Human genetics and clinical aspects of neurodevelopmental disorders

Abstract

There are ~12 billion nucleotides in every cell of the human body, and there are ~25-100 trillion cells in each human body. Given somatic mosaicism, 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. 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. The dichotomous 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. Comprehensive ancestry tracking and detailed family history data, when combined with WGS or at least cascade-carrier screening, 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 genome, if mutated or modified in a certain way and at a certain time and place, might influence some phenotype during embryogenesis or postnatal life.

Behavioral idiosyncrasy reveals genetic control of phenotypic variability

“…During the last decade, we have made remarkable progress in understanding the genetic basis of complex traits and diseases, thanks in part to the application of GWAS to large cohorts. Unfortunately, we have fallen short of the goal of explaining heritability for complex traits in terms of allelic effects (31,32). The traditional framework used to map QTLs focuses on the average effect of alternative alleles averaged in a population.…”

“…Maintaining variability could be advantageous in the context of evolutionary adaptation, but in human genetics, it could be deleterious when an extreme phenotype enhances disease risk. The implications for medical genetics are far-reaching (14,31,32), specifically for attempts to predict phenotypes from genotypes. This point is illustrated in Fig.…”

Reducing INDEL calling errors in whole-genome and exome sequencing data

“…However, we are still facing practical challenges for both analytic validity and clinical utility of genomic medicine [9][10][11][12][13]. In addition, the genetic architecture behind most human disease remains unresolved [14][15][16][17][18][19]. Some have argued that we should bring higher standards to human genetics research in order to return results and/or reduce false-positive reports of 'causality' without rigorous standards [20,21].…”

A variant inTAF1is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features

“…Of course, the differences in genetic background and the environment can certainly account for the phenotypic differences between the two brothers. This phenomenon has been well known for many years in genetics [74,75], but seems to be more recently appreciated and has become a current active research topic [76][77][78][79][80]. Other work .…”