A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay.

Genetic studies grounded on monogenic paradigms have accelerated both gene discovery and molecular diagnosis. At the same time, complex genomic rearrangements are also appreciated as potent drivers of disease pathology. Here, we report two male siblings with a dysmorphic face, ambiguous genitalia, intellectual disability, and speech delay. Through quad-based whole-exome sequencing and concomitant molecular cytogenetic testing, we identified two copy-number variants (CNVs) in both affected individuals likely arising from a balanced translocation: a 13.5-Mb duplication on Chromosome 16 (16q23.1 → 16qter) and a 7.7-Mb deletion on Chromosome 5 (5p15.31 → 5pter), as well as a hemizygous missense variant in CXorf36 (also known as DIA1R). The 5p terminal deletion has been associated previously with speech delay, whereas craniofacial dysmorphia and genital/urinary anomalies have been reported in patients with a terminal duplication of 16q. However, dosage changes in either genomic region alone could not account for the overall clinical presentation in our family; functional testing of CXorf36 in zebrafish did not induce defects in neurogenesis or the craniofacial skeleton. Notably, literature and database analysis revealed a similar dosage disruption in two siblings with extensive phenotypic overlap with our patients. Taken together, our data suggest that dosage perturbation of genes within the two chromosomal regions likely drives the syndromic manifestations of our patients and highlight how multiple genetic lesions can contribute to complex clinical pathologies.

Fetal arterial and venous Doppler parameters in the interpretation of oligohydramnios in postterm pregnancies.

OBJECTIVE: The objective of the current study was to evaluate fetal arterial and venous Doppler parameters in postterm pregnancies with oligohydramnios and those with normal amniotic fluid. STUDY DESIGN: A cross-sectional study was performed in 38 pregnancies beyond 41 weeks' gestation. Pulsed Doppler imaging was used to determine the pulsatility index (PI) for the fetal middle cerebral artery (MCA), renal artery, umbilical artery, inferior vena cava (IVC) and ductus venosus. The amniotic fluid index (AFI) was used for semiquantitive assessment of amniotic fluid volume. Oligohydramnios was defined as an AFI < 5 cm. RESULTS: Oligohydramnios was detected in 10 cases, and a normal AFI was present in 28 cases. In the presence of oligohydramnios the PI of the MCA was decreased, while the renal artery PI and the MCA PI/UA PI ratio were found to be elevated. In cases of oligohydramnios the PI in the IVC was increased but was unchanged in the ductus venosus. CONCLUSION: Oligohydramnios in post-term pregnancies is associated with arterial redistribution of fetal blood flow typifying the brain sparing effect and with decreased resistance in the MCA and increased resistance in the fetal IVC.