Clinical and genetic analysis of a rare fetus with Protein C deficiency due to compound heterozygous variants of PROC gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage.@*METHODS@#Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents.@*RESULTS@#The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4).@*CONCLUSION@#The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.

β-Catenin Deletion in Regional Neural Progenitors Leads to Congenital Hydrocephalus in Mice / 神经科学通报·英文版

Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality; however, the underlying cellular and molecular mechanisms remain largely unknown. Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited. Here, we describe a new mouse model of congenital hydrocephalus through knockout of β-catenin in Nkx2.1-expressing regional neural progenitors. Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood. Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis after β-catenin knockout. Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages. Thus, knockout of β-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.

Correlation of fetal ventriculomegaly with copy number variations and pregnancy outcome / 中华医学遗传学杂志

OBJECTIVE@#To assess the correlation of borderline fetal ventriculomegaly with genomic copy number variations (CNVs) and outcome of pregnancy.@*METHODS@#For 84 singleton pregnancies diagnosed with VM, chromosomal microarray analysis (CMA) was carried out to detect the CNVs of the fetal genome. Outcome of the pregnancy and neonatal development were analyzed. The pregnant women were divided into mild group (10-12 mm), moderate group (12-15 mm) and severe group (>= 15 mm) based on the severity of fetal ventriculomegaly. The detection rate of pathogenic CNVs and pregnancy outcome were compared. Multivariate logistic regression was carried out to analyze the predictors for pregnancy outcome.@*RESULTS@#Respectively, 24, 28 and 32 fetuses were assigned into the mild, moderate and severe groups. CMA has detected 15 cases of chromosomal abnormalities, including 11 pathogenic CNVs and 4 abnormal karyotypes. Abnormal pregnancy outcomes were found in 20 fetuses, including 12 with hydrocephalus and 8 with chromosomal microdeletion syndromes. A significant difference was found in the detection rate of fetal pathogenic CNVs and abnormal pregnancy outcome among the three groups (P<0.05). Multivariate logistic regression analysis showed that the largest change of lateral ventricle width (OR = 1.868, 95%CI = 1.120-3.116) and the extent of lateral ventricle widening (OR = 1.571, 95%CI = 1.120-2.206) were the key factors affecting the outcome of pregnancy (P<0.05).@*CONCLUSION@#Borderline fetal VM is associated with the risk of pathogenic CNVs and adverse pregnancy outcome. A comprehensive examination is required after prenatal ultrasound diagnosis, which is conducive to prenatal consultation and prognostic evaluation of the fetus.

Analysis of a pedigree affected with HSAS syndrome due to a noval variant of L1CAM gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with hydrocephalus.@*METHODS@#The fetus was found to have hydrocephalus upon ultrasonography duringthe second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA and whole exome sequencing.Sanger sequencing was used to verify the suspected variants in the family.@*RESULTS@#The fetus was found to harbor a hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene (OMIM 308840),for which his mother and sister were heterozygous carriers. The same variant was not found in his father, uncle and grandparents.Based on the standards and guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PM1+PM2+PP3+PP4).@*CONCLUSION@#The hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene probably underlay the hydrocephalus in this fetus.

Craniosynostosis genetics: The mystery unfolds.

Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis is common form of isolated craniosynostosis. The sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. Crouzon syndrome is one of the most common of the craniosynostosis syndromes. Apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis require multidisciplinary management. The following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis and genetic counseling.

Importância da avaliação genético-clínica na hidrocefalia / Importance of the clinical genetics evaluation on hydrocephalus

Os objetivos deste estudo foram caracterizar a presença de possíveis quadros de etiologia genética entre portadores de hidrocefalia congênita de etiologia não anteriormente esclarecida e confirmar aqueles com etiologia identificada previamente. A casuística compôs-se de 16 pacientes portadores de hidrocefalia congênita. O protocolo de investigação incluiu anamnese, investigação de história familial, exame clínico-dismorfológico, tomografia computadorizada ou ressonância magnética de sistema nervoso central, radiografia vertebral simples, cariótipo e estudo dismorfológico. Para análise dos resultados, a casuística foi dividida em dois grupos. O Grupo I (3M:6F) caracterizado por indivíduos com hidrocefalia e sinais clínicos inespecíficos; o Grupo II (7M), em que os indivíduos apresentavam hidrocefalia congênita e sinais sugestivos do espectro da doença L1. Orientação genética específica foi possível em 11 casos. Os resultados demonstram a heterogeneidade etiológica envolvida na hidrocefalia, evidenciando a necessidade de avaliação clínico-dismorfológica como instrumento complementar na investigação dessa condição clínica.

Hidrocefalia de Walker-Warburg: descripción de caso clínico / Hydrocephaly of Walker-Warburg: description of clinical case

El síndrome de Walker-Warburg es una rara entidad autosómica recesiva que presenta una triada característica de malformaciones oculares, cerebrales y distrofia muscular. Presentamos un recién nacido que fue captado a través de ECLAMC (Estudio Colaborativo Latinoamericano de Malformaciones Congénitas). Las características clínicas, hallazgos paraclínicos y radiológicos junto a un patrón de herencia sugerido por el árbol genealógico corresponden con el diagnóstico de síndrome de Walker-Warburg

Síndrome hidroletal, Informe de una paciente en la maternidad Isidro Ayora (Quito-Ecuador) / Hidrolethalus syndrome. a case report

Introducción. El síndrome hidroletal es una rara entidad autosómica recesiva caracterizada principalmente por polihidramnios, hidrocefalia, letalidad y polidactilia. La gran mayoría de estos casos han sido descritos en Finlandia con escasos reportes de dicho problema en otros países. Caso clínico. Se reporta un caso con características compatibles con síndrome hidroletal en una pareja no consanguínea, sin ancestros europeos en cuyo caso el recién nacido no fallece a las pocas horas.Conclusión. Este sería el primer caso de síndrome hidroletal reportado en Latinoamérica y su presentación ligeramente diferente podría ser una variante alélica de su similar finlandés.

Anatomía ventricular endoscópica en pacientes con malformaciones congénitas cerebrales / Endoscopy ventricular anatomy in patients with cerebral congenital abnormalities

Revisar las alteraciones de la anatomía ventricular en pacientes con mielomeningocele. Análisis de los videos de las tercerventriculosomias realizadas entre Diciembre 1998 y Julio del 2000, según una pauta de variables prediseñana. Ventrículos laterales: ausencia de septum (8/9), ausencia de vena septal (7/9), presencia de plexos coroides (9/9), forámen de monro pequeños (4/9). III ventrículo: cuerpos mamilares irreconocibles en 2/9 de los casos, tabiques (5/9), venas anormales (5/9), ausencia de infundibulum (4/9), dorso celar difícilmente reconocible (5/9), umbilicaciones del piso ventricular (5/9), adherencias aracnoidales (6/9). La tercerventriculostomía en pacientes portadores de disrrafia espinal tiene connotaciones anatómicas especiales, cuyo reconocimiento resulta de ayuda al enfrentar este tipo de pacientes

Congenital hydrocephalus due to aqueductal stal stenosis of probable autosomal recessive inheritance

Hereditary stenosis of the aqueduct of Sylvius is known to be transmitted as an X-linked recessive trait, thus affecting only the male offspring. We describe a family of consanguineous marriage where 2 sons and 2 daughters were afflicted with congenital hydrocephalus associated with stenosis of aqueduct of Sylvius. The pattern of the disease in this family is consistent with autosomal recessive inheritance. The authors of this communication are not aware of any literature reporting a similar mode of inheritance regarding this condition. Perhaps this discordant genetic mode of inheritance could have been caused by the consanguinity between the parents

Congenital hydrocephalus due to aqueductal stenosis of probable autosomal recessive inheritance

Hereditary stenosis of the aqueduct of Sylvius is known to be transmitted as an X-linked recessive trait, thus affecting only the male offspring. We describe a family of consanguineous marriage where 2 sons and 2 daughters were afflicted with congenital hydrocephalus associated with stenosis of aqueduct of Sylvius. The pattern of the disease in this family is consistent with autosomal recessive inheritance. The authors of this communication are not aware of any literature reporting a similar mode of inheritance regarding this condition. Perhaps this discordant genetic mode of inheritance could have been caused by the consanguinity between the parents

Hidrocefalia congénita / Congenital hydrocephalus

Actualmente existe un reto diagnóstico y terapéutico en los niños con hidrocefalia congénita, para establecer la etiología precisa y dar un tratamiento adecuado. Con el auxilio de los métodos de imagen por tomografía y ultrasonografía, podemos detectar intrauterinamente o en el período de recién nacido en forma precoz una hidrocefalia, dándonos la oportunidad de ofrecer una terapéutica adecuada. Se analizarán conceptos históricos evolutivos que han llevado al enfoque actual de la hidrocefalia congénita

Hidrocefalia congênita: relato de oito casos na mesma família / Hydrocephalus congenita: report of 8 cases in a family

Foram estudados oito casos de hidrocefalia, em pacientes do sexo masculino, todos em uma mesma família. A proposta dos autores é demonstrar que estes casos podem estar incluídos em um tipo de hidrocefalia familiar ligada ao sexo.