RESUMEN
Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.
Asunto(s)
Ectromelia/diagnóstico , Ectromelia/genética , Secuenciación del Exoma , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas Adaptadoras Transductoras de Señales/genética , Alelos , Sustitución de Aminoácidos , Factor de Transcripción CDX2/genética , Proteínas de Unión al Calcio/genética , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Masculino , Linaje , FenotipoRESUMEN
We report on a fetus with Meckel syndrome diagnosed during the 21st gestational week, hydrocephalus and bilateral hyperechogenic kidneys were then detected on ultrasonography. Fetal pathological examination showed facial dysmorphism, occipital meningoencephalocele, characteristic renal cysts, mild hepatic ductal dysplasia, hydrocephalus in association with extreme cerebellar vermis hypoplasia and brainstem anomalies. Molecular and cytogenetic analysis identified a paternally inherited CEP290/MKS4 (MIM611134) (12q21) nonsense mutation and a maternal 12q21 microdeletion. Two cases with such a mechanism have previously been described in the literature, one of them involves an inherited microdeletion. The observation of such cases highlights the existence of a pathogenic mechanism which involves deletion and point mutation, and illustrates how homozygosity can hide hemizygosity when usual sequencing methods are used. The identification of hemizygosity enables to determine precisely the molecular mechanism and to understand some phenotypic variations. As they act as complete loss of function allele, deletions might give indication on the severity of the associated point mutation. This clinical report highlights the importance of fetal pathology following termination of pregnancies in order to guide molecular analysis and the potential role of cytogenetic cryptic disorders in autosomal recessive disease. The use of polymorphic marker analysis in association with FISH or arrayCGH provided an accurate identification of molecular mechanisms, accurate genetic counseling and optimized strategy for next pregnancies or preimplantation diagnosis.
Asunto(s)
Antígenos de Neoplasias/genética , Cromosomas Humanos Par 12/genética , Trastornos de la Motilidad Ciliar/diagnóstico por imagen , Encefalocele/diagnóstico por imagen , Proteínas de Neoplasias/genética , Enfermedades Renales Poliquísticas/diagnóstico por imagen , Feto Abortado/patología , Aborto Espontáneo/genética , Proteínas de Ciclo Celular , Deleción Cromosómica , Trastornos de la Motilidad Ciliar/genética , Proteínas del Citoesqueleto , Análisis Mutacional de ADN , Encefalocele/genética , Resultado Fatal , Femenino , Humanos , Riñón/patología , Enfermedades Renales Poliquísticas/genética , Embarazo , Diagnóstico Prenatal , Retinitis Pigmentosa , Eliminación de Secuencia , UltrasonografíaRESUMEN
OBJECTIVE: To assess the extent to which couples who could benefit from fetal karyotyping during the first or second trimester would agree to delay the examination until the third trimester. METHODS: In this prospective monocentric study, the same physician suggested to some couples to delay fetal karyotyping until the third trimester. RESULTS: 458 couples participated in this study. 230 couples (230/458 = 50.2%) refused to delay the examination until the third trimester of pregnancy (group 1). For these patients, four chromosomal abnormalities led to the termination of pregnancy. Fifty-six couples (56/458 = 12.2%) who initially agreed to delay the fetal karyotyping later changed their minds (group 2). 104 couples (104/458 = 22.7%) agreed to delay the examination (group 3). For these patients, one trisomy 21 was diagnosed and led to the subsequent termination of the pregnancy at 33 weeks of amenorrhea. Sixty-eight couples (68/458 = 14.8%) refused any form of invasive prenatal diagnosis (group 4). There was no difference in the rate of preterm premature rupture of membranes, pregnancy term, premature birth rate and birth weight between the four groups. CONCLUSIONS: Our study reports that about a quarter of couples did indeed agree to delay fetal karyotype assessment until the third trimester of pregnancy.