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BACKGROUND: TRAF7-related cardiac, facial, and digital anomalies with developmental delay (CAFDADD), a multisystemic neurodevelopmental disorder caused by germline missense variants in the TRAF7 gene, exhibits heterogeneous clinical presentations. METHODS: We present a detailed description of 11 new TRAF7-related CAFDADD cases, featuring eight distinct variants, including a novel one. RESULTS: Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects. In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay. Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods. Autistic traits, notably rigidity, are observed in the cohort. Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency. Cardiac defects, frequently severe, pose early-life complications. Facial features, including arched eyebrows, contribute to the distinct gestalt. A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germline TRAF7 variants and somatic changes linked to meningiomas. CONCLUSIONS: Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management. This study contributes to a better understanding of TRAF7-related CAFDADD, offering insights for improved diagnosis, intervention, and patient care.
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Discapacidades del Desarrollo , Cardiopatías Congénitas , Fenotipo , Humanos , Discapacidades del Desarrollo/genética , Masculino , Femenino , Niño , Preescolar , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/fisiopatología , Lactante , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Mutación Missense , AdolescenteRESUMEN
PURPOSE: Molecular classification of endometrial cancer (EC) has become a promising information to tailor preoperatively the surgical treatment. We aimed to evaluate the rate of lymph node metastases (LNM) in patients with EC according to molecular profile. METHODS: A systematic review and meta-analysis were performed according to PRISMA guidelines by searching in two major electronic databases (PubMed and Scopus), including original articles reporting lymph node metastases according to the molecular classification of EC as categorized in the ESGO-ESMO-ESP guidelines. RESULTS: Fifteen studies enrolling 3056 patients were included. Pooled prevalence LNM when considering only patients undergoing lymph node assessment was 4% for POLE-mutated (95%CI: 0-12%), 22% for no specific molecular profile (95% CI: 9-39%), 23% for Mismatch repair-deficiency (95%CI: 10-40%) and 31% for p53-abnormal (95%CI: 24-39%). CONCLUSIONS: The presence of LNM seems to be influenced by molecular classification. P53-abnormal group presents the highest rate of nodal involvement, and POLE-mutated the lowest.
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Neoplasias Endometriales , Metástasis Linfática , Humanos , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Proteína p53 Supresora de Tumor/genética , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genética , ADN Polimerasa II/genética , Ganglios Linfáticos/patología , Biomarcadores de Tumor/genéticaRESUMEN
PURPOSE: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. METHODS: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. RESULTS: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. CONCLUSION: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.
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Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Discapacidad Intelectual , Lisencefalia , Trastornos del Neurodesarrollo , Humanos , Animales , Ratones , Encéfalo/anomalías , Lisencefalia/genética , Discapacidad Intelectual/genética , Proteínas 14-3-3/genéticaRESUMEN
PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Fenotipo , Trastornos del Neurodesarrollo/genética , Vía de Señalización Wnt/genética , Discapacidad Intelectual/genética , Genómica , beta Catenina/genéticaRESUMEN
EVEN-PLUS syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the mitochondrial chaperone called mortalin, encoded by HSPA9. This genetic disorder, presenting with several overlapping features with CODAS syndrome, is characterized by the involvement of the Epiphyses, Vertebrae, Ears, and Nose (EVEN), PLUS associated findings. Only five individuals presenting with the EVEN-PLUS phenotype and biallelic variants in HSPA9 have been published. Here, we expand the phenotypic and molecular spectrum associated with this disorder, reporting two sibs with a milder phenotype and compound heterozygous pathogenic variants (a recurrent variant and a novel one). Also, we confirm a homozygous pathogenic variant in the family originally reported as EVE dysplasia.
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Anomalías Craneofaciales , Osteocondrodisplasias , Anomalías Dentarias , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/genética , Proteínas HSP70 de Choque Térmico/genética , Homocigoto , Humanos , Proteínas Mitocondriales/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , FenotipoRESUMEN
Early-onset high myopia (EoHM) is a disease that causes a spherical refraction error of ≥-6 diopters before 10 years of age, with potential multiple ocular complications. In this article, we report a clinical and genetic study of 43 families with EoHM recruited in our center. A complete ophthalmological evaluation was performed, and a sample of peripheral blood was obtained from proband and family members. DNA was analyzed using a customized next-generation sequencing panel that included 419 genes related to ophthalmological disorders with a suspected genetic cause, and genes related to EoHM pathogenesis. We detected pathogenic and likely pathogenic variants in 23.9% of the families and detected variants of unknown significance in 76.1%. Of these, 5.7% were found in genes related to non-syndromic EoHM, 48.6% in genes associated with inherited retinal dystrophies that can include a syndromic phenotype, and 45.7% in genes that are not directly related to EoHM or retinal dystrophy. We found no candidate genes in 23% of the patients, which suggests that further studies are needed. We propose a systematic genetic analysis for patients with EoHM because it helps with follow-up, prognosis and genetic counseling.
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Miopía , Distrofias Retinianas , Análisis Mutacional de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Miopía/diagnóstico , Miopía/genética , Linaje , Distrofias Retinianas/genéticaRESUMEN
De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.
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Trastorno del Espectro Autista , Enanismo , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Escoliosis , Trastorno del Espectro Autista/genética , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular , Trastornos del Neurodesarrollo/genética , Convulsiones , Aumento de PesoRESUMEN
OBJECTIVE: Pre-eclampsia and delivery of small-for-gestational-age (SGA) neonates can be predicted from the first trimester. A Gaussian model for prediction of PE has recently been described, although its capacity to predict SGA is still unknown. METHODS: This was a secondary analysis of a prospective cohort study conducted at Vall d'Hebron University Hospital (Barcelona) in 2483 single pregnancies from October 2015 to September 2017. Mean arterial blood pressure and mean uterine artery pulsatility index were recorded at the first-trimester scan. Serum concentrations of placental growth factor and pregnancy-associated plasma protein-A were assessed between 8+0 and 13+6 weeks. The predictive capacities of early (<32 weeks) and preterm (<37 weeks) SGA were tested. RESULTS: For SGA without pre-eclampsia, detection rates of 25.0% (95% confidence interval [CI] 0-75.0) for early SGA and 14.3% (95% CI 3.6-28.6) for preterm SGA were achieved. For SGA with pre-eclampsia, the algorithm showed detection rates of 100.0% (95% CI 25.0-100.0) for early SGA and 56.3% (95% CI 31.3-81.3) for preterm SGA. CONCLUSION: This algorithm identifies 62.5% of early SGA and 27.3% of preterm SGA. Combined screening for predicting both pre-eclampsia and SGA by using the Gaussian algorithm is feasible and would simplify clinical practice.
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Preeclampsia , Biomarcadores , Femenino , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Factor de Crecimiento Placentario , Preeclampsia/diagnóstico , Valor Predictivo de las Pruebas , Embarazo , Primer Trimestre del Embarazo , Estudios Prospectivos , Flujo Pulsátil , Ultrasonografía Prenatal , Arteria Uterina/diagnóstico por imagenRESUMEN
Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.
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Proteínas F-Box , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Proteínas F-Box/genética , Células HEK293 , Células HeLa , Humanos , Discapacidad Intelectual/genética , Mutación Missense/genética , Trastornos del Neurodesarrollo/genética , Proteína-Arginina N-Metiltransferasas/genéticaRESUMEN
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype-phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.
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Anomalías Congénitas/genética , Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Antígenos de Histocompatibilidad Menor/genética , Convulsiones/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/patología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Mutación Missense/genética , Fenotipo , Convulsiones/diagnóstico , Convulsiones/patología , Secuenciación del ExomaRESUMEN
PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
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Trastorno Autístico , Canales de Calcio Tipo L , Síndrome de QT Prolongado , Sindactilia , Trastorno Autístico/genética , Canales de Calcio Tipo L/genética , Humanos , FenotipoRESUMEN
Schuurs-Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50-74%), infrequent (26-49%) and rare (less than ≤25%).
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Trastornos del Neurodesarrollo/genética , Proteínas de Transporte Vesicular/genética , Anomalías Múltiples/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación/genética , Fenotipo , SíndromeRESUMEN
PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
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Trastorno del Espectro Autista , Encefalopatías , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Encéfalo , Homólogo 4 de la Proteína Discs Large/genética , Humanos , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
Stuve-Wiedemann syndrome (SWS; MIM 601559) is a rare autosomal recessive disease caused by mutations in the leukemia inhibitor factor receptor gene (LIFR). Common clinical and radiological findings are often observed, and high neonatal mortality occurs due to respiratory distress and hyperthermic episodes. Despite initially considered as a lethal disorder during the newborn period, in recent years, several SWS childhood survivors have been reported. We report a detailed clinical and radiological characterization of four unrelated childhood SWS molecularly confirmed patients and review 22 previously reported childhood surviving cases. We contribute to the definition of the childhood survival phenotype of SWS, emphasizing the evolving phenotype, characterized by skeletal abnormalities with typical radiological findings, distinctive dysmorphic features, and dysautonomia. Based on the typical features and clinical course, early diagnosis is possible and crucial to plan appropriate management and prevent potential complications. Genetic confirmation is advisable in order to improve genetic counseling to the patients and their families.
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Anomalías Múltiples/genética , Enfermedades del Desarrollo Óseo/genética , Exostosis Múltiple Hereditaria/diagnóstico por imagen , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/genética , Osteocondrodisplasias/diagnóstico por imagen , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enfermedades Óseas Metabólicas/genética , Preescolar , Consanguinidad , Discapacidades del Desarrollo/genética , Disautonomía Familiar/genética , Exostosis Múltiple Hereditaria/genética , Exostosis Múltiple Hereditaria/patología , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/deficiencia , Masculino , Hipotonía Muscular/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Fenotipo , Romaní/genética , SobrevivientesRESUMEN
Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.
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Anomalías Múltiples/genética , Proteínas/genética , Adulto , Preescolar , Análisis por Conglomerados , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mutación/genética , Adulto JovenRESUMEN
BACKGROUND: Cervical thoracic duct cysts are a rare anomaly. OBJECTIVE: To report a case of cervical thoracic duct cyst, and perform a literature review. CLINICAL CASE: A 78-year-old female, with a one-year history of a left-sided asymptomatic supraclavicular cystic mass. Computerized tomography revealed a cystic mass 42mm in diameter. We performed a fine needle aspiration puncture, obtaining a thick, milky, whitish liquid. The patient underwent surgery; finding a left-sided supraclavicular cystic mass, with some lymph vessels heading towards the jugulo subclavian venous junction. We performed a ligation of these lymph vessels and resection of the mass. The histopathologic study confirmed the diagnosis of thoracic duct cyst. CONCLUSION: Diagnosis of cervical thoracic duct cyst should be suspected with a cystic lesion in the left supraclavicular region, which when perforated exudes a very distinctive thick milky, whitish liquid with a high content of lymphocytes and triglycerides. Treatment should be complete removal with ligation of the lymphatic afferent vessels.