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1.
Am J Med Genet A ; 191(9): 2428-2432, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37462082

RESUMO

Mitogen-activated protein kinase 8-interacting protein 3 gene (MAPK8IP3) encodes the c-Jun-amino-terminal kinase-interacting protein 3 (JIP3) and is involved in retrograde axonal transport. Heterozygous de novo pathogenic variants in MAPK8IP3 result in a neurodevelopmental disorder with or without brain abnormalities and possible axonal peripheral neuropathy. Whole-exome sequencing was performed on an individual presenting with severe congenital muscle hypotonia of neuronal origin mimicking lethal spinal muscular atrophy. Compound heterozygous rare variants (a splice and a missense) were detected in MAPK8IP3, inherited from the healthy parents. Western blot analysis in a muscle biopsy sample showed a more than 60% decrease in JIP3 expression. Here, we suggest a novel autosomal recessive phenotype of a lower motor neuron disease caused by JIP3 deficiency.


Assuntos
Atrofia Muscular Espinal , Doenças Musculares , Anormalidades Musculoesqueléticas , Humanos , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Fenótipo , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal/genética
2.
Eur J Med Genet ; 63(10): 104027, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32758661

RESUMO

The short arm of chromosome 16 (16p) is enriched for segmental duplications, making it susceptible to recurrent, reciprocal rearrangements implicated in the etiology of several phenotypes, including intellectual disability, speech disorders, developmental coordination disorder, autism spectrum disorders, attention deficit hyperactivity disorders, obesity and congenital skeletal disorders. In our clinical study 73 patients were analyzed by chromosomal microarray, and results were confirmed by fluorescence in situ hybridization or polymerase chain reaction. All patients underwent detailed clinical evaluation, with special emphasis on behavioral symptoms. 16p rearrangements were identified in 10 individuals. We found six pathogenic deletions and duplications of the recurrent regions within 16p11.2: one patient had a deletion of the distal 16p11.2 region associated with obesity, while four individuals had duplications, and one patient a deletion of the proximal 16p11.2 region. The other four patients carried 16p variations as second-site genomic alterations, acting as possible modifying genetic factors. We present the phenotypic and genotypic results of our patients and discuss our findings in relation to the available literature.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Deficiências do Desenvolvimento/genética , Transtorno do Espectro Autista/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Ontologia Genética , Estudos de Associação Genética , Humanos , Hungria , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Análise em Microsséries , Obesidade/genética , Fenótipo , Duplicações Segmentares Genômicas , Deleção de Sequência , Tomógrafos Computadorizados
3.
Eur J Med Res ; 22(1): 20, 2017 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-28629449

RESUMO

BACKGROUND: Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities characterized by variable hair, skin, and ocular hypopigmentation. Six known genes and a locus on human chromosome 4q24 have been implicated in the etiology of isolated OCA forms (OCA 1-7). METHODS: The most frequent OCA types among Caucasians are OCA1, OCA2, and OCA4. We aimed to investigate genes responsible for the development of these OCA forms in Hungarian OCA patients (n = 13). Mutation screening and polymorphism analysis were performed by direct sequencing on TYR, OCA2, SLC45A2 genes. RESULTS: Although the clinical features of the investigated Hungarian OCA patients were identical, the molecular genetic data suggested OCA1 subtype in eight cases and OCA4 subtype in two cases. The molecular diagnosis was not clearly identifiable in three cases. In four patients, two different heterozygous known pathogenic or predicted to be pathogenic mutations were present. Seven patients had only one pathogenic mutation, which was associated with non-pathogenic variants in six cases. In two patients no pathogenic mutation was identified. CONCLUSIONS: Our results suggest that the concomitant screening of the non-pathogenic variants-which alone do not cause the development of OCA, but might have clinical significance in association with a pathogenic variant-is important. Our results also show significant variation in the disease spectrum compared to other populations. These data also confirm that the concomitant analysis of OCA genes is critical, providing new insights to the phenotypic diversity of OCA and expanding the mutation spectrum of OCA genes in Hungarian patients.


Assuntos
Albinismo Oculocutâneo/genética , Heterogeneidade Genética , Albinismo Oculocutâneo/epidemiologia , Albinismo Oculocutâneo/patologia , Antígenos de Neoplasias/genética , Feminino , Humanos , Hungria/epidemiologia , Masculino , Proteínas de Membrana Transportadoras/genética , Mutação , Linhagem , Fenótipo , População Branca/genética
4.
Am J Med Genet A ; 167A(12): 2985-91, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26289989

RESUMO

Craniosynostosis, the premature closure of cranial sutures, is a common craniofacial disorder with heterogeneous etiology and appearance. The purpose of this study was to investigate the clinical and molecular characteristics of craniosynostoses in Hungary, including the classification of patients and the genetic analysis of the syndromic forms. Between 2006 and 2012, 200 patients with craniosynostosis were studied. Classification was based on the suture(s) involved and the associated clinical features. In syndromic cases, genetic analyses, including mutational screening of the hotspot regions of the FGFR1, FGFR2, FGFR3, and TWIST1 genes, karyotyping and FISH study of TWIST1, were performed. The majority (88%) of all patients with craniosynostosis were nonsyndromic. The sagittal suture was most commonly involved, followed by the coronal, metopic, and lambdoid sutures. Male, twin gestation, and very low birth weight were risk factors for craniosynostosis. Syndromic craniosynostosis was detected in 24 patients. In 17 of these patients, Apert, Crouzon, Pfeiffer, Muenke, or Saethre-Chotzen syndromes were identified. In one patient, multiple-suture craniosynostosis was associated with achondroplasia. Clinical signs were not typical for any particular syndrome in six patients. Genetic abnormalities were detected in 18 syndromic patients and in 8 relatives. In addition to 10 different, known mutations in FGFR1,FGFR2 or FGFR3, one novel missense mutation, c.528C>G(p.Ser176Arg), was detected in the TWIST1 gene of a patient with Saethre-Chotzen syndrome. Our results indicate that detailed clinical assessment is of paramount importance in the classification of patients and allows indication of targeted molecular testing with the highest possible diagnostic yield.


Assuntos
Craniossinostoses/etiologia , Mutação , Acrocefalossindactilia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Craniossinostoses/genética , Feminino , Humanos , Hungria , Lactente , Masculino , Proteínas Nucleares/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Fatores de Risco , Proteína 1 Relacionada a Twist/genética
5.
Orv Hetil ; 156(24): 979-84, 2015 Jun 14.
Artigo em Húngaro | MEDLINE | ID: mdl-26051134

RESUMO

Muir-Torre syndrome is a rare genodermatosis with autosomal dominant inheritance. The syndrome is considered to be a subtype of the hereditary nonpolyposis colorectal cancer (or Lynch-syndrome). In two-third of the cases, it develops as the consequence of germline mutations in mismatch-repair genes--most commonly MutS Homolog-2 and MutL Homolog-1. Its diagnosis can be established if at least one sebaceous tumor (sebaceoma, sebaceous adenoma, epithelioma, carcinoma or basal-cell carcinoma with sebaceous differentiation) and/or keratoacanthoma and at least one internal neoplasm are present. Here the authors present the history of a 52-year-old man with multiple sebaceous carcinomas on his back. Immunohistochemical analysis showed the lack of MutL Homolog-1 protein expression in the tumor cells. Detailed clinical workup in order to identify internal malignancy found malignant coecum tumor. Histopathological evaluation of the sample from the right hemicolectomy revealed mid-grade adenocarcinoma with MutL Homolog-1 and postmeiotic segregation increased-2 deficiency. The detection of the cutaneous sebaceous carcinoma and the application of the modern diagnostic methods resulted in identification of the associated colorectal cancer in an early stage; hence, definitive treatment was available for the patient.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/isolamento & purificação , Neoplasias do Colo/diagnóstico , Síndrome de Muir-Torre/etiologia , Proteínas Adaptadoras de Transdução de Sinal/isolamento & purificação , Adenocarcinoma/química , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Neoplasias do Colo/química , Neoplasias do Colo/complicações , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA/isolamento & purificação , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Síndrome de Muir-Torre/metabolismo , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/isolamento & purificação , Proteína 3 Homóloga a MutS , Proteínas Nucleares/isolamento & purificação
6.
Am J Med Genet A ; 164A(12): 3176-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25251565

RESUMO

Pfeiffer syndrome is an autosomal dominant disorder classically characterized by craniosynostosis, facial dysmorphism and limb anomalies. The majority of cases are caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. A specific, rare mutation p.Pro252Arg, located between the second and third extracellular immunoglobulin-like domain of FGFR1, is associated with mild clinical signs. We report on a three-generation family with five members having a heterozygous FGFR1 p.Pro252Arg mutation. Phenotypic features within the family showed high variability from the apparently normal skull and limbs to the characteristic brachycephaly and digital anomalies. The typical features of Pfeiffer syndrome appeared only in the third generation allowing us to unveil the syndrome in several further family members in two previous generations. Variable expressivity can complicate the recognition of Pfeiffer syndrome, principally the mild type 1, requiring careful phenotyping and genetic counseling.


Assuntos
Acrocefalossindactilia/genética , Acrocefalossindactilia/patologia , Mutação de Sentido Incorreto/genética , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Feminino , Genes Dominantes/genética , Humanos , Hungria , Linhagem
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