Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease.

BACKGROUND: Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. RESULTS: We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. CONCLUSIONS: In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.

[Neurology in Byzantine medicine. An analysis of Alexander of Tralles' Medici libri duodecim]. / La neurología en la medicina bizantina. Análisis del Medici libri duodecim de Alejandro de Tralles.

INTRODUCTION: Byzantium continued Greek and Roman habit of texts compilation, and so, preserved medical knowledge. In addition, assimilating the influence of Monastic and Arabic medicine, Byzantine physicians transmitted original contributions including references to neurological diseases. Alexander of Tralles was one of major exponents of Byzantine medicine. He received his early medical training with his father, and in extensive travels, gathered medical knowledge and experience. AIM: Medici libri duodecim is a treatise on pathology and therapeutics of internal diseases, in twelve books. It comprises views from observation of different diseases. Its influence was prolonged and it was translated and edited until Renaissance. We analyze grecolatin edition by Henricum Petrum (1556), with special interest in neurological disease citations. DEVELOPMENT. First of twelve books is dedicated to head and brain diseases. When considering headache, he classifies them, following Aretaeus of Cappadocia, in cephalalgia, cephalea and hemicrania, suggesting different pathogenic mechanisms and therapies. Headache is included among symptoms conducting, as well as memory or sleep disturbances, to delirium. Medici libri duodecim considers memory complaints among systemic diseases, mainly with cardiac involvement. Alexander distinguishes between paralysis (privation of sensibility and mobility concerning half of the body), and apoplexy (including main soul functions loss, even conducting to death). Regarding epilepsy, Medici libri duodecim considers that its origin can be outside the head, mainly in the stomach, and offers us descriptions of epileptic auras. CONCLUSION: Analysis of Alexander of Tralles' Medici libri duodecim shows how byzantine physicians understood neurological diseases. Therapeutics was based on venesection, medicinal plants and avoidance of noxious substances.