ABSTRACT
OBJECTIVE@#To explore the genetic basis of a child with holoprosencephaly.@*METHODS@#Genomic DNA of the child was extracted and subjected to whole exome sequencing. Suspected variant was verified by Sanger sequencing of her family members.@*RESULTS@#Cranial MRI suggested lobulated holoprosencephaly with partial absence of corpus callosum. Genetic testing revealed that she has carried a heterozygous c.517C>G (p.His173Asp) variant of the SIX3 gene, for which both of her parents were of wild type. Based on the American College of Medical Genetics and Genomics guidelines, the c.517C>G variant of SIX3 gene was predicted to be pathogenic (PS2+PM1+PM2+PM5+PP3).@*CONCLUSION@#The SIX3 gene c.517C>G variant probably underlay the multiple malformations in this child. Above finding has enabled her definite diagnosis.
Subject(s)
Child , Female , Humans , Family , Heterozygote , Holoprosencephaly/genetics , Mutation , Exome SequencingABSTRACT
OBJECTIVE: Holoprosencephaly (HPE) is heterogeneous in pathogenesis, integrating genetic susceptibility with the influence of environmental factors. Submicroscopic aberrations may contribute to the etiology of HPE. Our aim was to report the molecular analysis of 4 fetuses with HPE and normal metaphase karyotype. METHOD: A whole genome BAC-array based Comparative Genomic Hybridization (array CGH) was carried out in fetal blood samples. All potential cytogenetic alterations detected on the arrays were matched against the known copy number variations databases. RESULTS: The array CGH analysis showed copy number gains and losses in all cases. We found a recurrent deletion in 15q14 (clone RP11-23J11) and in 15q22 (clone RP11-537k8) in 2 out 4 cases analyzed. We also observed submicroscopic gain in 6p21 in 3 out of 4 fetuses in nearby clones. All these regions were tested in known databases and no copy number variations have been described for them. CONCLUSION: This is the first report of molecular characterization through a whole genome microarray CGH of fetuses with HPE. Our results may contribute to verify the effectiveness and applicability of the molecular technique of array CGH for prenatal diagnosis purposes, and contributing to the knowledge of the submicroscopic genomic instability characterization of HPE fetuses.
OBJETIVO: Holoprosencefalia (HPE) é uma malformação heterogênea na patogênese, integrando a suscetibilidade genética com a influência de fatores ambientais. Aberrações submicroscópicas podem contribuir para a etiologia da HPE. Nosso objetivo foi relatar a análise molecular de 4 fetos com HPE e cariótipo normal. MÉTODO: Foi realizado um estudo descritivo prospectivo dos achados da técnica de hibridação genômica comparativa baseada em microarranjos utilizando BAC clones de ampla cobertura genômica (BAC-array CGH) em amostras sanguíneas de fetos portadores de holoprosencefalia e com cromossomos numericamente normais ao bandamento G. Todas as potenciais alterações citogenéticas detectadas foram comparadas com bancos de dados com variações do número de cópias conhecidas. RESULTADOS: A análise de array CGH evidenciou ganhos e perdas do número de cópias em todos os 4 casos. Foram encontradas deleções recorrentes em 15q14 (clone RP11-23J11) e em 15q22 (clone RP11-537k8) em 2 dos 4 casos analisados. Observou-se em 3 fetos ganho genômico na região 6p21 em clones próximos. Todas estas regiões não apresentaram variações do número de cópias descritas em bancos de dados conhecidos. CONCLUSÃO: Este é o primeiro relato de caracterização molecular através de um microarray CGH de fetos com HPE. Nossos resultados podem contribuir para verificar a eficácia e aplicabilidade da técnica molecular de array CGH para fins de diagnóstico pré-natal, contribuindo para o conhecimento da caracterização de instabilidades genômicas submicroscópicas de fetos com HPE.
Subject(s)
Adolescent , Adult , Female , Humans , Pregnancy , Genomic Instability/genetics , Holoprosencephaly/genetics , /genetics , /genetics , Comparative Genomic Hybridization/methods , Gene Deletion , Karyotyping , Metaphase/genetics , Prospective Studies , Prenatal Diagnosis/methodsABSTRACT
La holoprosencefalia es la malformación prosencefálica más frecuente; su etiología es heterogénea y en ocasiones se asocia alteraciones genéticas e infecciones virales. Se presenta el caso de una paciente de 27 años de edad, IIG, IP, 1 Aborto, con embarazo de 27 semanas + 4 días, amenaza de parto pretérmino, holoprosencefalia y antecentes de herpes genital durante el primer trimestre.
Holoprosencephaly is the more frequent prosencephalic malformation. The etiology is heterogeneous an d some times is associated with genetic alterations and uterine viral infections. We present a pregnant 27 old year patient with 27 weeks and 4 days, preterm labor and genital herpes infection on the first trimester.
Subject(s)
Humans , Adult , Female , Pregnancy , Herpes Genitalis/pathology , Holoprosencephaly/ethnology , Holoprosencephaly/genetics , Nervous System Malformations/pathology , Virus Diseases/pathology , Abortion , Obstetric Labor, PrematureABSTRACT
A holoprosencefalia (HPE) é a mais freqüente das malformações craniofaciais descritas na literatura. Diversos genes já foram identificados como causadores desse tipo de anomalia, entre eles, o Sonic Hedgehog (SHH), ZIC2, SIX3 e TGIF. O objetivo deste estudo foi avaliar as habilidades neuropsicolingüísticas de um indivíduo com HPE e mutação no gene SHH, apresentando características fenotípicas do tipo Like. Os resultados evidenciaram que, apesar de se tratar de um grau leve de HPE (fenótipo Like), o paciente apresentou perdas significativas nas habilidades lingüísticas, com aspecto cognitivo dentro da normalidade. O exame de ressonância magnética do encéfalo revelou hipoplasia da comissura anterior e presença de cisto temporal à esquerda, achados aparentemente não relacionados à sintomatologia clínica.
The holoprosencephaly (HPE) is the most frequent of the craniofacial malformations described in literature. Several genes have already been identified as responsible for this kind of anomaly, among them, the Sonic Hedgehog (SHH), ZIC2, SIX3 and TGIF. The aim of this study was to evaluate the neuropsycholinguistic abilities of an individual with the HPE and mutation of the SHH gene, presenting phenotypic characteristics of the Like type. The results evidenced that, in spite of the lightness of the degree of HPE (Like phenopype), the patient showed significant loss of the linguistic abilities, although the cognitive aspects were adequate. The magnetic resonance of the encephalon revealed hypoplasia of the anterior commissure and presence of a temporal cyst on the left side, findings apparently not related to the clinic symptomatology.
Subject(s)
Cognition , Holoprosencephaly/genetics , Language , Mutation/genetics , PsycholinguisticsABSTRACT
The purpose of this series was to describe the sonographic features of fetal holoprosencephaly prenatally. The study was undertaken at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University. A total of 12 fetuses with prenatal diagnosis of holoprosencephaly were sonographically evaluated and followed-up. The study revealed that all showed monoventricular cavity, fused thalami, no falx and cavum septum pellucidum. Eight of them were correctly diagnosed sonographically in the first two trimesters. Extrafacial anomalies were also identified in half of the fetuses and all of them had facial abnormalities. Twenty-five per cent (3 cases) had polyhydramnios and only one case had oligohydramnios. Chromosome study revealed that 70 per cent had normal chromosomes, 30 per cent were aneuploidy, trisomy 13; 2 cases and trisomy 18; 1 case. In conclusion, this series indicates that ultrasound has a high predictive value in the diagnosis of holoprosencephaly. The most valuable clue to the diagnosis is the demonstration of the single ventricle. Additionally, demonstration of facial abnormalities may add confidence to the diagnosis. Conversely, should any of these facial features be serendipitously encountered, a careful examination of the intracranial contents is recommended.
Subject(s)
Adult , Female , Holoprosencephaly/genetics , Humans , Parity , Pregnancy , Ultrasonography, PrenatalABSTRACT
Se presenta un caso de diagnóstico prenatal de trisomía 13 y holoprosencefalia, durante el segundo trimestre de embarazo. Se practica una revisión de la literatura existente, incluyendo criterios de diagnóstico sonográfico y aspectos genéticos asociados. Se insiste en la importancia del diagnóstico sonográfico y genético antenatal, en la determinación de un pronóstico para el manejo ante e intraparto de estos casos