title: Combined ultrasound and exome sequencing approach recognizes Opitz G/BBB syndrome in two malformed fetuses.
abstract: Orofacial clefts are the most common congenital craniofacial anomalies and can occur as an isolated defect or be associated with other anomalies such as posterior fossa anomalies as a part of several genetic syndromes. We report two consecutive voluntary pregnancy interruptions in a nonconsanguineous couple following the fetal ultrasound finding of cleft lip and palate and posterior fossa anomalies confirmed by means of post-termination examination on the second fetus. The quantitative fluorescent PCR, the karyotype, and the comparative genomic hybridization-array analysis after amniocentesis were normal. Exome sequencing on abortive material from both fetuses detected a missense mutation in MID1, resulting in a clinical diagnosis of Opitz G/BBB syndrome. The same mutation was found in the mother and in her brother, who both revealed cerebellar anomalies at an MRI examination. Our study supports the efficacy of exome sequencing in the presence of both a family history suggestive of an inherited disorder and well-documented ultrasound findings. It reveals the importance of a synergistic effort between gynecologists and geneticists aimed at the integration of the most sophisticated ultrasound techniques with the next-generation sequencing tools to provide a definite diagnosis essential to orient the final decision and to estimate a proper recurrence risk.
authors.affiliation: aMedical Genetics, Department of Medical Biotechnologies bBioengineering Unit, Department of Medical Biotechnologies, University of Siena cMedical Genetics Unit, Department of Medical Biotechnologies dDepartment of Neurology NINT (Neuroimmagini e Neurointerventistica), Azienda Ospedaliera Universitaria Senese eDepartment of Obstetrics and Gynecology, Azienda, Siena, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pinto
authors.forename: Valentina
authors.initials: V
authors.lastname: Imperatore
authors.forename: Laura
authors.initials: L
authors.lastname: Bianciardi
authors.forename: Margherita
authors.initials: M
authors.lastname: Baldassarri
authors.forename: Paolo
authors.initials: P
authors.lastname: Galluzzi
authors.forename: Simone
authors.initials: S
authors.lastname: Furini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Centini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
mesh_terms: D000028:Abortion, Induced; D055028:Comparative Genomic Hybridization; D004947:Esophagus / Q000002:abnormalities*; D059472:Exome; D005260:Female; D005333:Fetus; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006972:Hypertelorism / Q000175:diagnosis* / Q000235:genetics*; D007021:Hypospadias / Q000175:diagnosis* / Q000235:genetics*; D007621:Karyotyping; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D016216:Ultrasonography, Prenatal