Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

This research demonstrates patients' resistance to risk information. Inappropriately high risk perception derived from a risk communication with a health care provider can lead patients to make different, and potentially worse, medical decisions than they would with an accurate risk perception and to be unnecessarily distressed about their risk.

INTRODUCTION: We present a case where non-invasive prenatal screening (NIPS) detected a similar pattern of multiple aneuploidies in sequential pregnancies. METHODS: Case Presentation (with patient consent): A 25 year-old G3P2 patient had NIPS, by massively parallel sequencing (MPS), in her second and third pregnancies. Her first NIPS result was positive for trisomies 18 and 21. Further bioinformatics review revealed possible partial trisomy 13 and complete trisomies 14 and 20, in addition to the previously reported trisomies. NIPS by MPS repeated at another lab was non-reportable. Amniocentesis revealed normal karyotype, microarray, FISH for the chromosomes of interest, and chromosome 14 uniparental disomy testing. Maternal karyotype, microarray, and chromosomal breakage studies were normal. Patient had a negative oncology evaluation. Patient had an insignificant medical and medication history. Patient delivered a healthy girl. Placenta was small with a normal karyotype. Her current pregnancy shows a similar NIPS pattern. Patient declined amniocentesis and further aneuploidy screening. Second trimester ultrasound detected fetal hyperechoic bowel. Repeat maternal chromosomal breakage studies were normal. CONCLUSION: NIPS analyzes cell-free DNA in maternal blood originating from maternal and cytotrophoblast cells. The similar NIPS pattern in both pregnancies indicates a likely maternal etiology. When multiple aneuploidies are observed by NIPS, possible etiologies include maternal benign tumor or malignancy and fetal, placental or maternal chromosome abnormalities. However, subsequent fetal and maternal evaluations were normal. This case highlights that NIPS may yield unexpected results that are not representative of the fetal or maternal karyotypes and an extensive multi-specialty work-up may be recommended in these scenarios.