Recurrent ATP1A1 variant Gly903Arg causes developmental delay, intellectual disability, and autism.

ATP1A1 encodes a sodium-potassium ATPase that has been linked to several neurological diseases. Using exome and genome sequencing, we identified the heterozygous ATP1A1 variant NM_000701.8: c.2707G>A;p.(Gly903Arg) in two unrelated children presenting with delayed motor and speech development and autism. While absent in controls, the variant occurred de novo in one proband and co-segregated in two affected half-siblings, with mosaicism in the healthy mother. Using a specific ouabain resistance assay in mutant transfected HEK cells, we found significantly reduced cell viability. Demonstrating loss of ATPase function, we conclude that this novel variant is pathogenic, expanding the phenotype spectrum of ATP1A1.

EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder.

Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.

Much ado about nothing: A qualitative study of the experiences of an average-risk population receiving results of exome sequencing.

The increasing availability of exome sequencing to the general ("healthy") population raises questions about the implications of genomic testing for individuals without suspected Mendelian diseases. Little is known about this population's motivations for undergoing exome sequencing, their expectations, reactions, and perceptions of utility. In order to address these questions, we conducted in-depth semi-structured interviews with 12 participants recruited from a longitudinal multi-omics profiling study that included exome sequencing. Participants were interviewed after receiving exome results, which included Mendelian disease-associated pathogenic and likely pathogenic variants, pharmacogenetic variants, and risk assessments for multifactorial diseases such as type 2 diabetes. The primary motivation driving participation in exome sequencing was personal curiosity. While they reported feeling validation and relief, participants were frequently underwhelmed by the results and described having expected more from exome sequencing. All participants reported discussing the results with at least some family, friends, and healthcare providers. Participants' recollection of the results returned to them was sometimes incorrect or incomplete, in many cases aligning with their perceptions of their health risks when entering the study. These results underscore the need for different genetic counseling approaches for generally healthy patients undergoing exome sequencing, in particular the need to provide anticipatory guidance to moderate participants' expectations. They also provide a preview of potential challenges clinicians may face as genomic sequencing continues to scale-up in the general population despite a lack of full understanding of its impact.