptibility. In addition to examine the novel gene variations associated with ischemic stroke we utilized the Illumina NovaSeq 6000 platform for whole-exome sequencing (WES). Results identified 11 novel gene variants in the GSTT4 gene by targeted whole-exome sequencing, including one deletion GSTT4p.Asn232LysfsTer6, one insertion c.688_689insCG, and 9 SNVs c.699 T > C, c.701C > G, c.708G > T, c.710 T > G, c.712A > G, c.712A > G, c.718A > T, c.719G > A, c.721A > T, c.722G > T in the ischemic stroke patients. We also identified several rare, intermediate, and most common gene variants in cholesterol associated genes LDLR, LDLRAD2, LDLRAD3, APOA2, APOA3, APOA4, APOA5, and PCSK9. Also, several common gene variants were reported in MTHFR, KLF14, eNOS3, and ACE by whole-exome sequencing. Furthermore, the eNOS3-GG and eNOS3-GT genotypes were associated with susceptibility to ischemic stroke (OR = 1.95, p < 0.05). This case-control study identified 11 novel GSTT4 variants and several known polymorphisms associated with ischemic stroke risk in Saudi patients. These findings highlight population-specific genetic factors that warrant further functional and large-scale validation.

Nonimmune hydrops fetalis (NIHF) is a severe prenatal condition with a broad etiological spectrum, including chromosomal abnormalities, structural malformations, congenital infections, and inherited metabolic disorders. Early identification of the underlying cause is essential for accurate prognosis, clinical decision-making, and genetic counseling. Here, we report the prenatal diagnosis of a fetus presenting with early-onset NIHF caused by a homozygous missense variant in the SUMF1 gene, detected through first-trimester chorionic villus sampling (CVS). A 27-year-old gravida 5 woman with a history of two previous pregnancies affected by unexplained hydrops fetalis was referred at 12 weeks and 3 days of gestation. Ultrasound examination revealed markedly increased nuchal translucency, generalized hydrops fetalis, and absence of the nasal bone. Given the recurrent phenotype and early gestational presentation, invasive prenatal diagnosis was performed using CVS. Clinical exome sequencing identified a homozygous SUMF1 variant (NM_182760.4: c.538T&gt;A, p.Trp180Arg), which is absent from population databases and has been reported only once in ClinVar as a variant of uncertain significance. Subsequent Sanger sequencing confirmed heterozygous carrier status in both parents and the unaffected sibling, consistent with autosomal recessive inheritance. SUMF1 encodes the sulfatase-modifying factor 1, a critical enzyme required for post-translational activation of all sulfatases. Biallelic pathogenic variants in SUMF1 cause multiple sulfatase deficiency, an ultra-rare lysosomal storage disorder that may present prenatally with hydrops fetalis. The severe and recurrent fetal phenotype observed in this family strongly supports the pathogenic relevance of the identified variant. This case highlights the diagnostic value of early invasive prenatal testing, particularly CVS combined with next-generation sequencing, in pregnancies complicated by early-onset or recurrent NIHF. Early molecular diagnosis enables timely counseling, informed reproductive decision-making, and appropriate planning for future pregnancies.

Objectives The aim of this study was to characterize the clinical features and outcomes of patients with JAK2 V617F- and CALR-unmutated essential thrombocythemia (ET) and to identify potential driver mutations through whole-exome sequencing (WES). Methods This was a cross-sectional study including patients diagnosed with ET between 2007 and 2024. Clinical characteristics and outcomes were compared between patients with and without JAK2V617F and CALR mutations. WES was analyzed in JAK2V617F- and CALR-unmutated ET patients. Results Thirty-nine out of 162 ET patients (24%) were JAK2V617F- and CALR-unmutated. This group was younger than patients in the JAK2V617F mutated group (mean age 53.7 vs. 61.1 years, p = 0.012) and had lower incidence of thrombotic events (5.1% vs. 9.1%, p = 0.327). The median overall survival was 13.51 years compared to 12.61 years in patients with JAK2V617F or CALR mutations (p = 0.63). There were no statistically significant differences in clinical symptoms, incidence of thrombosis, bleeding, myelofibrosis, or leukemic transformation. WES was analyzed in 15 patients. Uncommon MPL mutations were identified, including MPLL265F, MPLP70L, and MPLR321Q. Potential novel CALR mutations were detected in exon 5 (c.540C > T, N180 = ) and exon 6 (c.703-3del). Non-driver gene mutations were detected, including RUNX1 (57.1%), ASXL1, DNMT3A, SETBP1, and MSH6. Discussion and Conclusions Patients with JAK2V617F- and CALR-unmutated ET tend to present at a younger age and exhibit a lower incidence of thrombosis compared to those with JAK2V617F-mutated ET. The application of WES enabled the detection of uncommon and potential driver mutations in JAK2V617F- and CALR-unmutated ET.

Introduction . Aortic arch anomalies, especially the “bovine arch”, can cause the development of an ascending aortic aneurysm. There is a high coefficient of heritability of this pathology, however, genetic studies are rare. Since the “bovine arch” is one of the variants of the development of the aortic arch and large vessels during embryogenesis, this pathology may be associated with genes encoding proteins involved in the embryonic development of the cardiovascular system. Aim: To identify rare, clinically significant variants of genes of cardiovascular embryonic development in patients with sporadic ascending aortic aneurysm and a “bovine arch”. Material and Methods . The study included 42 patients with a sporadic form of ascending aortic aneurysm, including 11 patients with a “bovine arch”. Analysis of the clinical exome was performed based on DNA sequencing data using Clinical Exome Solution (Sophia Genetics, Switzerland) and NextSeq 500 genetic sequencer (Illumina, USA). The search for rare, clinically significant variants (minor allele frequency &lt;1%) was carried out in exons and adjacent introns of 120 genes of embryonic development of the cardiovascular system. Validation of identified variants was performed using Sanger sequencing. Results. In patients with aortic aneurysm and “bovine arch”, the following clinically significant variants were identified: the pathogenic variant c.610-2A&gt;G of the CCDC39 gene, which is a single-nucleotide substitution leading to the loss of the acceptor splice site (ΔScore = 0.97 Spliceailookup) and a variant of uncertain clinical significance (VUS) c.2564T&gt;C in the ANKS6 gene, which has high pathogenicity rates on the CADD (Phred = 28.3) and AlphaMissense (0.972) scales. A likely pathogenic variant c.1151T&gt;C of the ACVR2B gene was identified in the group of patients with aortic aneurysm without supraaortic vessels anomaly (AlphaMissense = 0.966). Among the 38 genes whose sequences revealed VUS in both groups of patients, the protein products of 17 (44.7%) are involved in the functioning of cilia and microtubules, and the proteins encoded by the genes MKS1, CCDC40, DNAAF1, ANKS6, CCDC39, DNAH5, DNAAF3 are also responsible for the development of the cardiovascular system. Conclusion . Rare, clinically significant variants in the CCDC39 and ANKS6 genes, which are crucial for primary cilia function, contribute to the development of sporadic ascending aortic aneurysm in combination with a “bull’s arch.” When a normal aortic arch is present, variants in the ACVR2B gene, belonging to the TGF-beta signaling protein superfamily, play an important role.

IntroductionPaget's disease of bone is a metabolic bone disorder characterized by abnormal bone remodeling and is often detected incidentally through elevated alkaline phosphatase (ALP) or pathological fractures. Presentation with severe hypocalcemia is unusual. Here, we describe a rare case of Paget's disease admitted to the emergency department with profound hypocalcemia and extensive cranial bone involvement.Clinical CaseA 64-year-old woman presented with progressive somnolence and speech difficulties. Neurological evaluation revealed disorientation with a Glasgow Coma Scale score of 11, frontal and temporal bone prominence, and increased head size. Cranial changes had gradually progressed over the previous four years, with hearing loss and recurrent headaches emerging during the last two years. Her vital signs were stable. Chvostek’s and Trousseau’s signs were positive. Arterial blood gas analysis revealed pH 7.39, bicarbonate (HCO₃⁻) 30 mmol/L, and ionized calcium 2.3 mg/dL. Brain CT and diffusion MRI excluded acute stroke and intracranial hemorrhage. ECG demonstrated a prolonged QT interval of 490 ms. Laboratory tests showed severe hypocalcemia (Ca: 4.1 mg/dL), low phosphorus (2.1 mg/dL), markedly elevated ALP (1550 U/L), low vitamin D (<5 ng/mL), elevated parathyroid hormone (PTH: 125 pg/mL), and reduced 24-hour urinary calcium excretion (32 mg/day). She was treated with intravenous calcium infusion together with magnesium, requiring 8–10 ampoules of calcium gluconate daily (≈0.74–0.93 g elemental calcium) to maintain normocalcemia. She also received 150,000 IU/week intramuscular cholecalciferol, and oral calcitriol was initiated at 0.5 mcg/day. Electrolytes and clinical status were monitored daily. Skull X-ray revealed mixed lytic and sclerotic lesions consistent with the classic “cotton wool” appearance. Bone scintigraphy showed diffuse cranial uptake, suggesting active-phase Paget’s disease. The maximal skull thickness measured 6 cm. Given the extensive cranial involvement and unusual biochemical presentation, clinical exome sequencing was performed, which did not reveal any germline variant to explain this presentation. By the 10th day of hospitalization, her oral intake had improved, and intravenous treatment was tapered. She was discharged after stabilization with a prescription including 40,000 IU/week of cholecalciferol, 3 g/day of oral calcium carbonate, and 365 mg/day of oral magnesium supplementation. At her 3-month follow-up, laboratory results were: PTH 40.7 pg/mL, creatinine 0.9 mg/dL, calcium 9.7 mg/dL, phosphorus 3.8 mg/dL, albumin 4.0 g/dL, magnesium 2.0 mg/dL, and ALP 1000 U/L. She received 5 mg intravenous zoledronic acid at that visit.ConclusionThis case illustrates a rare presentation of Paget’s disease with severe hypocalcemia and massive skull involvement. Although radiological findings were consistent with Paget’s disease of bone, other causes of cranial bone thickening, such as osteopetrosis, should be excluded.Figure 1:Lateral skull X-ray of a patient with Paget’s disease of bone, showing massive cranial involvement with mixed lytic and sclerotic changes, giving the classic “cotton wool” appearance. Table 1:Laboratory Findings and Treatment Timeline in Paget’s DiseaseLaboratory parameters at admission and after treatment in a patient with Paget’s disease presenting with profound hypocalcemia and massive skull involvement. The table also summarizes the therapeutic interventions administered during hospitalization and follow-up.

Purpose The sucrase-isomaltase (SI) gene encodes sucrase-isomaltase enzyme found on the intestinal brush-border that has a major function in the hydrolysis of sucrose, oligosaccharides, and starch. Mutations disrupting its function cause genetic sucrase-isomaltase deficiency (GSID). Variants leading to mild to moderate reductions in enzyme activity may mimic disorders of gut–brain interaction (DGBI), and differentiating the etiology is crucial for initiating appropriate treatment. In this study, we aim to determine the rate of GSID in individuals who underwent whole exome or clinical exome sequencing (WES/CES) for indications other than chronic gastrointestinal symptoms in a single-center cohort. We also focused on a second group, the pediatric DGBI patients, who underwent SI gene analysis, to evaluate the rate of GSID in pediatric DGBI patients and assess the clinical utility of SI gene testing in GSID diagnosis. Methods We retrospectively reviewed 980 patients who underwent WES/CES between 2017–2022, and 148 pediatric patients with DGBI evaluated between May 2021 and August 2022 who received SI gene analysis. Results The frequency of symptomatic GSID was found to be 0.3% among patients who underwent WES/CES, whereas it was 10% among pediatric DGBI patients. In DGBI patients carrying SI gene mutations, clinical improvement with a sucrose- and starch-free diet in combination with a sacrosidase response proved effective for establishing a diagnosis in all cases. Conclusion GSID has been frequently detected among pediatric DGBI patients. SI gene analysis combined with a sucrose-restricted diet and a sacrosidase challenge provides a reliable, non-invasive approach for definitive diagnosis.

Congenital insensitivity to pain with anhidrosis (CIPA), caused by biallelic pathogenic variants in the NTRK1 gene, is a rare disorder characterized by the loss of pain sensation, anhidrosis, and impaired temperature regulation. We present a clinical case of a 2-year-old male Chinese patient, compound heterozygous for 2 NTRK1 pathogenic variants-c.851-33T>A and c.1805G>A-confirmed by clinical exome sequencing. The patient exhibited classic CIPA symptoms, including recurrent fever episodes, xerotic skin, sparce hair, abnormality of the dentition, and anhidrosis. The child also displayed preserved fine touch but lacked pain response to stimuli, emphasizing the clinical challenges posed by pain insensitivity, including an increased risk of injury. Multidisciplinary management approach involving dermatology, pediatrics, pediatric neurology, pediatric dentistry, pain management, and genetics was coordinated. This case reinforces the importance of early diagnosis and lifelong palliative care to prevent complications and manage symptoms. In addition, this report highlights the higher prevalence of CIPA in Asian populations and the need for ongoing research to explore potential therapeutic interventions targeting pain perception and neurodevelopmental pathways.

To evaluate whether the causative variants found upon clinical exome sequencing in fetuses affected with selected structural anomalies would also be detected if PanelApp-R21 or Human Phenotype Ontology (HPO)-driven gene selection terms were applied instead. During 9 years (2016-2024), the whole exome was sequenced in 206 pregnancies with selected fetal structural anomalies, with prospective interpretation of about 5000 morbid OMIM genes. Retrospectively, 79 causative and 19 incidental findings were reviewed and assessed for their detectability under two alternative strategies: PanelApp-R21 or HPO-driven gene lists. Among the 79 causative genes identified by interpreting morbid OMIM genes in 78 structurally abnormal fetuses, PanelApp-R21 was able to detect 76 (96%) genes, while HPO-driven terms identified only 56 (71%). For 19 incidental findings, the PanelApp-R21 pathway could identify eight (42%), while HPO terms captured only one (5.3%). In prenatal ES, reliance on HPO-driven gene selection significantly lowers diagnostic yield compared with clinical ES, with nearly one-third of primary findings and most incidental findings missed. PanelApp represents a pragmatic alternative, preserving a high primary diagnostic yield while limiting incidental findings.

To report a case of non-hereditary bilateral foveomacular and peripheral retinoschisis in a young female, with electrophysiological abnormalities in the absence of high myopia. A 25-year-old female with recent-onset diminution of vision in the left eye (LE) underwent comprehensive ophthalmic evaluation including best-corrected visual acuity (BCVA), slit lamp biomicroscopy, indirect ophthalmoscopy, optical coherence tomography (OCT), full field electroretinography (ERG) and genetic evaluation. BCVA at presentation was 6/6, N6 in the right eye(RE) and 6/9, N8 in the LE. The patient had a prior history of laser refractive surgery for moderate myopia. Anterior segment examination was unremarkable. Fundus evaluation revealed bilateral foveoschisis and peripheral retinal schisis. OCT showed retinoschisis predominantly involving outer plexiform and outer nuclear layer, along with mild vitreoschisis. Foveal detachment was noted in the LE. ERG demonstrated rod and cone system dysfunction, severe rod bipolar cell dysfunction in both eyes, and a borderline electronegative waveform in the LE. There was no family history, and clinical exome sequencing did not reveal any pathogenic variants associated with the phenotype. Electrophysiological abnormalities with bipolar cell dysfunction, similar to those seen in hereditary retinoschisis, can also occur in non-hereditary retinoschisis. Genetic evaluation is recommended to differentiate between the two, as ERG may show abnormalities in both.

BACKGROUND Stickler syndrome is a genetically heterogeneous connective tissue disorder caused by mutations in collagen genes (COL2A1, COL11A1, COL11A2, COL9A1, and COL9A2). It is characterized by a distinctive craniofacial appearance, high myopia, vitreoretinal degeneration, hearing loss, and early-onset arthritis. Type 1, the most common autosomal-dominant form, results from COL2A1 variants and is strongly associated with ocular complications, including high myopia, vitreous degeneration, and retinal detachment. Early recognition of systemic and ocular findings is essential for timely management and genetic counseling. CASE REPORT An 8-year-old Saudi girl presented to the emergency department with sudden deterioration of vision in the right eye. External examination revealed midfacial hypoplasia. Ophthalmologic evaluations, including best-corrected visual acuity measurement, fundus photography, optical coherence tomography, and genetic testing, were performed. Rhegmatogenous retinal detachment was identified and surgically managed. Revision surgery was performed; at 3 years post-revision, best-corrected visual acuity in the right eye had improved to 20/30. The family history included childhood retinal detachment in the patient's father. Clinical exome sequencing identified a novel heterozygous COL2A1 frameshift variant, c.3642delT (p.Gly1215Alafs*12), that introduced a premature stop codon; Sanger sequencing confirmation and segregation analysis were consistent with pathogenicity. CONCLUSIONS This report describes a previously undocumented COL2A1 frameshift variant causing Stickler syndrome type 1. The truncating mutation may be associated with the early-onset, ocular-predominant presentation observed in the present case. This variant expands the known COL2A1 mutational spectrum and underscores the importance of molecular testing for accurate diagnosis and family counseling in pediatric collagenopathies.

Neurodegenerative diseases (ND) represent a growing worldwide problem due to the increase in population aging that is advancing rapidly and where age is the most recognized risk factor for the development of multiple ND. Population aging is occurring more rapidly in low- and middle-income countries, such as Panama, making it a priority for the country to identify genetic factors associated with these conditions at an early stage, which is necessary information for the development of effective preventive and therapeutic strategies. The objective of this study was to identify genetic variants related to ND in older adults in Panama. A total of 44 DNA samples from participants ≥ 50 years recruited in the community by the Panama Aging Research Initiative-Health Disparities (PARI-HD) were analyzed by massive sequencing using clinical exome. The data obtained were analyzed using a customized virtual panel for the identification of variants in 138 genes related to ND. A total of 294 genetic variants were identified, 73.9% being benign, 20.7% variants of uncertain significance (VUS), 3.4% probably pathogenic and 2.0% pathogenic. Presenting variants such as CR1 and TREM2 related to Alzheimer's disease, PRKN, NEFH and GIGYF2 related to Parkinson's disease, HLA-DRB1 with multiple sclerosis, amyotrophic lateral sclerosis and GRN variant related to frontotemporal dementia. This study establishes the basis for a better understanding of genetic risk factors in our population, and is conducive to the integration of massive sequencing as a tool for the personalization of the clinical management of these pathologies.