Robertsonian translocations are among the most common balanced structural rearrangements seen in the general population, with a frequency in newborn surveys of about 1 in 1,000. Robertsonian translocations have their own peculiar characteristics and need to be considered separately. These translocations arise from fusions between different acrocentric chromosomes (heterologous Robertsonian translocation) or, rather rarely, between the same chromosome (homologous Robertsonian translocation). The imbalances which may be seen in gametes/offspring of carriers are either pure aneuploidies, or full uniparental disomies. There is also an association with male infertility. This chapter considers the case of the phenotypically normal person who carries, in balanced form, a Robertsonian translocation.

PURPOSE:The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis.METHODS:A 20-gene panel was designed based on the genes' association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively.RESULTS:Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre-Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10.CONCLUSION:These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre-Chotzen syndrome.

The laminins are a family of large basement membrane proteins that influence cell differentiation, adhesion, migration, and phenotype stability. They are heterotrimeric glycoproteins that exist in at least 16 different chain combinations of α, β and γ chains. The different isoforms have highly cell and tissue specific locations and specific biological roles in respective tissues. We have produced nine of those isoforms as human recombinant proteins and initiated studies on their effects on various types of cultured cells. We have previously shown that laminin-511 (α5:β1:γ1), that is expressed by pluripotent human stem (hES) cells, alone can support long-term self-renewal of hES and iPS (hES/iPS) cells in a xeno-free cell culture environment (Rodin et al., 2010, Nat Biotechnol). However, this laminin did not permit survival of the cells after replating from single cell suspension. In contrast, another recombinant human laminin-521, also expressed by cultured pluripotent hES cells and which is part of the natural niche of cells of the blastocyst inner cell mass, did allow both derivation of single hES cells and expansion from single cell suspension. The hES cells can be propagated as homogenous monolayers on laminin-521 in a completely defined, feeder-free and xeno-free cell culture system. The effects of laminins 511 and 521 on pluripotent stem cells are mediated by interaction with integrin α6β1 via the PI3K/Akt signaling pathway. Laminin-based cell culture systems for hES and hiPS cells have made culturing of such cells easy and they can greatly facilitate the generation of stem cell derived differentiated cells for cell therapy purposes. Other laminin isoforms exert various effects, including differentiation and phenotype stabilization, on other cell types, and those properties will be discussed briefly. Plenary Lectures