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1.
Life (Basel) ; 14(6)2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38929714

ABSTRACT

The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli. These variants functionally converge towards the overactivation of the pathway, leading to various constitutional and mosaic conditions. These syndromes show overlapping though distinct clinical presentations and share congenital heart defects, hypertrophic cardiomyopathy (HCM), and lymphatic dysplasia as major clinical features, with highly variable prevalence and severity. Available treatments have mainly been directed to target the symptoms. However, repurposing MEK inhibitors (MEKis), which were originally developed for cancer treatment, to target evolutive aspects occurring in these disorders is a promising option. Animal models have shown encouraging results in treating various RASopathy manifestations, including HCM and lymphatic abnormalities. Clinical reports have also provided first evidence supporting the effectiveness of MEKi, especially trametinib, in treating life-threatening conditions associated with these disorders. Nevertheless, despite notable improvements, there are adverse events that occur, necessitating careful monitoring. Moreover, there is evidence indicating that multiple pathways can contribute to these disorders, indicating a current need to more accurate understand of the underlying mechanism of the disease to apply an effective targeted therapy. In conclusion, while MEKi holds promise in managing life-threatening complications of RASopathies, dedicated clinical trials are required to establish standardized treatment protocols tailored to take into account the individual needs of each patient and favor a personalized treatment.

2.
Eur J Hum Genet ; 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824260

ABSTRACT

Hypertrophic cardiomyopathy (HCM) is the major contributor to morbidity and mortality in Noonan syndrome (NS). Gain-of-function variants in RAF1 are associated with high prevalence of HCM. Among these, NM_002880.4:c.770C > T, NP_002871.1:p.(Ser257Leu) accounts for approximately half of cases and has been reported as associated with a particularly severe outcome. Nevertheless, comprehensive studies on cases harboring this variant are missing. To precisely define the phenotype associated to the RAF1:c.770C > T, variant, an observational retrospective analysis on patients carrying the c.770C > T variant was conducted merging 17 unpublished patients and literature-derived ones. Data regarding prenatal findings, clinical features and cardiac phenotypes were collected to provide an exhaustive description of the associated phenotype. Clinical information was collected in 107 patients. Among them, 92% had HCM, mostly diagnosed within the first year of life. Thirty percent of patients were preterm and 47% of the newborns was admitted in a neonatal intensive care unit, mainly due to respiratory complications of HCM and/or pulmonary arterial hypertension. Mortality rate was 13%, mainly secondary to HCM-related complications (62%) at the average age of 7.5 months. Short stature had a prevalence of 91%, while seizures and ID of 6% and 12%, respectively. Two cases out of 75 (3%) developed neoplasms. In conclusion, patients with the RAF1:c.770C > T pathogenic variant show a particularly severe phenotype characterized by rapidly progressive neonatal HCM and high mortality rate suggesting the necessity of careful monitoring and early intervention to prevent or slow down the progression of HCM.

3.
J Pediatr ; 274: 114177, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38945442

ABSTRACT

OBJECTIVE: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. STUDY DESIGN: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield. RESULTS: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions, and 11% reclassified. Beckwith-Wiedemann spectrum was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PIK3CA-related overgrowth spectrum had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. Vascular overgrowth demonstrated significant clinical overlap with other syndromes. A molecular diagnosis of isolated LO proved challenging, with only 21% of cases classifiable into a specific condition. CONCLUSIONS: LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which is crucial for addressing potential cancer predisposition, enabling precision medicine treatments, and guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of a tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.

4.
Hum Genet ; 143(6): 761-773, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38787418

ABSTRACT

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.


Subject(s)
DNA Methylation , Intellectual Disability , Humans , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Male , Female , Haploinsufficiency/genetics , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/diagnosis , Child
5.
Blood Cells Mol Dis ; 107: 102859, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38820707

ABSTRACT

We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.


Subject(s)
Blood Transfusion , Deferasirox , Deferiprone , Deferoxamine , Iron Chelating Agents , Iron , Pyridones , beta-Thalassemia , Humans , Iron Chelating Agents/therapeutic use , beta-Thalassemia/mortality , beta-Thalassemia/therapy , beta-Thalassemia/drug therapy , beta-Thalassemia/complications , Female , Male , Adult , Retrospective Studies , Deferoxamine/therapeutic use , Deferiprone/therapeutic use , Iron/metabolism , Deferasirox/therapeutic use , Pyridones/therapeutic use , Iron Overload/etiology , Iron Overload/drug therapy , Benzoates/therapeutic use , Ferritins/blood , Adolescent , Triazoles/therapeutic use , Young Adult , Child , Treatment Outcome , Middle Aged , Liver/metabolism , Liver/drug effects , Liver/pathology , Cohort Studies
6.
HGG Adv ; 5(3): 100309, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-38751117

ABSTRACT

Analysis of genomic DNA methylation by generating epigenetic signature profiles (episignatures) is increasingly being implemented in genetic diagnosis. Here we report our experience using episignature analysis to resolve both uncomplicated and complex cases of neurodevelopmental disorders (NDDs). We analyzed 97 NDDs divided into (1) a validation cohort of 59 patients with likely pathogenic/pathogenic variants characterized by a known episignature and (2) a test cohort of 38 patients harboring variants of unknown significance or unidentified variants. The expected episignature was obtained in most cases with likely pathogenic/pathogenic variants (53/59 [90%]), a revealing exception being the overlapping profile of two SMARCB1 pathogenic variants with ARID1A/B:c.6200, confirmed by the overlapping clinical features. In the test cohort, five cases showed the expected episignature, including (1) novel pathogenic variants in ARID1B and BRWD3; (2) a deletion in ATRX causing MRXFH1 X-linked mental retardation; and (3) confirmed the clinical diagnosis of Cornelia de Lange (CdL) syndrome in mutation-negative CdL patients. Episignatures analysis of the in BAF complex components revealed novel functional protein interactions and common episignatures affecting homologous residues in highly conserved paralogous proteins (SMARCA2 M856V and SMARCA4 M866V). Finally, we also found sex-dependent episignatures in X-linked disorders. Implementation of episignature profiling is still in its early days, but with increasing utilization comes increasing awareness of the capacity of this methodology to help resolve the complex challenges of genetic diagnoses.


Subject(s)
DNA Methylation , Neurodevelopmental Disorders , Humans , DNA Methylation/genetics , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/diagnosis , Male , Female , Transcription Factors/genetics , Child , Epigenesis, Genetic , Child, Preschool , DNA-Binding Proteins/genetics , Mutation , Adolescent
8.
HGG Adv ; 5(3): 100289, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-38571311

ABSTRACT

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by pathogenic variants in TCF4, leading to intellectual disability, specific morphological features, and autonomic nervous system dysfunction. Epigenetic dysregulation has been implicated in PTHS, prompting the investigation of a DNA methylation (DNAm) "episignature" specific to PTHS for diagnostic purposes and variant reclassification and functional insights into the molecular pathophysiology of this disorder. A cohort of 67 individuals with genetically confirmed PTHS and three individuals with intellectual disability and a variant of uncertain significance (VUS) in TCF4 were studied. The DNAm episignature was developed with an Infinium Methylation EPIC BeadChip array analysis using peripheral blood cells. Support vector machine (SVM) modeling and clustering methods were employed to generate a DNAm classifier for PTHS. Validation was extended to an additional cohort of 11 individuals with PTHS. The episignature was assessed in relation to other neurodevelopmental disorders and its specificity was examined. A specific DNAm episignature for PTHS was established. The classifier exhibited high sensitivity for TCF4 haploinsufficiency and missense variants in the basic-helix-loop-helix domain. Notably, seven individuals with TCF4 variants exhibited negative episignatures, suggesting complexities related to mosaicism, genetic factors, and environmental influences. The episignature displayed degrees of overlap with other related disorders and biological pathways. This study defines a DNAm episignature for TCF4-related PTHS, enabling improved diagnostic accuracy and VUS reclassification. The finding that some cases scored negatively underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants.


Subject(s)
DNA Methylation , Hyperventilation , Intellectual Disability , Transcription Factor 4 , Humans , Transcription Factor 4/genetics , Hyperventilation/genetics , Hyperventilation/diagnosis , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Female , Male , Child , Facies , Adolescent , Epigenomics/methods , Epigenesis, Genetic , Hyperkinesis/genetics , Child, Preschool , Adult , Young Adult
9.
Ann Hematol ; 103(7): 2283-2297, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38503936

ABSTRACT

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent ß-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time.


Subject(s)
Blood Transfusion , Iron Overload , beta-Thalassemia , Humans , Female , Iron Overload/mortality , Iron Overload/blood , Iron Overload/etiology , Male , beta-Thalassemia/therapy , beta-Thalassemia/mortality , beta-Thalassemia/blood , beta-Thalassemia/complications , Adult , Retrospective Studies , Adolescent , Ferritins/blood , Young Adult , Middle Aged , Iron/blood , Iron/metabolism , Cohort Studies , Child , Follow-Up Studies , Italy/epidemiology
10.
Eur J Hum Genet ; 32(6): 619-629, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38351292

ABSTRACT

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.


Subject(s)
DNA Methylation , Facies , Hirschsprung Disease , Homeodomain Proteins , Intellectual Disability , Microcephaly , Repressor Proteins , Zinc Finger E-box Binding Homeobox 2 , Humans , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Zinc Finger E-box Binding Homeobox 2/genetics , Zinc Finger E-box Binding Homeobox 2/metabolism , Microcephaly/genetics , Microcephaly/diagnosis , Microcephaly/pathology , Hirschsprung Disease/genetics , Hirschsprung Disease/diagnosis , Hirschsprung Disease/pathology , Homeodomain Proteins/genetics , Repressor Proteins/genetics , Female , Male , Child , Child, Preschool , Adolescent , CpG Islands
11.
Am J Hematol ; 99(3): 490-493, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38165006

ABSTRACT

Rate and risk factors for phenoconversion from non-transfusion-dependent ß-thalassemia (NTDT) to transfusion-dependent ß-thalassemia (TDT) during a 10-year follow up of adult patients in Italy.


Subject(s)
beta-Thalassemia , Adult , Humans , beta-Thalassemia/therapy , Blood Transfusion , Risk Factors , Italy
13.
Genes (Basel) ; 14(12)2023 11 27.
Article in English | MEDLINE | ID: mdl-38136956

ABSTRACT

PIK3CA-related disorders encompass many rare and ultra-rare conditions caused by somatic genetic variants that hyperactivate the PI3K-AKT-mTOR signaling pathway, which is essential for cell cycle control. PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations and PIK3CA-related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping. Therefore, diagnosis and management frequently involve various health specialists. Given the rarity of these disorders and the limited number of centers offering optimal care, the Scientific Committee of the Italian Macrodactyly and PROS Association has proposed a revision of the most recent recommendations for the diagnosis, molecular testing, clinical management, follow-up, and treatment strategies. These recommendations give insight on molecular diagnosis, eligible samples, preferable sequencing, and validation methods and management of negative results. The purpose of this paper is to promote collaboration between health care centers and clinicians with a joint shared approach. Finally, we suggest the direction of present and future research studies, including new systemic target therapies, which are currently under evaluation in several clinical trials, such as specific inhibitors that can be employed to downregulate the signaling pathway.


Subject(s)
Phosphatidylinositol 3-Kinases , Humans , Phosphatidylinositol 3-Kinases/genetics , Consensus , Mutation , Class I Phosphatidylinositol 3-Kinases/genetics , Italy
14.
Neuropediatrics ; 54(6): 433-438, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37802085

ABSTRACT

BACKGROUND: Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene (EHMT1, *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking. The purpose of this study is to investigate epilepsy features in a cohort of epileptic patients with KS. METHODS: This multicenter study investigated eight patients with KS and epilepsy. Our findings were compared with literature data. RESULTS: We included five patients with 9q or 9q34.33 deletions, a subject with a complex translocation involving EHMT1, and two with pathogenic EHMT1 variants. All patients presented with moderate to severe developmental delay, language impairment, microcephaly, and infantile hypotonia. Although the epileptic manifestations were heterogeneous, most patients experienced focal seizures. The seizure frequency differs according to the age of epilepsy onset, with patients with early-onset epilepsy (before 36 months of age) presenting more frequent seizures. An overtime reduction in seizure frequency, as well as in antiseizure drug number, was observed in all patients. Developmental delay degree did not correlate with seizure onset and frequency or drug resistance. CONCLUSION: Epilepsy is a frequent finding in KS, but the underlying pathogenetic mechanism and specific features remain elusive.


Subject(s)
Autism Spectrum Disorder , Epilepsy , Intellectual Disability , Language Development Disorders , Humans , Child, Preschool , Intellectual Disability/complications , Intellectual Disability/genetics , Muscle Hypotonia/genetics , Mutation , Epilepsy/genetics , Seizures
16.
Eur J Hum Genet ; 31(12): 1430-1439, 2023 12.
Article in English | MEDLINE | ID: mdl-37673932

ABSTRACT

Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to identify novel APVR genes. Based on data from this analysis, published case reports, mouse models, and/or similarity to known APVR genes as revealed by a machine learning algorithm, we identified 3 genes-EFTUD2, NAA15, and NKX2-1-for which there is sufficient evidence to support phenotypic expansion to include APVR. We also provide evidence that 3 recurrent copy number variants contribute to the development of APVR: proximal 1q21.1 microdeletions involving RBM8A and PDZK1, recurrent BP1-BP2 15q11.2 deletions, and central 22q11.2 deletions involving CRKL. Our results suggest that ES and chromosomal microarray analysis (or genome sequencing) should be considered for individuals with non-isolated APVR for whom a genetic etiology has not been identified, and that genetic testing to identify an independent genetic etiology of APVR is not warranted in individuals with EFTUD2-, NAA15-, and NKX2-1-related disorders.


Subject(s)
Abnormalities, Multiple , Heart Defects, Congenital , Scimitar Syndrome , Animals , Mice , Scimitar Syndrome/genetics , Exome Sequencing , Abnormalities, Multiple/genetics , Chromosome Deletion , Genetic Testing , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/genetics , RNA-Binding Proteins/genetics
17.
medRxiv ; 2023 Jun 16.
Article in English | MEDLINE | ID: mdl-37398376

ABSTRACT

Purpose: De novo variants in CUL3 (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. Methods: Genetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. Results: We assembled a cohort of 35 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells. Conclusion: Our study further refines the clinical and mutational spectrum of CUL3 -associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.

18.
Genes Chromosomes Cancer ; 62(12): 703-709, 2023 12.
Article in English | MEDLINE | ID: mdl-37395289

ABSTRACT

Heterozygous germline or somatic variants in AKT3 gene can cause isolated malformations of cortical development (MCDs) such as focal cortical dysplasia, megalencephaly (MEG), Hemimegalencephaly (HME), dysplastic megalencephaly, and syndromic forms like megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, and megalencephaly-capillary malformation syndrome. This report describes a new case of HME and capillary malformation caused by a somatic AKT3 variant that differs from the common p.E17K variant described in literature. The patient's skin biopsy from the angiomatous region revealed an heterozygous likely pathogenic variant AKT3:c.241_243dup, p.(T81dup) that may affect the binding domain and downstream pathways. Compared to previously reported cases with a common E17K mosaic variant, the phenotype is milder and patients showed segmental overgrowth, an uncommon characteristic in AKT3 variant cases. These findings suggest that the severity of the disease may be influenced not only by the level of mosaicism but also by the type of variant. This report expands the phenotypic spectrum associated with AKT3 variants and highlights the importance of genomic analysis in patients with capillary malformation and MCDs.


Subject(s)
Megalencephaly , Vascular Malformations , Humans , Mutation , Megalencephaly/genetics , Megalencephaly/pathology , Vascular Malformations/genetics , Phenotype , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism
19.
Genet Med ; 25(11): 100922, 2023 11.
Article in English | MEDLINE | ID: mdl-37403762

ABSTRACT

PURPOSE: RPH3A encodes a protein involved in the stabilization of GluN2A subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders. METHODS: By using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants. RESULTS: Four cases had a neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDA ionotropic glutamate receptor currents for both variants and alteration of postsynaptic calcium levels. Finally, expression of the Rph3AThr450Ser variant in neurons affected dendritic spine morphology. CONCLUSION: Overall, we provide evidence that missense gain-of-function variants in RPH3A increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder.


Subject(s)
Autism Spectrum Disorder , Epilepsy , Animals , Humans , Rats , Autism Spectrum Disorder/genetics , Epilepsy/genetics , Mutation, Missense/genetics , N-Methylaspartate/metabolism , Neurons/metabolism , Rabphilin-3A
20.
Nat Commun ; 14(1): 2034, 2023 04 11.
Article in English | MEDLINE | ID: mdl-37041138

ABSTRACT

Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFß and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFß, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.


Subject(s)
Hedgehog Proteins , Ossification, Heterotopic , Female , Humans , Connective Tissue/metabolism , Hedgehog Proteins/metabolism , Ossification, Heterotopic/metabolism , Signal Transduction/physiology , Transforming Growth Factor beta
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