Large-scale discovery of novel genetic causes of developmental disorders.

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders

Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin

Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here, we used Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause of cisplatin-induced infertility. RNA sequencing data indicate that cisplatin triggers a systemic stress response, in which DAF-16/FOXO and SKN-1/NRF2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA damage-induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrated that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian thioredoxin reductase 1 TRXR1, display cisplatin resistance. By CRISPR/Cas9, we determined that such resistance relies on the presence of the single selenocysteine residue in TRXR-1.Instituto de Salud Carlos III PI15/00895 PI16/01898European Regional Development Fund/FEDERNetherlands Organization for Scientific Research 711.014.005Sociedad Española de Oncología MédicaMinisterio de Economía y Competitividad BFU2007-67123 BFU2015-64408-PEuropean Social Fund BFU2015-64408-

Five year state plan

This is the five-year state plan for the South Carolina Developmental Disabilities Council for 2021-2026. The goals include objectives relating to employment, community supports, and self-advocacy

Partners in policymaking

Partners in Policymaking is a leadership program for adults living with disabilities and the parents of children with disabilities. This newsletter includes program updates, graduating class information, social media links, history, and notes from the program coordinator

Partners in policymaking

Partners in Policymaking is a leadership program for adults living with disabilities and the parents of children with disabilities. This newsletter includes program updates, graduating class information, social media links, history, and notes from the program coordinator

Positive abilities

The South Carolina Developmental Disabilities Council has published Positive Abilities a newsletter featuring stories and pictures of recent activities, a calendar of upcoming events, and information for people with developmental disabilities and their families

Partners in policymaking

Partners in Policymaking is a leadership program for adults living with disabilities and the parents of children with disabilities. This newsletter includes program updates, graduating class information, social media links, history, and notes from the program coordinator

The 2017-2021 state plan survey report on results

The purpose of the Developmental Disability Council state plan survey is to engage a broad spectrum of stakeholders with particular focus on people with Intellectual/Developmental Disabilities and their families in order to set funding and advocacy priorities for the Council for years 2017-2021

Positive abilities

The South Carolina Developmental Disabilities Council has published Positive Abilities a newsletter featuring stories and pictures of recent activities, a calendar of upcoming events, and information for people with developmental disabilities and their families