Clinical genetics of neurodevelopmental disorders

CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. Introduction " our incomplete studies do not permit actual classification; but it is better to leave things by themselves rather than to force them into classes which have their foundation only on paper " – Edouard Seguin 1 " The fundamental mistake which vitiates all work based upon Mendel's method is the neglect of ancestry, and the attempt to regard the whole effect upon offspring, produced by a particular parent, as due to the existence in the parent of particular structural characters ; while the contradictory results obtained by those who have observed the offspring of parents apparently identical in certain characters show clearly enough that not only the parents themselves, but their race, that is their ancestry, must be taken into account before the result of pairing them can be predicted " – Walter Frank Raphael Weldon 2. There are ~6 billion nucleotides in every cell of the human body, and there are ~25-100 trillion cells in each human body. Given somatic mosai-cism, epigenetic changes and environmental differences , no two human beings are the same, particularly as there are only ~7 billion people on the planet. One of the next great challenges for studying human genetics will be to acknowledge and embrace complexity 3-13. Every human is unique, and the study of human disease phenotypes (and phenotypes in general) will be greatly enriched by moving from a deterministic to a more stochastic/probabilistic model 14-19. The dichoto-mous distinction between 'simple' and 'complex' diseases is completely artificial, and we argue instead for a model that considers a spectrum of diseases that are variably manifesting in each person. The rapid adoption of whole genome sequencing (WGS) and the Internet-mediated networking of people promise to yield more insight into this century old debate 2,20-25. Comprehensive ancestry tracking and detailed family history data, when combined with WGS or at least cascade-carrier screening 26 , might eventually facilitate a degree of genetic prediction for some diseases in the context of their familial and ancestral etiologies. However, it is important to remain humble, as our current state of knowledge is not yet sufficient, and in principle, any number of nucleotides in the ge-nome, if mutated or modified in a certain way and at a certain time and place, might influence some phenotype …