Expression of the human RHO P23H transgene in the retina creates a miniature swine model with an inheritance pattern and retinal function that mimics adRP. This large-animal model can serve as a novel tool for the study of the pathogenesis and therapeutic intervention in the most common form of adRP.

Williams syndrome (WS) is a multisystem disorder caused by deletion of about 1.55 Mb of DNA (including 26 genes) on chromosome 7q11.23, a region predisposed to recombination due to its genomic structure. Deletion of the Williams syndrome chromosome region (WSCR) occurs sporadically. To better define chance for familial recurrence and to investigate the prevalence of genomic rearrangements of the region, 257 children with WS and their parents were studied. We determined deletion size in probands by metaphase FISH, parent-of-origin of the deleted chromosome by molecular genetic methods, and inversion status of the WSCR in both parents by interphase FISH. The frequency of WSCR inversion in the transmitting parent group was 24.9%. In contrast, the rate of inversion in the non-transmitting parent group (a reasonable estimate of the rate in the general population) was 5.8%. There were no significant gender differences with respect to parent-of-origin for the deleted chromosome or the incidence of the inversion polymorphism. There was no difference in the rate of spontaneous abortion for mothers heterozygous for the WSCR inversion relative to mothers without the inversion. We calculate that for a parent heterozygous for a WSCR inversion, the chance to have a child with WS is about 1 in 1750, in contrast to the 1 in 9500 chance for a parent without an inversion.

Elastin haploinsufficiency is responsible for a significant portion of the Williams syndrome (WS) phenotype including hoarse voice, supravalvar aortic stenosis (SVAS), hernias, diverticuli of bowel and bladder, soft skin, and joint abnormalities. All of the connective tissue signs and symptoms are variable in the WS population, but few factors other than age and gender are known to influence the phenotype. We examined a cohort of 205 individuals with WS for mutations in SERPINA1, the gene that encodes alpha-1-antitrypsin (AAT), the inhibitor of elastase. Individuals with classic WS deletions and SERPINA1 genotypes PiMS or PiMZ were more likely than those with a SERPINA1 PiMM genotype to have joint dislocation or scoliosis. However, carrier status for AAT deficiency was not correlated with presence of inguinal hernia or with presence or severity of SVAS. These findings suggest that genes important in elastin metabolism are candidates for variability in the connective tissue abnormalities in WS.

BackgroundIntellectual disability (ID) affects 2–3% of the population and may occur with or without multiple congenital anomalies (MCA) or other medical conditions. Established genetic syndromes and visible chromosome abnormalities account for a substantial percentage of ID diagnoses, although for ∼50% the molecular etiology is unknown. Individuals with features suggestive of various syndromes but lacking their associated genetic anomalies pose a formidable clinical challenge. With the advent of microarray techniques, submicroscopic genome alterations not associated with known syndromes are emerging as a significant cause of ID and MCA.Methodology/Principal FindingsHigh-density SNP microarrays were used to determine genome wide copy number in 42 individuals: 7 with confirmed alterations in the WS region but atypical clinical phenotypes, 31 with ID and/or MCA, and 4 controls. One individual from the first group had the most telomeric gene in the WS critical region deleted along with 2 Mb of flanking sequence. A second person had the classic WS deletion and a rearrangement on chromosome 5p within the Cri du Chat syndrome (OMIM:123450) region. Six individuals from the ID/MCA group had large rearrangements (3 deletions, 3 duplications), one of whom had a large inversion associated with a deletion that was not detected by the SNP arrays.Conclusions/SignificanceCombining SNP microarray analyses and qPCR allowed us to clone and sequence 21 deletion breakpoints in individuals with atypical deletions in the WS region and/or ID or MCA. Comparison of these breakpoints to databases of genomic variation revealed that 52% occurred in regions harboring structural variants in the general population. For two probands the genomic alterations were flanked by segmental duplications, which frequently mediate recurrent genome rearrangements; these may represent new genomic disorders. While SNP arrays and related technologies can identify potentially pathogenic deletions and duplications, obtaining sequence information from the breakpoints frequently provides additional information.

Research Study. MATERIALS AND METHODS: Human zygotes with 3 pronuclei (PN) were cryopreserved with consent, thawed, and placed into control (CON; n¼23) or reduced nutrient (RN; n¼25) sequential culture medium, both supplemented with HSA. Embryos were cultured individually in an Embryo-Scope and were assessed for blastocyst development on D5 and D6. On D6, blastocysts were placed into fibronectin coated dishes for outgrowth culture in IVC1 (Cell Guidance Systems) medium, along with thawed D6 human blastocyst controls donated to research after culture under standard clinical conditions (Sage CM/BM with SPS; CBL). After 48h in outgrowth, attachment was assessed and media was replaced with IVC2. Media was replaced daily until 96h of outgrowth (D10), at which point embryos were fixed and imaged to measure outgrowth area. Embryos were then stained with F-actin, DAPI, and POUF51, and imaged using confocal microscopy to determine outgrowth volume, total cell number, and epiblast cell number, respectively.RESULTS: Blastocyst development was not different between 3PN embryos cultured in CON and RN medium on D5 (30.4% and 24.0%) or D6 (34.7% and 28.0%). All embryos placed into outgrowth were attached by 48h (CON n¼11; RN n¼7; CBL n¼7). There was no difference in the area of outgrowth between treatments, either at 48h (0.05AE0.02mm 2 , CON; 0.09AE0.04mm 2 , RN; 0.06AE0.02mm 2 , CBL) or 96h (0.12AE0.06mm 2 , CON; 0.23AE0.10mm 2 , RN; 0.20AE0.10mm 2 , CBL). Of embryos placed into outgrowth, 73% CON, 60% RN, and 100% CBL had a 3D volume that was assessed using confocal microscopy. Of these embryos, 50% of CON, 67% of RN, and 40% of CBL embryos contained a visible epiblast; these embryos had similar average numbers of epiblast cells (59, CON; 41, RN; 67, CBL).CONCLUSIONS: This data demonstrates that an environment of reduced nutrient concentration successfully supports the development of human zygotes to the blastocyst stage, with equal developmental potential to both those cultured in control medium and those cultured in standard clinical conditions. In addition, 3PN zygotes developed to the blastocyst stage and successfully organized peri-implantation embryonic development equivalent to normally fertilized embryos. This innovative approach to safely investigating novel culture conditions for human embryos could significantly enhance research in the development of more effective embryo culture media for human ART.

Rates of live birth or ongoing pregnancy after euploid SET (n¼987 transfers) did not differ by platform (Table ; p¼0.83).CONCLUSIONS: Euploid call rates differ as a function of PGT-A technology platform after adjusting for age and eggs collected. However, these differences do not seem to translate into different pregnancy outcomes after SET of a ''euploid'' blastocyst. Further investigation should attempt to reconcile these differences and clarify if and how advances in PGT-A technology platforms translate to patients.

Among the relevant gynecologic and obstetric history are: eight pregnancies (6 natural births, 1 caesarean section and 1 spontaneous abortion) and one sexual partner. She denies any previous sexually transmitted disease. She did not perform annual gynecological screening.On gynecological physical examination: an exophytic, friable and bleeding lesion of 3 cm is observed and palpated, which compromises the posterior face of the vagina, in its middle-upper third; respecting the rest of the organ and the cervix. On rectal examination, the ampulla is empty, without lesions; the parametria are free.A transvaginal pelvic ultrasound was performed in which no ovarian or uterine lesions were found. And an excisional biopsy was performed.The anatomopathological study showed: small cell neuroendocrine carcinoma. Immunohistochemistry: CK7 positive, synaptophysin positive, focal positive chromogranin, p40 negative, p16 positive and Ki67 90%.

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