Search Results (91)

Twenty causative genes have been reported that cause non-syndromic childhood glaucoma associated with anterior segment dysgenesis. FOXC1, PAX6 and PITX2 are the most well-known, but cases linked to SLC4A11, PITX3 and SOX11 have also been reported. As genetic testing becomes increasingly widespread and rates of molecular diagnosis rise, the extent of phenotypic overlap between the different genetic causes of non-syndromic glaucoma associated with anterior segment dysgenesis is becoming more evident. Taking aniridia as an example, whilst PAX6 mutations remain the predominant cause, variants in CYP1B1, FOXC1, PXDN and SOX11 have also been reported in patients with childhood glaucoma and aniridia. Developments in molecular-based therapies for retinal and corneal disease are advancing rapidly, and pre-clinical studies of gene-based treatments for glaucoma and aniridia are showing promising results. Use of adeno-associated viral vectors for gene delivery is most common, with improvements in intraocular pressure and retinal ganglion cell survival in Tg-MYOC^Y437H mouse models of glaucoma, and successful correction of a germline PAX6^G194X nonsense variant in mice using CRISPR-Cas9 gene editing. This review will explore the actions and interactions of the genetic causes of non-syndromic glaucoma associated with anterior segment dysgenesis and discuss the current developments in molecular therapies for these patients. Full article

Background: Differences of sex development (DSD) are a group of congenital conditions characterized by atypical development of genital structures. The diagnosis is complex and involves clinical, hormonal, and genetic evaluations. Objective: To describe the clinical profile, diagnosis, and management of patients with DSD, with particular attention to genetic diagnosis. Study design: Retrospective study from a tertiary care pediatric hospital in Italy. Methods: 420 patients with DSD referred to the Endocrine Unit of Bambino Gesù Children’s Hospital in Rome, Italy, between 2016 and 2023 were included. Results: 75 patients had a 46,XY karyotype, 135 had a 46,XX karyotype, and 210 had chromosomal mosaicism. In our group of pediatric DSD patients, 21/420 patients were born from pregnancies induced with assisted reproduction techniques (ICSI/FIVET). Of these 21 patients, 5 had sex chromosome mosaicism. Using next-generation sequencing (NGS), we identified three new genetic variants: one in the AR gene, one in the NR5A1 gene, and one in the SRY gene. The use of NGS significantly improved the diagnostic yield, and a definitive diagnosis was reached in 84.76% of the entire cohort. Conclusions: This study highlights the challenges in the management of patients with DSD from early recognition to treatment and follow-up. A multidisciplinary approach is essential for a comprehensive evaluation of these conditions and to understand the role and clinical significance of the genetic variants. Full article

Temporal changes in testicular traits have been reported in both humans and dogs. Analysis of % living sperm and motility from semen collections from 186 Labrador Retrievers and 113 Golden Retrievers between 2006 and 2023, and of incidents of cryptorchidism in over 15,000 dogs of the same breeds and crosses born between 1994 and 2023 was undertaken to determine influential factors. A general temporal increase in incidence of cryptorchidism masked significant differences in the trend between breeds, which persisted after accounting for genetic and litter effects. The incidence in the F1 cross was significantly lower than in either pure breed, implying hybrid vigour. The semen traits were both moderately repeatable within individuals, but this belied breed differences in its composition; for both traits, only the heritability was significantly greater than zero in the Golden Retriever, while only the permanent environment effect was present in Labrador Retrievers. There were significant negative temporal trends in Golden Retrievers for both semen traits, but not in Labrador Retrievers; significant negative effects of age (except on % motility in Labrador Retrievers); and significant negative effects of a diagnosis of benign prostatic hyperplasia on both traits in both breeds. These results reveal complex breed by environment interactions in traits related to testicular form and function. Full article

Collagen IV α1/α2 heterotrimers are the major constituents of all basement membranes (BM). Consistently, COL4A1/A2 mutations cause a complex multisystem disorder. While mouse models are invaluable, they alone cannot support the rapid functional validation needed for clinical translation. The FishCOLler project establishes zebrafish as a scalable in vivo platform to model COL4A1/A2 disease, employ rapid assays to monitor key disease traits, and enable mechanistic studies. Our first fish disease faithfully models patient symptoms, i.e., brain hemorrhage and ocular dysgenesis. The work supports FishCOLler as a platform for rapid variant interpretation, therapeutics testing, and highlights potential consequences of gene dosage modulation strategies. Full article

Peters anomaly (PA) is a rare congenital disorder within the anterior segment dysgenesis (ASD) spectrum, characterized by corneal opacity, iridocorneal adhesions, and potential systemic involvement. The genetic basis of PA and related syndromes are complex and incompletely understood. This study investigates novel genetic variants and their clinical impact in two unrelated individuals diagnosed with PA spectrum disorder. Whole-exome sequencing (WES), long-range PCR, and breakpoint analysis were applied to identify pathogenic variants. In the first patient, a heterozygous ~1.6 Mb deletion was detected, spanning the genes PEX2 and ZFHX4 (GRCh37 chr8:g.76760782_78342600del). The second patient carried a heterozygous FOXC1 variant (NM_001453.3:c.310A>G), classified as likely pathogenic. Both variants were confirmed by Sanger sequencing and considered de novo, as they were not present in the biological parents. Clinical evaluations revealed phenotypic variability, with the first patient displaying both ocular and systemic anomalies as in a Peters plus-like syndrome phenotype, while the second patient had isolated ocular manifestations as in a PA type 1 phenotype. These findings expand the genetic landscape of PA, underscoring the importance of comprehensive genomic analysis in subclassifying ASD disorders. Further studies are needed to elucidate the functional consequences of these variants and improve diagnostic and therapeutic strategies. Full article

Background/Objectives: Inherited retinal diseases (IRDs) are a heterogeneous group of rare eye disorders characterized by progressive photoreceptor degeneration, leading to severe visual impairment or even blindness. This study aims to investigate the prevalence, types, and clinical significance of ophthalmic comorbidities in Portuguese patients with IRDs. Methods: This nationwide Portuguese population-based retrospective study was based on the IRD-PT registry (retina.com.pt). Statistical analysis was conducted using Microsoft^® Excel^® for Microsoft 365 and IBM SPSS Statistics version 29.0.2.0. Informed consent was obtained from all participants. Results: A total of 1531 patients (1254 families) from six centers were enrolled. The cohort consisted of 51% males, with a mean age of 45.8 ± 19.3 years and a mean age at diagnosis of 39.4 ± 19.5 years. Overall, ocular comorbidities were reported in 644 patients (42.1%). In 176 individuals (11.5%), multiple concurrent comorbidities were found. Cataract was the most common comorbidity (21.3%), followed by amblyopia (6.3%) and high myopia (5.9%). Statistically significant associations with ocular comorbidities were observed in isolated progressive IRDs. Specifically, AR RP was associated with cataract (p < 0.001), and gene analysis revealed several significant associations. CRB1 was statistically linked to epiretinal membrane (ERM) (p = 0.003), EYS with cataract (p = 0.001), PROM1 with choroidal neovascularization (CNV) (p = 0.0026), and USH2A with macular hole (p = 0.01). Patients with the RPE65 mutation in Leber congenital amaurosis were associated with ERM (p = 0.019). There was also a significant association between X-linked RP and high myopia (p < 0.001) and CNV in Best disease (p < 0.001); in syndromic IRDs, cataract, cystoid macular edema, and ERM were observed in Usher syndrome, p = 0.002, p = 0.002, and p = 0.005, respectively, and the MYO7A gene was linked to cataract (p = 0.041) and strabismus (p = 0.013); pseudoxanthoma elasticum was significantly associated with CNV (p = 0.002); and foveal hypoplasia was associated with anterior segment dysgenesis (p < 0.001). Conclusions: This study enhances the current understanding of ocular comorbidities in IRDs in Portuguese patients. Common findings were cataract, refractive error, and CME. Stationary IRDs and pattern dystrophies showed fewer concomitant comorbidities, supporting their classification as non-progressive or benign conditions. The significance of registries like IRD-PT cannot be overstated, particularly in the context of rare diseases. These databases serve multiple crucial functions in enabling detailed documentation of disease characteristics and long-term monitoring of disease progression. Full article

Background: Primary congenital glaucoma (PCG) is a rare disease with an incidence of 1 in 12,000 to 18,000 in Europeans. The scarcity of the disease and limited access to genetic testing have hindered research, particularly within the Latvian population. Objectives: This study aims to present the preliminary results of a molecular genetic investigation into PCG in a Latvian cohort and to compare the prevalence of gene CYP1B1 variants with other European studies as well as to the general population in Latvia. Methods: Twenty probands with clinically diagnosed PCG and 36 family members enrolled in the study. Genetic testing was conducted using genomic DNA from peripheral blood using next generation sequencing (NGS) of seven selected genes: CYP1B1, FOXC1, FOXE3, PXDN, PITX2, PITX3, PAX6, and CPAMD8. Four probands had whole-genome sequencing (WGS). Results: All participants were of European ancestry, with no family history of PCG. Most probands were diagnosed in their first year of life, with a female to male ratio of 1:1.2 and with 80.0% of cases being unilateral. No CYP1B1 pathogenic variants were identified in the screened subjects. However, a heterozygous missense variant c.4357C>A (p.Pro4357Thr) in the PXDN gene was found in one proband and one of her parents that was classified as a variant of uncertain significance. Conclusions: This study represents the first genetic characterization of PCG in the Latvian population. Using NGS, we identified no pathogenic variants in the CYP1B1 gene among affected individuals. Preliminary evidence from this cohort does not support CYP1B1 variants as a predominant cause of PCG, though larger studies are needed to confirm this observation. Comprehensive genetic screening using whole-exome or whole-genome sequencing will be essential to identify the underlying genetic etiology of PCG in Latvia. Full article

Congenital hypothyroidism (CH) is among the most common endocrine disorders in neonates. Genetic testing is essential for elucidating the underlying etiology, especially in cases of permanent CH. We enrolled 32 patients diagnosed with permanent CH from the Pediatric Endocrinology Clinics at Jeju National University Hospital and Soonchunhyang University Cheonan Hospital. Whole-exome sequencing (WES) was performed on genomic DNA extracted from buccal swabs. Variants were classified according to guidelines established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). WES identified 21 distinct genetic variants in 20 of the 32 patients (62.5%), spanning 6 CH-related genes: DUOX2, DUOXA2, TPO, PAX8, TG, and TSHR. Of these, 12 variants classified as pathogenic or likely pathogenic were detected in 15 patients (50%). When classified by inheritance patterns, nine patients had either homozygous (n = 1) or compound heterozygous (n = 8) variants, four patients exhibited oligogenic variants, and two patients carried a single heterozygous variant with pathogenicity. The most frequently affected gene was DUOX2, with pathogenic or likely pathogenic variants found in six patients. Notably, none of the six patients with thyroid agenesis or ectopic thyroid glands harbored detectable pathogenic variants. Our findings underscore the critical role of genetic analysis in determining the etiology of permanent CH. Whole-exome sequencing demonstrated a high prevalence of pathogenic variants, particularly in DUOX2, in Korean patients with CH. These data enhance our understanding of the genetic architecture of CH and have important implications for personalized treatment and genetic counseling. Full article

Background/Objectives: To assess the association of residential-level maternal particulate matter of 2.5 μm diameter or less (PM_2.5) exposure during pregnancy with anterior segment dysgenesis (ASD) risk. Methods: This study used data from children diagnosed with ASD (i.e., aniridia, iris hypoplasia, Peters anomaly, Axenfeld–Rieger syndrome, or primary congenital glaucoma) by an experienced pediatric ophthalmologist at a National Referral Center for Rare Diseases between 2004 and 2021 and their biological mothers. Individual PM_2.5 exposure concentration was assessed by reference to residential addresses and district-specific PM_2.5 concentrations predicted by the universal Kriging prediction model. Results: The study included 2328 children (582 ASD cases and 1746 controls [1:3 matched for birth year, sex, and birth-place]). The mean (SD) annual PM_2.5 exposure was 29.2 (16.9) μg/m³. An IQR increase in PM_2.5 during the preconception period (11.6 μg/m³; RR, 1.18; 95% CI, 1.03–1.34), the 1st trimester (11.1 μg/m³; RR, 1.15; 95% CI, 1.03–1.27), and the 2nd trimester (11.2 μg/m³; RR 1.14; 95% CI, 1.01–1.29) significantly increased ASD risk. Meanwhile, the association between IQR increase in PM_2.5 during the 3rd trimester and ASD risk showed borderline significance (11.0 μg/m³; RR, 1.10; 95% CI, 0.99–1.21). An IQR increase in PM_2.5 (6.9 μg/m³) from the preconception period to the 3rd trimester was associated with a significantly increased risk of ASD (RR, 1.13; 95% CI, 1.08–1.20). Conclusions: The findings of this study suggest that PM_2.5 exposure during the preconception period and pregnancy is associated with increased risk of ASD, supporting a need for further improvements in air quality to prevent congenital ocular anomalies. Full article

The CYP1B1 gene encodes a cytochrome p450 monooxygenase enzyme, and over 150 variants have been associated with a spectrum of eye diseases, including primary congenital glaucoma, anterior segment dysgenesis, juvenile open-angle glaucoma, and primary open-angle glaucoma. Clinical genetics has yielded insights into the functions of the various CYP1B1 gene domains; however, animal studies are required to investigate the molecular role of CYP1B1 in the eye. While both zebrafish and mice express CYP1B1 in the developing eye, embryonic studies have shown disparate species-specific functions. In zebrafish, CYP1B1 regulates ocular fissure closure such that overexpression causes a remarkable phenotype consisting of the absence of the posterior eye wall. Adult CYP1B1 null zebrafish lack an ocular phenotype but show mild craniofacial abnormalities. In contrast, CYP1B1^−/− mice display post-natal mild to severe trabecular meshwork degeneration due to increased oxidative stress damage. Interestingly, the retinal ganglion cells in CYP1B1 null mice may be more susceptible to damage secondary to increased intraocular pressure. Future studies, including detailed genotype–phenotype information and animal work elucidating the regulation, substrates, and downstream effects of CYP1B1, will yield important insights for developing molecularly targeted therapies that will aim to prevent vision loss in CYP1B1-related eye diseases. Full article

The relatively rare proximal 17q12 microdeletion, including the deletion of the HNF1B gene, is associated with renal cysts and diabetes syndrome (RCAD). This genomic rearrangement results in a wide range of phenotypes, including renal cysts and diabetes, which are consistent with maturity-onset diabetes of the young type 5 (MODY5), Mullerian aplasia/dysgenesis, autism spectrum disorder and schizophrenia, speech delay, learning difficulties, transient neonatal hypercalcemia, and neonatal cholestasis. We describe a girl with a 17q12 microdeletion identified using CGH array analysis (about 1.4 Mb, including HNF1B and LHX1 genes). The same deletion was identified in her mother. The proband had shown cystic and hypodysplastic bilateral kidneys since birth and hypertension, while her mother had bilateral renal cysts and diabetes. Despite suggestive findings in the girl and in the mother, no clinical suspicion arose, and genetic testing was carried out only after referral to a pediatric nephrologist. In children, the identification of 17q12 microdeletion may have a significant impact on the diagnosis, prognosis, and management of renal disease and early-onset type II diabetes. This family with a 17q12 microdeletion confirms intrafamilial phenotypic variability and highlights the importance of including it early on in the analysis of the diagnostic workup of children with renal cystic diseases. Full article

(1) Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder, the symptoms of which include both ocular and systemic abnormalities. In the studied subjects, the cornea was significantly opacified with peripheral scarring neovascularization, which is not specific to this syndrome. A suspicion of incorrect diagnosis was raised despite an initial diagnosis of a bilateral Chandler syndrome. (2) In order to provide the proper diagnosis, a DNA sequencing genetic test was conducted with three sisters carrying the presence of a genome imbalance in the FOXC1 gene. The aim of this study is to report a case of a Polish family with a novel gene mutation and its relation with ARS. (3) Our findings implicate the novel deletion of the FOXC1 gene in the pathogenesis of ARS in the affected family. The phenotypic variability observed, including differences in corneal and systemic anomalies, underscores the importance of genetic testing and suggests the influence of non-genetic factors on ARS manifestation. Full article

Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype–phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4–100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP–response–element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient’s genotype for a correct diagnostic confirmation. Full article

Background/Objectives: In recent years, changing paradigms, both culturally and scientifically, have fundamentally altered the approach to the treatment of children with Disorders of Sexual Development (DSD) prior to reaching the age of legal consent. In Germany, the situation changed with the introduction of legislation that includes a partial ban on DSD surgery in children in 2021. This study aims to analyze the impact of this legislation on clinical practice. Methods: From 2014 to 2024, all patients with DSD in our institution were included. The study group comprised all patients operated on after the legislation. All patients operated on before the legislation served as the control group. Karyotype, phenotype, resulting type of DSD, age at presentation and age at operation were recorded. Results: A total of 35 patients were included in this study, with 15 in the study group and 20 in the control group. The operation was authorized by the family court for all patients in the study group. A total of 46,XY patients with severe hypospadias and clinical aspect of intersexual outer genitalia were the largest proportion (25 patients, 71.4%). Nine patients (25.7%) were 46,XX girls with classical congenital adrenal hyperplasia (CAH) type. One patient (2.9%) showed a mixed gonadal dysgenesis. The mean age of the patients at first presentation in our institution was 10.7 months in the control group and 11.0 months in the study group. The mean age at operation was significantly higher in the study group (20.1 months) compared to the control group (15.1 months; p = 0.032, unpaired t-test). Conclusions: The introduction of the legislation with a partial ban of genital surgery in DSD children in Germany has led to a significant delay in surgery. Since the majority of the patients comprise severe hypospadias and 46,XX CAH patients, further amendments of the law are proposed to minimize potential harm. Full article

Background: Duplications on the short arm of chromosome X, including the gene NR0B1, have been associated with gonadal dysgenesis and with male to female sex reversal. Additional clinical manifestations can be observed in the affected patients, depending on the duplicated genomic region. Here we report one of the largest duplications on chromosome X, in a Lebanese patient, and we provide the first comprehensive review of duplications in this genomic region. Case Presentation: A 2-year-old female patient born to non-consanguineous Lebanese parents, with a family history of one miscarriage, is included in this study. The patient presents with sex reversal, dysmorphic features, optic atrophy, epilepsy, psychomotor and neurodevelopmental delay. Single nucleotide variants and copy number variants analysis were carried out on the patient through exome sequencing (ES). This showed an increased coverage of a genomic region of around 23.6 Mb on chromosome Xp22.31-p21.2 (g.7137718-30739112) in the patient, suggestive of a large duplication encompassing more than 60 genes, including the NR0B1 gene involved in sex reversal. A karyotype analysis confirmed sex reversal in the proband presenting with the duplication, and revealed a balanced translocation between the short arms of chromosomes X and 14:46, X, t(X;14) (p11;p11) in her/his mother. Conclusions: This case highlights the added value of CNV analysis from ES data in the genetic diagnosis of patients. It also underscores the challenges encountered in announcing unsolicited incidental findings to the family. Full article