First prenatal case of proximal 19p13.12 microdeletion syndrome: New insights and new delineation of the syndrome

Abstract Proximal 19p13.12 microdeletion has been rarely reported. Only five postnatal cases with intellectual disability, facial dysmorphism, branchial arch defects and overlapping deletions involving proximal 19p13.12 have been documented. Two critical intervals were previously defined: a 700 kb for branchial arch defects and a 350 kb for hypertrichosis-synophrys-protruding front teeth. We describe the first prenatal case, a fetal death in utero at 39 weeks of gestation. Agilent 180K array-CGH analysis identified a heterozygous interstitial 745 kb deletion at 19p13.12 chromosome region, encompassing both previously reported critical intervals, including at least 6 functionally relevant genes: NOTCH3 , SYDE1 , AKAP8 , AKAP8L , WIZ and BRD4 . Quantitative PCR showed that the deletion occurred de novo with a median size of 753 kb. NOTCH3 and SYDE1 were candidate genes for placental pathology whilst AKAP8 , AKAP8L , WIZ and BRD4 were highly expressed in the branchial arches. Molecular characterization and sequencing of candidate genes for placental pathology and branchial arch defects were carried out in order to correlate the genotype-phenotype relationship and unravel the underlying mechanism of proximal 19p13.12 microdeletion syndrome. This case also contributes to define the novel critical interval and expand the clinical phenotype spectrum of proximal 19p13.12 microdeletion syndrome.