Despite their clinical significance, characterization of balanced chromosomal abnormalities (BCAs) has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and revealed complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. This study proposes that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements, and provides insight into novel pathogenic mechanisms such as altered regulation due to changes in chromosome topology.

During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of illumination. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal pathways, causing either progressive degeneration or stationary deficits. Congenital stationary night blindness (CSNB) is a group of stable retinal disorders that are characterized by abnormal night vision. Genetic subtypes of CSNB have been defined and different disease actions have been postulated. The molecular bases have been elucidated in several subtypes, providing a better understanding of the disease mechanisms and developmental retinal neurobiology. Here we have studied 22 families with 'complete' X-linked CSNB (CSNB1; MIM 310500; ref. 4) in which affected males have night blindness, some photopic vision loss and a defect of the ON-pathway. We have found 14 different mutations, including 1 founder mutation in 7 families from the United States, in a novel candidate gene, NYX. NYX, which encodes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich proteoglycan (SLRP) family. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-bipolar cells, leading to the visual losses seen in patients with complete CSNB.

No abstract

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. We identified two patients with defective serum transferrin glycosylation and mutations in the MAGT1 gene. These patients present with a phenotype that is mainly characterized by intellectual and developmental disability. MAGT1 has been described to be a subunit of the oligosaccharyltransferase (OST) complex and more specifically of the STT3B complex. However, it was also claimed that MAGT1 is a magnesium (Mg 2+ ) transporter. So far, patients with mutations in MAGT1 were linked to a primary immunodeficiency, characterized by chronic EBV infections attributed to a Mg 2+ homeostasis defect (XMEN). We compared the clinical and cellular phenotype of our two patients to that of an XMEN patient that we recently identified. All three patients have an N-glycosylation defect, as was shown by the study of different substrates, such as GLUT1 and SHBG, demonstrating that the posttranslational glycosylation carried out by the STT3B complex is dysfunctional in all three patients. Moreover, MAGT1 deficiency is associated with an enhanced expression of TUSC3, the homolog protein of MAGT1, pointing toward a compensatory mechanism. Hence, we delineate MAGT1-CDG as a disorder associated with two different clinical phenotypes caused by defects in glycosylation.congenital disorders of glycosylation | CDG | XMEN | oligosaccharyltransferase complex C ongenital disorders of glycosylation (CDG) are a rapidly growing group of genetic diseases caused by defects in glycan synthesis, processing, and/or attachment. Glycosylation is an important co-and posttranslational modification of proteins and lipids, mediating their function, stability, and dynamics (1, 2). In the N-glycosylation of proteins, the lipid-linked oligosaccharide (LLO) is first built in the endoplasmic reticulum (ER) and subsequently transferred en bloc by the oligosaccharyltransferase (OST) complex from a lipidic dolichol carrier to an N-X-S/T residue of a nascent protein. Next, remodeling of the glycan structure continues in the Golgi apparatus (3). Patients with CDG show an extremely variable phenotype, ranging from intellectual disability (ID) to severe multiorgan failure and death (1).Indispensable in this meticulously orchestrated glycosylation machinery is the transfer of glycans by the OST, a multisubunit protein complex consisting of a catalytic subunit (STT3A or STT3B), six shared subunits, and complex specific accessory subunits (4). The two complexes have distinct roles: STT3A is associated with the protein translocation channel and acts in a cotranslational fashion, while sites that are missed by STT3A can be posttranslationally glycosylated by STT3B (5). This interplay ensures the full N-glycosylation of proteins in mammalian cells. Both have accessory proteins that are specific for each of the catalytic subunits: DC2 and KCP2 are indispensable for STT3A function (6), while STT3B requires either MAGT1 or TUSC3 (7, 8). These two mu...

No abstract