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OBJECTIVE: To explore the clinical and genetic characteristics of two children with mental retardation and microcephaly. METHODS: Two children who had visited the Anhui Children's Hospital respectively on March 12 and June 22, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from them and their parents, and subjected to chromosomal karyotyping and whole exome sequencing analyses. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. RESULTS: Chromosomal karyotyping and copy number detection of the two children had found no abnormality. Whole exome sequencing revealed that child 1 has harbored a c.471delT (p.Pro157Profs*9) frameshifting variant of the CASK gene, whilst child 2 has harbored a c.1259_1269delCTGAGAATAAC (p.Pro420fs*27) frameshifting variant of the CASK gene. Sanger sequencing confirmed that both variants were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), both variants were rated as pathogenic (PVS1+PS2+PP3). CONCLUSION: The de novo variants of the CASK gene probably underlay the pathogenesis of mental retardation and microcephaly in both children.
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Mutación del Sistema de Lectura , Guanilato-Quinasas , Discapacidad Intelectual , Microcefalia , Humanos , Microcefalia/genética , Discapacidad Intelectual/genética , Guanilato-Quinasas/genética , Masculino , Femenino , Preescolar , Niño , Secuenciación del Exoma , CariotipificaciónRESUMEN
OBJECTIVE: To explore the genetic basis for a child with pachygyria. METHODS: A proband who had visited Qinzhou Maternal and Child Health Care Hospital for pachygyria and mental retardation in June 2020 was selected as the study subject. Clinical data was collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. RESULTS: The proband, a 4-year-and-6-month-old female, was clinically diagnosed with megagyrus deformity. WES revealed that she has harbored compound heterozygous variants of the ADGRG1 gene, namely c.781G>T (p.E261*) in exon 6 and c.1369A>C (p.S457R) in exon 11, which were verified by Sanger sequencing to be derived from her mother and father, respectively. Her younger sister was also heterozygous for the c.1369A>C (p.S457R) variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1+PM2_ Supporting; PM1+PM2_Supporting+PM3+PP3). CONCLUSION: The c.781G>T (p.E261*) and c.1369A>C (p.S457R) compound heterozygous variants of the ADGRG1 gene probably underlay the pachygyria malformation in this child.
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Secuenciación del Exoma , Humanos , Femenino , Preescolar , Heterocigoto , Mutación , Lisencefalia/genética , Pruebas Genéticas , Exones , Discapacidad Intelectual/genética , LinajeRESUMEN
BACKGROUND: Chromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty. RESULTS: We identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene. CONCLUSION: This report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.
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Deleción Cromosómica , Cromosomas Humanos Par 16 , Síndrome de Dandy-Walker , Microcefalia , Fenotipo , Humanos , Cromosomas Humanos Par 16/genética , Microcefalia/genética , Microcefalia/patología , Microcefalia/complicaciones , Femenino , Síndrome de Dandy-Walker/genética , Síndrome de Dandy-Walker/complicaciones , Síndrome de Dandy-Walker/patología , Variaciones en el Número de Copia de ADN/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Niño , Masculino , Arabia Saudita , Preescolar , Trastorno AutísticoRESUMEN
BACKGROUND: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. CASE PRESENTATION: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. CONCLUSIONS: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Síndrome del Ovario Poliquístico , Riñón Único , Humanos , Femenino , Adolescente , Trastorno del Espectro Autista/genética , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/diagnóstico , Discapacidad Intelectual/genética , Riñón Único/complicaciones , Secuenciación del Exoma , Proteínas del Tejido Nervioso/genética , Proteínas de Homeodominio/genética , Cardiopatías , Facies , Trastornos del NeurodesarrolloRESUMEN
Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca2+/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.
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Agresión , Trastorno Autístico , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Agresión/fisiología , Masculino , Femenino , Niño , Células HEK293 , Neuronas/metabolismo , Adolescente , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Adulto , Animales , Preescolar , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Adulto Joven , Sinapsis/metabolismo , Dominios PDZ/genéticaRESUMEN
OBJECTIVE: The objective of this study was to establish the genotype-phenotype correlation between karyotype results and the neurological and psychiatric alterations presented in patients with Turner syndrome (TS). METHODS: A retrospective study was conducted on the medical records of 10/140 patients with TS and neurophysiological abnormalities seen at a university hospital in southern Brazil. In addition, a literature review spanning the period from January 1, 2012 to January 1, 2023 was carried out using the PubMed and Virtual Health Library databases. RESULTS: Our study showed a potential correlation between neurological and psychiatric alterations in patients with TS. These findings are in accordance with those described in literature such as a high prevalence of learning or intellectual disabilities. However, our sample found more seizure episodes than those reported in other studies. CONCLUSIONS: The correlation established could be due to X chromosome dose-effect, as the review suggests that sex chromosome number and hormonal development can be associated with verbal, social, and cognitive skills or impairments.
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Síndrome de Turner , Síndrome de Turner/complicaciones , Síndrome de Turner/psicología , Síndrome de Turner/genética , Humanos , Estudios Retrospectivos , Femenino , Niño , Adolescente , Preescolar , Estudios de Asociación Genética , Brasil/epidemiología , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Discapacidad Intelectual/epidemiologíaRESUMEN
BACKGROUND: Advances in understanding the etiology of intellectual disability (ID) has led to insights in potential (targeted) treatments and personalized care. Implications of ID on health are often complex and require a multidisciplinary approach. The aim was to investigate the reporting of genetic diagnoses in multidisciplinary ID care and to identify associated clinical and demographic factors. METHODS: A retrospective chart review was performed on a randomly selected sample of individuals (n = 380) of a large ID care organization in the Netherlands. Data on genetic etiology, including genetic testing and diagnoses, and clinical and demographic characteristics were collected from files held by multidisciplinary team members. RESULTS: Reports on genetic etiology were available in 40% of the study sample (n = 151), with a genetic diagnosis recorded in 34% (n = 51), which is 13% of the total sample. In those with reported genetic diagnoses, this was reported in 90% of medical, 39% of psychodiagnostic, and 75% of professional caregivers' files. Older age, mild ID, and the legal representative not being a family member were associated with less reported information on genetic etiology. CONCLUSIONS: This study revealed that genetic diagnoses were often not reported in ID care files. Recommendations were formulated to reduce delay in diagnosis, and enable personalized care for individuals with ID.
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Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Estudios Retrospectivos , Masculino , Femenino , Adulto , Adolescente , Adulto Joven , Niño , Pruebas Genéticas , Países Bajos , Persona de Mediana Edad , PreescolarRESUMEN
OBJECTIVE: To explore the clinical characteristics and genetic etiology of four children with Phelan-McDermid syndrome (PMS). METHODS: Four children who had visited the Ningbo Women and Children's Hospital between June 2, 2022 and May 8, 2023 were selected as the study subjects. Clinical data of the children were collected. Genomic DNA was extracted from peripheral blood samples of the children and their parents and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and quantitative PCR (q-PCR) analysis. RESULTS: All children had presented with speech and language delays and intellectual disability. Children 3 and 4 also presented with autistic behaviors. WES showed that the children 1 and 2 had respectively carried a heterozygous c.731T>C (p.Leu244Pro) and a c.2782_2851del (p.Gly928ArgfsTer4) variant of the SHANK3 gene. Sanger sequencing confirmed that their parents did not carry the same variant, suggesting that they were de novo in origin. Children 3 and 4 had respectively harbored a 121 Kb and 52.02 Kb heterozygous deletion at chromosome 22q13.33, which had both encompassed the SHANK3 and ACR genes mapped to 22q13.33. q-PCR results showed that the deletion of SHANK3 and ACR genes were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.731T>C and c.2782_2851del variants were predicted to be likely pathogenic (PS2+PM2_Supporting+PP3) and pathogenic (PVS1+PM2_Supporting+PS2_Supporting), respectively. Furthermore, the 52.02 Kb and 121 Kb heterozygous deletions in 22q13.33 were both predicted to be pathogenic (2D+4C, 1.05 in score; 2D+4C, 1 in score). CONCLUSION: The four children were all diagnosed with PMS by genetic testing. Above finding has enriched the phenotypic and mutational spectrum of PMS, and provided a basis for clinical diagnosis and genetic counseling for their families.
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Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 22 , Humanos , Cromosomas Humanos Par 22/genética , Femenino , Masculino , Preescolar , Niño , Trastornos de los Cromosomas/genética , Proteínas del Tejido Nervioso/genética , Secuenciación del Exoma , Pruebas Genéticas , Discapacidad Intelectual/genéticaRESUMEN
OBJECTIVE: To explore the genetic basis for a child with developmental delay and intellectual deficit (DD/ID). METHODS: A child who was admitted to the Maternal and Child Health Care Hospital of Longhua District of Shenzhen City on June 3, 2023 due to DD/ID, craniofacial malformations, and recurrent infections of upper respiratory tract was selected as the study subject. G-banded chromosomal karyotyping was carried out for the child and her parents. Low-depth genome-wide copy number variation sequencing (CNV-seq) and chromosomal microarray analysis (CMA) were used to screen for genome-wide copy number variations (CNV), and fluorescence in situ hybridization (FISH) was used to verify the origin of candidate CNV. RESULTS: The child, an 8-year-old girl, had featured unexplained growth and intellectual development delay, multiple craniofacial malformations, and recurrent infections of the upper respiratory tract. She was found to have a karyotype of 46,XX,der(6)add(6)(q23), while both of her parents were normal. Both CNV-seq and CMA showed that the child has harbored a 21.38 Mb interstitial duplication at 6p25.3p22.3 and a 0.78 Mb terminal deletion at 6p25. FISH verified that both the duplication and deletion had occurred de novo. CONCLUSION: The abnormal phenotype of the child may be attributed to the 6p duplication and terminal deletion.
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Deleción Cromosómica , Variaciones en el Número de Copia de ADN , Fenotipo , Humanos , Femenino , Niño , Cromosomas Humanos Par 6/genética , Cariotipificación , Discapacidad Intelectual/genética , Discapacidades del Desarrollo/genética , Hibridación Fluorescente in Situ , Duplicación CromosómicaAsunto(s)
Electrocardiografía , Discapacidad Intelectual , Síndrome de QT Prolongado , Mutación , Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Humanos , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Discapacidad Intelectual/genética , Niño , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa A N-Terminal/genética , Masculino , Propranolol/uso terapéutico , Exones , Heterocigoto , FemeninoRESUMEN
Ramon syndrome (MIM 266270) is an extremely rare genetic syndrome, characterized by gingival fibromatosis, cherubism-like lesions, epilepsy, intellectual disability, hypertrichosis, short stature, juvenile rheumatoid arthritis, and ocular abnormalities. Hereditary or non-syndromic gingival fibromatosis (HGF) is also rare and considered to represent a heterogeneous group of disorders characterized by benign, slowly progressive, non-inflammatory gingival overgrowth. To date, two genes, ELMO2 and TBC1D2B, have been linked to Ramon syndrome. The objective of this study was to further investigate the genetic variants associated with Ramon syndrome as well as HGF. Clinical, radiographic, histological, and immunohistochemical examinations were performed on affected individuals. Exome sequencing identified rare variants in TBC1D2B in both conditions: a novel homozygous variant (c.1879_1880del, p.Glu627LysfsTer61) in a Thai patient with Ramon syndrome and a rare heterozygous variant (c.2471A>G, p.Tyr824Cys) in a Cambodian family with HGF. A novel variant (c.892C>T, p.Arg298Cys) in KREMEN2 was also identified in the individuals with HGF. With support from mutant protein modeling, our data suggest that TBC1D2B variants contribute to both Ramon syndrome and HGF, although variants in additional genes might also contribute to the pathogenesis of HGF.
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Fibromatosis Gingival , Humanos , Fibromatosis Gingival/genética , Fibromatosis Gingival/patología , Masculino , Femenino , Linaje , Secuenciación del Exoma , Niño , Proteínas Activadoras de GTPasa/genética , Mutación , Variación Genética , Adulto , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Predisposición Genética a la EnfermedadRESUMEN
The human 16p11.2 chromosomal region is rich in segmental duplications which mediate the formation of recurrent CNVs. CNVs affecting the 16p11.2 region are associated with an increased risk for developing neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID), as well as abnormal body weight and head circumference and dysmorphic features, with marked phenotypic variability and reduced penetrance. CNVs affecting the 16p11.2 region mainly affect a distal interval of ~220 Kb, between Breakpoints 2 and 3 (BP2-BP3), and a proximal interval of ~593 Kb (BP4-BP5). Here, we report on 15 patients with recurrent 16p11.2 rearrangements that were identified among a cohort of 1600 patients (0.9%) with neurodevelopmental disorders. A total of 13 deletions and two duplications were identified, of which eight deletions included the proximal 16p11.2 region (BP4-BP5) and five included the distal 16p11.2 region (BP2-BP3). Of the two duplications that were identified, one affected the proximal and one the distal 16p11.2 region; however, both patients had additional CNVs contributing to phenotypic severity. The features observed and their severity varied greatly, even between patients within the same family. This article aims to further delineate the clinical spectrum of patients with 16p11.2 recurrent rearrangements in order to aid the counselling of patients and their families.
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Cromosomas Humanos Par 16 , Discapacidad Intelectual , Fenotipo , Humanos , Cromosomas Humanos Par 16/genética , Masculino , Femenino , Niño , Adolescente , Preescolar , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Variaciones en el Número de Copia de ADN , Deleción Cromosómica , Adulto , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Aberraciones Cromosómicas , Adulto JovenRESUMEN
BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is a rare autosomal dominant disease caused by mutations in KIF11 which disrupt EG5 protein function, impacting the development and maintenance of retinal and lymphatic structures due to its expression in the retinal photoreceptor cilia. The primary ocular finding in MCLMR is chorioretinopathy. Additional features can include microphthalmia, angle-closure glaucoma, persistent hyperplastic primary vitreous, cataract, pseudo-coloboma, persistent hyaloid artery, and myopic or hypermetropic astigmatism. The appearance of the chorioretinal lesions as white to pinkish, round, non-elevated atrophic areas devoid of blood vessels resembles the lacunae in Aicardy syndrome. Due to the lack of systematic description of the lesions and significant phenotypical variability, there is an impending need for a detailed report of each case. CASE PRESENTATION: A child with microcephaly detected in the third trimester of gestation began her following in the ophthalmology department due to a non-visually significant cataract. Shortly after, she developed nystagmus and large-angle alternating esotropia with cross-fixation. Her fundus initially showed a pallid optic disc and pigmentary changes, developing thereafter retinal lacunae and a retinal fold. Her differential diagnosis accompanied the dynamic changes in her fundus, which included congenital infections, Leber´s Congenital Amaurosis and Aicardy syndrome. At 19 months old, genetic testing identified a heterozygous mutation (c.1159 C > T, p.Arg387*) in the KIF11 gene. The patient underwent bilateral medial rectus muscle recession surgery at 2 years old for persistent esotropia, with significant improvement. Refraction revealed a hyperopic astigmatism in both eyes (+ 0.25 -2.50 × 180 OD and + 0.75 -2.00 × 170 OS). She continues to require right eye patching for 2 hours daily. CONCLUSIONS: This case report expands the phenotypic spectrum of MCLMR by demonstrating a unique combination of retinal features which sheds new light on differential diagnosis from Aicardy syndrome. Our findings emphasize the significant phenotypic variability associated with MCLMR, particularly regarding ocular involvement. This underscores the importance of detailed clinical evaluation and comprehensive reporting of cases to improve our understanding of the disease spectrum and genotype-phenotype correlations.
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Discapacidad Intelectual , Linfedema , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/diagnóstico , Femenino , Linfedema/genética , Linfedema/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Displasia Retiniana , Cinesinas , FaciesRESUMEN
Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.
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Micrognatismo , Regiones Promotoras Genéticas , Proteínas Represoras , Tumor Rabdoide , Proteína SMARCB1 , Factores de Transcripción , Animales , Humanos , Masculino , Ratones , Anomalías Múltiples , Línea Celular Tumoral , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Sistemas CRISPR-Cas , Cara/anomalías , Deformidades Congénitas del Pie/genética , Deformidades Congénitas del Pie/metabolismo , Deformidades Congénitas de la Mano , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Micrognatismo/genética , Micrognatismo/metabolismo , Mutación , Cuello/anomalías , Regiones Promotoras Genéticas/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patología , Proteína SMARCB1/metabolismo , Proteína SMARCB1/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Transcripción GenéticaRESUMEN
of Medical History: A male infant, 8 months old, was admitted to hospital with cough and fever. The clinical symptoms were found to be mental retardation, obesity, dystonia, movement limitation, and visual retardation. Early development was normal, but after 6 months, the child developed upright head instability, difficulty grasping, and seizures. Symptoms and Signs: The child presents with mental retardation, obesity, increased muscle tone, motor dysfunction, visual impairment, and seizures. DIAGNOSIS: A whole exon test was performed to detect a neurite extension and migration factor (NEXMIF) gene mutation (NM_001008537.2: c.1042C > T (p. Arg348*)), which is known to be associated with intellectual disability and neurological symptoms. In addition, the test revealed a mutation in the Kinase D interacting substrate of 220 kDa (KIDINS220) gene (NM_020738.2: c.3242_3243insC (p. Leu1082AIafs*5)) with a heterozygous mutation in the father and wild type in the mother. TREATMENT: The patient was treated with anti-infection, aerosol inhalation, calcium supplement, and anti-epileptic drugs (levetiracetam), and the disease was controlled. Home and hospital rehabilitation is also underway. CLINICAL OUTCOME: The condition of the child improved after treatment and no seizures occurred again. The patient needs continuous rehabilitation treatment and follow-up observation. CONCLUSION: For male children with unexplained neurodevelopmental disorders and comorbidities such as obesity, dystonia, and seizures, mutations in related genes such as NEXMIF should be considered. Clinical practice should improve genetic testing as early as possible to provide a basis for genetic counseling.
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Epilepsia , Mutación , Trastornos del Neurodesarrollo , Humanos , Masculino , Epilepsia/genética , Lactante , Trastornos del Neurodesarrollo/genética , Proteínas del Tejido Nervioso/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genéticaRESUMEN
The carbon catabolite repression 4-negative on TATA-less transcription complex subunit 3 gene (CONT3) plays a key role in regulating the mRNA transcription and protein translation of other genes. Mutations in CONT3 have also recently been implicated as a causative factor of intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF). However, to date, only a few CONT3 mutations have been reported to be associated with IDDSADF-related diseases. In the present case, we report a Chinese patient with developmental delay, verbal regression, and facial dysmorphism, in whom cerebral magnetic resonance imaging showed an expansion of the lateral ventricle. The patient was diagnosed with an IDDSADF-related disease caused by a de novo c.1616_1623del mutation in exon 14 of CONT3, which was confirmed by whole-exome sequencing and direct Sanger sequencing. This case report is the first known documentation of a pathogenic mutation at the c.1616_1623del locus of CONT3 in the worldwide population. It provides a critical theoretical basis for the specific gene-based diagnosis of IDDSADF-related diseases and expands the mutation profile of CONT3.
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Discapacidad Intelectual , Mutación , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Trastorno Autístico/genética , Trastorno Autístico/diagnóstico , Secuenciación del Exoma , Trastornos del Desarrollo del Lenguaje/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/patología , Femenino , Imagen por Resonancia Magnética , PreescolarRESUMEN
The mediator complex subunit 23 (MED23) gene encodes a protein that acts as a tail module mediator complex, a multi-subunit co-activator involved in several cellular activities. MED23 has been shown to have substantial roles in myogenesis and other molecular mechanisms. The functions of MED23 in the neurological system remain unclear and the clinical phenotype is not thoroughly described. Whole exome sequencing was used to identify a novel mutation in the MED23 gene. DNA capture probes using next-generation sequencing-based copy number variation analysis with Illumina array were performed. The clinical, demographic, neuroimaging, and electrophysiological data of the patients were collected, and similarly, the data of all reported cases in the literature were extracted to compare findings. Screening a total of 9,662 articles, we identified 22 main regulatory processes for the MED23 gene, including suppressive activity for carcinogenic processes. MED23 is also involved in the brain's neurogenesis and functions. The identified cases mainly presented with intellectual disability (87.5%) and developmental delay (50%). Seizures were present in only 18.75% of the patients. Slow backgrounds and spike and sharp-wave complexes were reported on the electroencephalogram (EEG) of a few patients and delayed myelination, thin corpus callosum, and pontine hypoplasia on magnetic resonance imaging (MRI). The MED23 gene regulates several processes in which its understanding promotes considerable therapeutic potential for patients. It is crucial to consider genetic and laboratory testing, particularly when encountering potential carriers. Intellectual disability and developmental delay are the most notable clinical signs with heterogeneous features on EEG and MRI.
Asunto(s)
Complejo Mediador , Niño , Femenino , Humanos , Masculino , Variaciones en el Número de Copia de ADN/genética , Electroencefalografía , Secuenciación del Exoma , Genómica/métodos , Discapacidad Intelectual/genética , Complejo Mediador/genética , Mutación/genética , FenotipoRESUMEN
While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.
Asunto(s)
Mutación de Línea Germinal , Discapacidad Intelectual , Proteína Smad4 , Humanos , Masculino , Proteína Smad4/genética , Discapacidad Intelectual/genética , Contractura/genética , Adulto , Facies , Espermatozoides/metabolismo , Espermatozoides/patología , Criptorquidismo/genética , Trastornos del Crecimiento/genética , Deformidades Congénitas de la Mano/genética , Selección Genética , Alelos , Edad Paterna , Testículo/patología , Testículo/metabolismoRESUMEN
BACKGROUND: SYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID. METHODS: Participants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4-16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires. RESULTS: Our results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p = < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p = .35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p = .49) or oppositional defiant disorder (7.7%;0%; p = .15). CONCLUSION: For the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management.