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Genet Med ; 21(10): 2216-2223, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30976099


PURPOSE: To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype-phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies. METHODS: We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT. RESULTS: All patients had hypotonia, severe developmental delay, and epilepsy. Epilepsy onset ranged from first day of life to two years of age. Severity of the seizure disorder varied from treatable seizures to severe neonatal onset epileptic encephalopathies. The facial gestalt of patients resembled that of previously published PIGT patients as they were closest to the center of the PIGT cluster in the clinical face phenotype space and were distinguishable from other gene-specific phenotypes. CONCLUSION: We expand our knowledge of PIGT. Our cases reaffirm that the use of genetic testing is essential for diagnosis in this group of disorders. Finally, we show that computer-assisted facial gestalt analysis accurately assigned PIGT cases to the multiple congenital anomalies-hypotonia-seizures syndrome phenotypic series advocating the additional use of next-generation phenotyping technology.

Genome Med ; 10(1): 3, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29310717


BACKGROUND: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. METHODS: We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. RESULTS: We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. CONCLUSIONS: Due to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.

Citometria de Fluxo/métodos , Glicosilfosfatidilinositóis/biossíntese , Processamento de Imagem Assistida por Computador , Anormalidades Múltiplas/metabolismo , Automação , Biomarcadores/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Fenótipo , Distúrbios do Metabolismo do Fósforo/metabolismo , Síndrome
Brain ; 140(11): 2879-2894, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29053855


Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.

Encefalopatias/genética , Fissura Palatina/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Facies , Deficiência Intelectual/genética , Nistagmo Patológico/genética , Receptores de GABA-A/genética , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Variação Genética , Humanos , Masculino , Microcefalia/genética , Mutagênese Sítio-Dirigida , Oócitos/metabolismo , Técnicas de Patch-Clamp , Linhagem , Receptores de GABA-A/metabolismo , Síndrome , Xenopus laevis , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
Cleft Palate Craniofac J ; 52(5): e161-7, 2015 09.
Artigo em Inglês | MEDLINE | ID: mdl-25489771


OBJECTIVE: To examine the role of the IRF6 mutations in Polish families with Van der Woude syndrome and popliteal pterygium syndrome and to determine the effect of IRF6 single nucleotide polymorphisms (rs7552506, rs2013162, and rs2235375) on cleft lip and/or palate susceptibility. DESIGN: IRF6 mutation screening was performed by direct sequencing of all coding exons of the gene and their flanking intronic regions. Cosegregation analysis was performed to establish the relation of single nucleotide polymorphisms and cleft lip and/or palate phenotypes. PATIENTS: We screened the IRF6 gene in eight families with clinical recognition of Van der Woude syndrome and popliteal pterygium syndrome. RESULTS: In five families we identified pathogenic mutations, all affecting the DNA-binding or the protein-binding domain of IRF6. Two of the mutations were novel-a missense mutation Arg31Thr and a small deletion Trp40Glyfs*23. In most cases we found also a haplotype of three single nucleotide polymorphisms-rs7552506, rs2013162, and rs2235375. The association of the single nucleotide polymorphisms and cleft lip and/or palate susceptibility has been previously published. The variants did not cosegregate with phenotype in examined families nor did they cosegregate with pathogenic mutations. The single nucleotide polymorphisms were deemed not causative, due to their presence in unaffected family members. CONCLUSIONS: Two novel mutations (Arg31Thr and Trp40Glyfs*23) in the IRF6 gene were identified to be causative for Van der Woude and popliteal pterygium syndromes. In the present study no association between the single nucleotide polymorphisms rs7552506, rs2013162, and rs2235375 and the cleft lip and/or palate phenotype was found. The hypothesis, whether the haplotype of the three single nucleotide polymorphisms was correlated with IRF6 expression level, demands further investigation.

Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Anormalidades do Olho/genética , Dedos/anormalidades , Fatores Reguladores de Interferon/genética , Articulação do Joelho/anormalidades , Lábio/anormalidades , Deformidades Congênitas das Extremidades Inferiores/genética , Polimorfismo de Nucleotídeo Único , Sindactilia/genética , Anormalidades Urogenitais/genética , Feminino , Haplótipos , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Polônia
Hum Mutat ; 36(1): 106-17, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25385192


Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.

Encéfalo/patologia , Proteínas Culina/genética , Proteínas Culina/metabolismo , Malformações do Desenvolvimento Cortical/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Estudos de Associação Genética , Células HEK293 , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/metabolismo , Malformações do Desenvolvimento Cortical/patologia , Retardo Mental Ligado ao Cromossomo X/metabolismo , Retardo Mental Ligado ao Cromossomo X/patologia , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA , Adulto Jovem