From embryonic lethal to no phenotype: What autozygome can teach us about loss of function in the human genome. F. S. Alkuraya Genetics, KFSHRC, Riyadh, Riyadh, Saudi Arabia.

   Autozygous inheritance of loss of function alleles in the human genome has greatly contributed to our ability to annotate the human genome in a clinically relevant manner. Tracking down these alleles by virtue of their existence within the autozygome has been key to this process both before and after the advent of next-generation sequencing. However, the advent of next-generation sequencing made it possible to fully unlock the potential of the autozygome in the context of unmasking phenotypic aspects that have historically evaded the application of classical autozygosity mapping, particularly at the extremes of the phenotypic spectrum. On one end of the spectrum is embryonic lethality, which we know from mouse studies is likely to be caused in some instances by biallelic loss of function of genes but these genes were difficult to identify in humans. We show here that careful selection of cases can maximize the power of combined exome/autozygome analysis to map novel human embryonic lethal genes. The other end of the phenotypic spectrum is when no phenotype can be assigned to the biallelic loss of function of some genes. Such genes may be truly dispensable as in genes that are on their way of turning into pseudogenes, dispensable in a context-dependent manner as in genes that are only required for the metabolism of certain substrates that are no widely available in contemporary human diet, or may be associated with subtle phenotypes that we are unable to quantify such as genes that contribute to the external appearance. We show that exome sequencing of well-phenotyped individuals enriched for the size of autozygome i.e. offspring of first cousin parents, can be an effective way of mapping such genes particularly when the loss of function alleles are very rare. Thus, our data demonstrate that next-generation sequencing can unlock the full potential of the autozygome to add to the global effort to assign clinically relevant information to the human genome by expanding the repertoire of phenotypes that can be interrogated.