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1.
Am J Hum Genet ; 107(5): 977-988, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33058759

RESUMEN

PRKACA and PRKACB code for two catalytic subunits (Cα and Cß) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cß subunits of PKA during human development.


Asunto(s)
Anomalías Múltiples/genética , Disfunción Cognitiva/genética , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Dedos/anomalías , Mutación de Línea Germinal , Defectos de los Tabiques Cardíacos/genética , Polidactilia/genética , Dedos del Pie/anomalías , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/patología , Adolescente , Adulto , Animales , Secuencia de Bases , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patología , AMP Cíclico/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/química , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/deficiencia , Femenino , Dedos/patología , Regulación del Desarrollo de la Expresión Génica , Defectos de los Tabiques Cardíacos/diagnóstico , Defectos de los Tabiques Cardíacos/patología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Holoenzimas/química , Holoenzimas/deficiencia , Holoenzimas/genética , Humanos , Recién Nacido , Masculino , Ratones , Modelos Moleculares , Mosaicismo , Células 3T3 NIH , Linaje , Polidactilia/diagnóstico , Polidactilia/patología , Estructura Secundaria de Proteína , Dedos del Pie/patología
2.
Neurol Sci ; 42(7): 2737-2745, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33123925

RESUMEN

At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.


Asunto(s)
Proteínas de la Membrana/genética , Trastorno Peroxisomal , Síndrome de Zellweger , Niño , Egipto , Efecto Fundador , Humanos , Recién Nacido , Mutación , Trastorno Peroxisomal/diagnóstico por imagen , Trastorno Peroxisomal/genética
3.
Am J Med Genet A ; 182(12): 2857-2866, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32949109

RESUMEN

Blepharophimosis-ptosis-intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, long philtrum, high arched palate, micrognathia, microcephaly, and intellectual disability. Other findings were congenital heart disease (5 patients), talipes equinovarus (5 patients), genital anomalies (5 patients), autistic features (4 patients), cleft palate (2 patients), hearing loss (2 patients), and renal anomalies (1 patient). New or rarely reported findings were spherophakia, subvalvular aortic stenosis and hypoplastic nails, and terminal phalanges. Brain MRI, performed for 7 patients, showed hypogenesis or almost complete agenesis of corpus callosum. Genetic studies revealed five novel homozygous UBE3B variants. Of them, the c.1076G>A (p.W359*) was found in three patients from two unrelated families who shared similar haplotype suggesting a likely founder effect. Our results strengthen the clinical, dysmorphic, and brain imaging characteristic of this unique type of BID and extend the mutational spectrum associated with the disorder.


Asunto(s)
Blefarofimosis/genética , Homocigoto , Discapacidad Intelectual/genética , Mutación , Fenotipo , Anomalías Cutáneas/genética , Ubiquitina-Proteína Ligasas/genética , Anomalías Urogenitales/genética , Blefarofimosis/patología , Niño , Preescolar , Egipto , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/patología , Masculino , Linaje , Anomalías Cutáneas/patología , Anomalías Urogenitales/patología
4.
Am J Med Genet A ; 182(6): 1407-1420, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32267100

RESUMEN

PCNT encodes a large coiled- protein localizing to pericentriolar material and is associated with microcephalic osteodysplastic primordial dwarfism type II syndrome (MOPD II). We report our experience of nine new patients from seven unrelated consanguineous Egyptian families with the distinctive clinical features of MOPD II in whom a customized NGS panel showed homozygous truncating variants of PCNT. The NGS panel results were validated thereafter using Sanger sequencing revealing three previously reported and three novel PCNT pathogenic variants. The core phenotype appeared homogeneous to what had been reported before although patients differed in the severity showing inter and intra familial variability. The orodental pattern showed atrophic alveolar ridge (five patients), rootless tooth (four patients), tooth agenesis (three patients), and malformed tooth (three patients). In addition, mesiodens was a novel finding found in one patient. The novel c.9394-1G>T variant was found in two sibs who had tooth agenesis. CNS anomalies with possible vascular sequelae were documented in two male patients (22.2%). Simplified gyral pattern with poor development of the frontal horns of lateral ventricles was seen in four patients and mild thinning of the corpus callosum in two patients. Unilateral coronal craniosynstosis was noted in one patient and thick but short corpus callosum was an unusual finding noted in another. The later has not been reported before. Our results refine the clinical, neuroradiological, and orodental features and expand the molecular spectrum of MOPD II.


Asunto(s)
Antígenos/genética , Enanismo/epidemiología , Enanismo/genética , Retardo del Crecimiento Fetal/epidemiología , Retardo del Crecimiento Fetal/genética , Predisposición Genética a la Enfermedad , Microcefalia/epidemiología , Microcefalia/genética , Osteocondrodisplasias/epidemiología , Osteocondrodisplasias/genética , Adolescente , Niño , Preescolar , Consanguinidad , Enanismo/complicaciones , Enanismo/patología , Egipto/epidemiología , Femenino , Retardo del Crecimiento Fetal/patología , Estudios de Asociación Genética , Genotipo , Humanos , Lactante , Masculino , Microcefalia/complicaciones , Microcefalia/patología , Mutación , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/patología , Fenotipo , Hermanos
5.
Am J Hum Genet ; 99(2): 501-10, 2016 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-27453578

RESUMEN

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.


Asunto(s)
Alelos , Citocinesis/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Microcefalia/genética , Microcefalia/patología , Mitosis/genética , Mutación Missense/genética , Proteínas Serina-Treonina Quinasas/genética , Apoptosis/genética , Centrosoma/metabolismo , Niño , Preescolar , Femenino , Genes Recesivos , Humanos , Recién Nacido , Masculino , Linaje
6.
Am J Med Genet A ; 179(2): 237-242, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30575274

RESUMEN

GAPO syndrome is a very rare disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy. It is caused by biallelic mutations in the ANTXR1 gene. Herein, we describe the clinical and molecular findings of seven new patients with GAPO syndrome. Our patients presented with the characteristic clinical features of the syndrome except for one patient who did not display total alopecia till the age of two years. Strikingly, optic atrophy and glaucoma were observed in all patients and one patient showed keratopathy in addition. Moreover, craniosynstosis was an unusual associated finding in one patient. Mutational analysis of ANTXR1 gene identified five novel homozygous mutations including two frameshift, two splice site and a large intragenic deletion of exon 3. Our results reinforce the clinical characteristics of the syndrome, expand the mutational spectrum and provide more insights into the role of the ANTXR1 protein in the regulation of extracellular matrix.


Asunto(s)
Alopecia/genética , Anodoncia/genética , Trastornos del Crecimiento/genética , Proteínas de Microfilamentos/genética , Atrofias Ópticas Hereditarias/genética , Atrofia Óptica/genética , Receptores de Superficie Celular/genética , Eliminación de Secuencia/genética , Alopecia/patología , Anodoncia/patología , Niño , Preescolar , Femenino , Trastornos del Crecimiento/patología , Homocigoto , Humanos , Lactante , Masculino , Atrofias Ópticas Hereditarias/patología , Atrofia Óptica/patología
7.
Am J Med Genet B Neuropsychiatr Genet ; 180(5): 305-309, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31033224

RESUMEN

BACKGROUND: Autism spectrum disorders (ASD) is a heterogeneous neurodevelopmental disease, various articles reported that dysfunctional folate-methionine pathway enzymes might assume a paramount part in the pathophysiology of autism. Methylene tetrahydrofolate reductase (MTHFR) is a basic catalyst for this pathway, also MTHFR gene C677T variant accounted as a risk factor of autism. OBJECTIVE: The present study aimed to investigate the association of MTHFR gene rs1801133(C677T) variant among Egyptian autistic children. METHODS: The study included 78 autistic children, and 80 matched healthy control children. Full clinical and radiological examinations were conducted. MTHFR genetic variant, rs1801133(C677T) was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods followed by direct sequencing technique. RESULTS: MTHFR (C677T) allele frequency was found to be higher significantly in ASD cases compared with nonautistic children. Also, we had a higher distribution of combined CT + TT genotypes among autistic patients with consanguinity and family history of psychological disease. In Gastrointestinal tract (GIT) and sleep disorders showed a higher distribution of hetero CT genotype as well as combined CT + TT genotypes. CONCLUSION: This study demonstrated a role of MTHFR gene (C667T) variant with the increased risk for ASD.


Asunto(s)
Trastorno del Espectro Autista/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Alelos , Estudios de Casos y Controles , Niño , Trastornos Generalizados del Desarrollo Infantil/genética , Preescolar , Egipto/epidemiología , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Longitud del Fragmento de Restricción/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
8.
Hum Genet ; 137(9): 753-768, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30167850

RESUMEN

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.


Asunto(s)
Proteínas Portadoras/genética , Canalopatías/genética , Discapacidades del Desarrollo/genética , Marcadores Genéticos , Variación Genética , Proteínas de la Membrana/genética , Canales de Sodio/genética , Adolescente , Adulto , Canalopatías/patología , Niño , Preescolar , Discapacidades del Desarrollo/patología , Femenino , Humanos , Lactante , Recién Nacido , Canales Iónicos , Masculino , Fenotipo , Adulto Joven
9.
Genet Med ; 20(12): 1609-1616, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29620724

RESUMEN

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.


Asunto(s)
Exoma/genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Anomalías Musculoesqueléticas/genética , Alelos , Proteínas Sanguíneas/genética , Hidrolasas de Éster Carboxílico , Estudios de Cohortes , Exorribonucleasas/genética , Femenino , Proteínas Fetales/genética , Efecto Fundador , Genética de Población , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteínas de la Membrana/genética , Anomalías Musculoesqueléticas/clasificación , Anomalías Musculoesqueléticas/patología , Proteínas de Neoplasias/genética , Proteínas Oncogénicas/genética , Fenotipo , Receptores de Superficie Celular/genética , Proteína Wnt3A/genética
10.
Am J Med Genet A ; 176(11): 2446-2450, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30244542

RESUMEN

We report two discordant clinical and imaging features in four male patients from two unrelated families of Egyptian descent with hemizygous pathogenic variants in PQBP1. The three patients of the first family displayed the typical features underlying PQBP1 such as the long triangular face, bulbous nose, hypoplastic malar region, and micrognathia, which were subsequently confirmed using targeted sequence analysis that showed a previously reported nonsense mutation c.586C>T p.R196*. Whole exome sequencing identified a novel missense PQBP1 variant c.530G>A:p.R177H in the second family, in which the index patient presented with intellectual disability and dysmorphic facial features reminiscent of Kabuki-like syndrome and his brain magnetic resonance imaging revealed partial agenesis of corpus callosum, mild vermis, and brainstem hypoplasia. These imaging features are distinct from the previously described with a well-known phenotype that is already known for PQBP1. This report expands the phenotypic spectrum of PQBP1-related disorders and is the second reported missense PQBP1 variant. Further, it highlights the possible role of PQBP1 in hindbrain development.


Asunto(s)
Proteínas Portadoras/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Proteínas Nucleares/genética , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Fenotipo
11.
Metab Brain Dis ; 31(5): 1171-9, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27389245

RESUMEN

Two genes causing megalencephalic leukoencephalopathy with subcortical cysts (MLC) have been discovered so far. Here, we identified MLC1 and HEPACAM mutations in ten and two patients, respectively. The molecular results included an unreported inframe duplication mutation (c.929_930dupCTGCTG; p.L309dup) of MLC1 and a novel missense mutation c.293G>A (p.R98H) of HEPACAM. Further, the previously reported missense (c.278C>T; p.S93L) and the deletion/insertion (c.908_918delinsGCA; p.V303Gfs*96) were found in one and 8 patients (75 %), respectively. The 8 patients carrying the p.V303Gfs*96 shared a similar haplotype suggesting a founder effect. All mutations were in the homozygous state proving the autosomal recessive mode of inheritance. The core phenotype of macrocephaly, subcortical cysts and white matter appeared homogeneous although the patients differed in the onset, clinical course, disease severity and brain imaging findings. Our study expands the spectrum of mutations in MLC1 and HEPACAM and supports the genetic and clinical heterogeneity. Further, It confirms c.908_918delinsGCA (p.V303Gfs*96) as a founder mutation among Egyptian patients. This finding will contribute to provide targeted testing for this mutation in MLC patients in our population.


Asunto(s)
Quistes/diagnóstico por imagen , Quistes/genética , Efecto Fundador , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Proteínas de la Membrana/genética , Mutación/genética , Proteínas/genética , Adolescente , Encéfalo/diagnóstico por imagen , Proteínas de Ciclo Celular , Niño , Preescolar , Estudios de Cohortes , Egipto , Femenino , Humanos , Lactante , Masculino , Adulto Joven
12.
Am J Med Genet A ; 167A(12): 3054-61, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26284319

RESUMEN

Robinow syndrome (RS) is a rare genetic disorder characterized by limb shortening, genital hypoplasia, and craniofacial/orodental abnormalities. The syndrome follows both autosomal dominant and recessive patterns of inheritance with similar phenotypic presentation and overlapping features. Autosomal recessive Robinow syndrome (ARRS) is caused by mutations in the ROR2 gene. Here, we present the clinical, radiological and molecular findings of 11 Egyptian patients from 7 unrelated consanguineous families with clinical features of ARRS. Mutation analyses of ROR2 gene identified five pathogenic mutations distributed all over the gene. The identified mutations included four novel (G326A, D166H, S677F, and R528Q) and one previously reported (Y192D). Our results extend the number of ROR2 mutations identified so far, suggest a founder effect in the Egyptian population, and emphasize the important role of genetic testing in proper counseling and patients' management.


Asunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/patología , Genes Recesivos/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Anomalías Maxilofaciales/genética , Anomalías Maxilofaciales/patología , Mutación/genética , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Columna Vertebral/anomalías , Niño , Preescolar , Análisis Mutacional de ADN , Egipto , Femenino , Genotipo , Humanos , Lactante , Masculino , Linaje , Fenotipo , Pronóstico , Columna Vertebral/patología , Síndrome
13.
Am J Hum Genet ; 86(5): 696-706, 2010 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-20381006

RESUMEN

Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly and is now shown to be commonly associated with kidney anomalies. We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS. LRP4 belongs to the low-density lipoprotein (LDL) receptor-related proteins (LRPs), which are essential for various developmental processes. LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations. Our findings increase the spectrum of congenital anomalies associated with abnormal lipoprotein receptor-dependent signaling.


Asunto(s)
Enfermedades Renales/genética , Proteínas Relacionadas con Receptor de LDL/genética , Deformidades Congénitas de las Extremidades/genética , Transducción de Señal/fisiología , beta Catenina/metabolismo , Humanos , Riñón/metabolismo , Enfermedades Renales/metabolismo , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad , Mutación , Oncogenes , Receptores de LDL/antagonistas & inhibidores , Sindactilia/genética , Sindactilia/metabolismo , Síndrome
14.
Am J Med Genet A ; 161A(8): 1875-81, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23794361

RESUMEN

We describe five patients from three different families with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), which was molecularly confirmed by homozygosity for the g.51G >A and g.55G >A mutations in RNU4ATAC, respectively. The patients showed the classical phenotype and demonstrated in addition variable degrees of gyration abnormalities and malformations of the callosal body with an interhemispheric cyst. One patient also showed underdevelopment of the cerebellar vermis. This confirms that cortical malformations should be considered cardinal manifestations of MOPD I. Oculocutaneous albinism, brain hemorrhage and chilblains have been found to be associated with MOPD I. The present study showed lack of retinal pigmentation in three patients of whom two had an unusually fair complexion of hair and skin. One patient was found to have a hematoma in the left thalamus. This may indicate that both pigmentary abnormalities and vascular anomalies may be part of the phenotype of MOPD I as well.


Asunto(s)
Anomalías Múltiples/genética , Cuerpo Calloso/patología , Enanismo/genética , Retardo del Crecimiento Fetal/genética , Hematoma/genética , Microcefalia/genética , Mutación/genética , Osteocondrodisplasias/genética , Trastornos de la Pigmentación/genética , Ribonucleoproteínas Nucleolares Pequeñas/genética , Enfermedades Talámicas/genética , Adulto , Enanismo/patología , Femenino , Retardo del Crecimiento Fetal/patología , Hematoma/patología , Humanos , Recién Nacido , Masculino , Microcefalia/patología , Osteocondrodisplasias/patología , Fenotipo , Trastornos de la Pigmentación/patología , Enfermedades Talámicas/patología , Adulto Joven
15.
ScientificWorldJournal ; 2013: 670621, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24453887

RESUMEN

Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.


Asunto(s)
Trastorno Autístico/epidemiología , Trastorno Autístico/genética , Variación Genética/genética , MicroARNs/genética , Neurotransmisores/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Preescolar , Egipto/epidemiología , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Padres , Prevalencia , Factores de Riesgo , Adulto Joven
16.
Arch Med Res ; 54(6): 102860, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37499571

RESUMEN

BACKGROUND: Besides its main role in the control of blood cholesterol, PCSK9 has a role in the regulation of neuronal development and apoptosis. We suggest, for the first time, the possible involvement of PCSK9 in autism. METHOD: In this case-control study, Sanger sequencing was used to analyze sequence variations in the PCSK9 gene exons and their flanking intronic sequences. ELISA assay was used to determine the plasma concentration of PCSK9. The methylation percentage of the PCSK9 gene promoter was assessed by methylation-specific PCR (MSP). RESULTS: Forty-three variants were found; out of them, seven showed differential frequency between patients and controls. rs.45448095, rs.45613943, rs.630431, rs.529500286, and rs.45439391 are risk factors for autism, while rs.11800231 and rs.483462 are protective variants. The concentration of plasma PCSK9 protein was significantly elevated and the methylation percentage of PCSK9 gene promoter was significantly lower in cases than in controls (p <0.001 and = 0.002, respectively). ROC curve analysis identified an area under the curve (AUC) of 0.915 for plasma protein concentration and 0.693 for percent gene promoter methylation. In addition, two new variants were identified (g.23809C>T in intron 11 and g.24071T>G in 3' UTR). CONCLUSION: This is the first study to investigate the correlation between PCSK9 protein and autism and suggests the potential involvement of PCSK9 as one of the susceptibility genes for autism. Further studies with a larger number of subjects are recommended.


Asunto(s)
Trastorno Autístico , Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/genética , Estudios de Casos y Controles , Metilación , Trastorno Autístico/genética
17.
Eur J Med Genet ; 65(1): 104377, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34748996

RESUMEN

Carpenter syndrome 1 (CRPT1) is an acrocephalopolysyndactyly (ACPS) disorder characterized by craniosynostosis, polysyndactyly, obesity, and other malformations. It is caused by mutations in the gene RAB23. We are reporting on two patients from two unrelated consanguineous Egyptian families. Patient 1 presented with an atypical clinical presentation of Carpenter syndrome including overgrowth with advanced bone age, epileptogenic changes on electroencephalogram and autistic features. Patient 2 presented with typical clinical features suggestive of Carpenter syndrome. Therefore, Patient 1 was subjected to whole exome sequencing (WES) to find an explanation for his unusual features and Patient 2 was subjected to Sanger sequencing of the coding exons of theRAB23 gene to confirm the diagnosis. We identified a novel homozygous missense RAB23 variant (NM_001278668:c.T416C:p.Leu139Pro) in Patient 1 and a novel homozygous splicing variant (NM_016277.5:c.398+1G > A) in Patient 2. We suggest that the overgrowth with advanced bone age, electroencephalogram epileptogenic changes, and autistic features seen in Patient 1 are an expansion of the Carpenter phenotype and could be due to the novel missense RAB23 variant. Additionally, the novel identified RAB23 variants in Patient 1 and 2 broaden the spectrum of variants associated with Carpenter syndrome.


Asunto(s)
Acrocefalosindactilia/genética , Proteínas de Unión al GTP rab/genética , Preescolar , Humanos , Masculino , Mutación , Fenotipo , Secuenciación del Exoma
18.
Mol Syndromol ; 12(5): 279-288, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34602954

RESUMEN

Desbuquois dysplasia type 1 (DBQD1) is a very rare skeletal dysplasia characterized by growth retardation, short stature, distinct hand features, and a characteristic radiological monkey wrench appearance at the proximal femur. We report on 2unrelated Egyptian patients having the characteristic features of DBQD1 with different expressivity. Patient 1 presented at the age of 45 days with respiratory distress, short limbs, faltering growth, and distinctive facies while patient 2 presented at 5 years of age with short stature and hypospadias. The 2 patients shared radiological features suggestive of DBQD1. Whole-exome sequencing revealed a homozygous frameshift mutation in the CANT1 gene (NM_001159772.1:c.277_278delCT; p.Leu93ValfsTer89) in patient 1 and a homozygous missense mutation (NM_138793.4:c.898C>T; p.Arg300Cys) in patient 2. Phenotypic variability and variable expressivity of DBQD was evident in our patients. Hypoplastic scrotum and hypospadias were additional unreported associated findings, thus expanding the phenotypic spectrum of the disorder. We reviewed the main features of skeletal dysplasias exhibiting similar radiological manifestations for differential diagnosis. We suggest that the variable severity in both patients could be due to the nature of the CANT1 gene mutations which necessitates the molecular study of more cases for phenotype-genotype correlations.

19.
Mol Genet Genomic Med ; 9(2): e1546, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33217222

RESUMEN

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) (OMIM 194190) is a multiple congenital anomalies/intellectual disability syndrome. It is caused by partial loss of genetic material from the distal portion of the short arm of chromosome. METHODS: We studied the phenotype-genotype correlation. RESULTS: We present the clinical manifestations and cytogenetic results of 10 unrelated Egyptian patients with 4p deletions. Karyotyping, FISH and MLPA was performed for screening for microdeletion syndromes. Array CGH was done for two patients. All patients exhibited the cardinal clinical manifestation of WHS. FISH proved deletion of the specific WHS locus in all patients. MLPA detected microdeletion of the specific locus in two patients with normal karyotypes, while array CGH, performed for two patients, has delineated the extent of the deleted segments and the involved genes. LETM1, the main candidate gene for the seizure phenotype, was found deleted in the two patients tested by array CGH; nevertheless, one of them did not manifest seizures. The study emphasized the previous. CONCLUSION: WHS is a contiguous gene syndrome resulting from hemizygosity of the terminal 2 Mb of 4p16.3 region. The Branchial fistula, detected in one of our patients is a new finding that, to our knowledge, was not reported.


Asunto(s)
Genotipo , Fenotipo , Síndrome de Wolf-Hirschhorn/genética , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Masculino , Proteínas de la Membrana/genética , Síndrome de Wolf-Hirschhorn/patología
20.
Behav Brain Res ; 378: 112272, 2020 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-31586564

RESUMEN

Catechol-O-methyltransferase (COMT) enzyme has a major role in the adjustment of catechol-dependent functions, for example, cognition, cardiac function, and pain processing. The pathogenesis of autism may be related to dysfunction in the midbrain dopaminergic system. Therefore, we aimed to clarify how COMT gene variants affect dopamine level, and its potential impact on phenotype traits of autistic patients. 52 autistic patients were subjected to comprehensive clinical investigation, sequencing of exon 4 of the COMT gene by direct Sanger Sequencing, and measuring of dopamine levels. The clinical presentations of autistic subjects were correlated with detected COMT variants and dopamine level. Our molecular results revealed that three COMT variants were found: rs8192488 [C > T], rs4680 (Val158Met) and rs4818 [C > G]. Within autistic subjects, Val158Met rs4680 carriers were significantly distributed (71.2% P = 0.014) accompanied with abnormal dopamine, abnormal Electroencephalogram (EEG) and increasing the severity of autistic behaviour. As regards the haplotypes, CC/VM/CG block was significantly distributed among the autistic subjects (30.8%) presented with low mean dopamine level (15.8 ±â€¯4.7 pg/ml, p = 0.05), while CC/MM/CC were presented with high mean level (77.8 ±â€¯8.6 pg/ml, p = 0.05). Evidence is currently limited and preliminary, further studies are necessary in order to set up a coherent dopaminergic model of Autism Spectrum Disorder (ASD), which would further pave the way for an adequate treatment.


Asunto(s)
Trastorno del Espectro Autista/sangre , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Catecol O-Metiltransferasa/genética , Dopamina/sangre , Adolescente , Niño , Preescolar , Electroencefalografía , Femenino , Humanos , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Índice de Severidad de la Enfermedad
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