Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome.

Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized by a prominent forehead, deep-set eyes, bulbous nasal tip, and subtle upper lip. Just a few hours after birth, congenital heart disease was suspected for cyanosis and confirmed by heart evaluation. In particular, echocardiography indicated pulmonary atresia with ventricular septal defect with severe hypoplasia of the pulmonary branches (1.5 mm), large patent ductus arteriosus and several major aortopulmonary collateral arteries. Due to the association of peculiar craniofacial appearance and congenital heart disease, a form of Alagille syndrome was suspected. In addition, on the fifth day after birth, the patient developed jaundice, had acholic stools, and high levels of conjugated bilirubin and gamma-glutamyltransferase (GGT) were detected in the blood. Genetic testing revealed the novel variant c.802del in a single copy of the JAG1 gene. No variants in the NOTCH2 gene were detected. To the best of our knowledge, this is the first clinical description of a congenital neural tube defect in a molecularly confirmed Alagille patient. This work demonstrates a novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagille patients.

Inverted duplications: how many of them are mosaic?

The best-known situation indissolubly linked to mosaicism is the uniparental disomy where a trisomic or monosomic zygote develops at least one cell line with 46 chromosomes. The mosaicism normal/abnormal cell lines may remain confined to placenta or persist in the embryo. Here, we describe a second situation that might also be indissolubly linked to a mosaic condition or at least to a confined placental mosaicism. We analysed the case of a mosaicism del(8p)/inv dup(8p) found in prenatal diagnosis. We had already demonstrated that the first product of the abnormal meiotic recombination at the basis of the inv dup rearrangements is a dicentric chromosome. Its breakage leads to the formation of a deleted and an inv dup chromosome. Although we had previously assumed that the dicentric underwent a breakage at meiosis II so that the zygote inherited the inv dup chromosome, our findings and those of others indeed indicate that the dicentric may be inherited in the zygote and that it might persist as such in early postzygotic stages, then undergoing different breakages in different cells leading to different abnormal chromosomes, either deleted or duplicated. Selection versus the most viable cell line(s) results either in a confined placental mosaicism with the inv dup cell line as the only one present in the embryo or in children with both the deleted and the inv dup cell lines. Phenotype/karyotype relationships in inv dup rearrangements must also take into account the influence of the other abnormal cell line during embryogenesis.