Powis, Z. | bioRxiv Science

bioRxiv2020

De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

High-impact pathogenic variants in more than 1,000 protein-coding genes cause Mendelian forms of neurodevelopmental disorders (NDD), including the newly reported AGO2 gene. This study describes the molecular and clinical characterization of 28 probands with NDD harboring heterozygous AGO1 coding variants. De novo status was always confirmed when parents were available (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Some variants were recurrently identified in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linkers domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behavior and additional behavioral manifestations. Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to AGO2 phenotype.

genetics↗

bioRxiv2018

De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies, but the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins, and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p=4.93 x 10-11) than expected from the estimated mutation rate. Further, all de novo variants described here affect conserved residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. We directly assayed GTP hydrolysis and RALA effector-protein binding, and all but one tested variant significantly reduced both activities. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.\n\nAuthor SummaryWhile many causes of developmental disabilities have been identified, a large number of affected children cannot be diagnosed despite extensive medical testing. Previously unknown genetic factors are likely to be the culprits in many of these cases. Using DNA sequencing, and by sharing information among many doctors and researchers, we have identified a set of individuals with developmental problems who all have changes to the same gene, RALA. The affected individuals all have similar symptoms, including intellectual disability, speech delay (or no speech), and problems with motor skills like walking. In nearly all of these cases (10 of 11), the genetic change found in the child was not inherited from either parent. The locations and biological properties of these changes suggest that they are likely to disrupt the normal functions of RALA and cause significant health problems. We also performed experiments to show that the genetic changes found in these individuals alter two key functions of RALA. Together, we have provided evidence that genetic changes in RALA can cause DD/ID. These results will allow doctors and researchers to identify additional children with the same condition, providing a clinical diagnosis to these families and leading to new research opportunities.

genetics↗