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Abstract Background Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. Methods We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. Results We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. Conclusions Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.

Purpose: Although costly, genome-wide sequencing (GWS) detects an extensive range of variants, enhancing our ability to diagnose and assess risk for an increasing number of diseases. In addition to detecting variants related to the indication for testing, GWS can detect secondary variants in BRCA1, BRCA2, and other genes for which early intervention may improve health. As the list of secondary findings grows, there is increased demand for surveillance and management by multiple specialists, adding pressure to constrained health care budgets. Secondary finding testing is actively debated because some consider it opportunistic screening for future health risks that may not manifest. Given the economic implications of secondary finding testing and follow-up and its unproven clinical utility, the objective is to assess the incremental cost-effectiveness of secondary finding ascertainment per case detected and per unit of improved clinical utility in families of children with unexplained suspected genetic conditions undergoing clinical GWS., Methods: Those undergoing trio genome or exome sequencing are eligible for the study. Positive secondary finding index cases will be matched to negative controls (1:2) based on age group, primary result(s) type, and clinical indication. During the 2-year study, 71 cases and 142 matched controls are expected. Health service use will be collected in patients and 1 adult family member every 6 months. The per-child and per-dyad total cost will be determined by multiplying use of each resource by a corresponding unit price and summing all cost items. Costs will be estimated from the public and societal payer perspectives. The mean cost per child and per dyad for secondary finding-positive and secondary finding-negative groups will be compared statistically. If important demographic differences are observed between groups, ordinary least-squares regression, log transformation, or other nonparametric technique will be used to compare adjusted mean costs. The ratio of the difference in mean cost to the secondary finding yield will be used to estimate incremental cost-effectiveness. In secondary analyses, effectiveness will be estimated using the number of clinical management changes due to secondary findings or the Clinician-Reported Genetic Testing Utility Index (C-GUIDE) score, a validated measure of clinical utility. Sensitivity analysis will be undertaken to assess the robustness of the findings to variation in key parameters., Implications: This study generates key evidence to inform clinical practice and funding allocation related to secondary finding testing. The inclusion of family members and a new measure of clinical utility represent important advancements in economic evaluation in genomics., Competing Interests: Declaration of Competing Interest Wendy J. Ungar reported receiving grant funding from Canadian Institutes of Health Research, Genome Canada, and Ontario Genomics Institute, serving as chair of the Ontario Genetics Advisory Committee, and serving as a member of the Ontario Health Technology Assessment Advisory Committee. Robin Z. Hayeems reported receiving grant funding from Canadian Institutes of Health Research. Christian R. Marshall reported receiving honoraria and travel funds from Illumina for an American Society of Human Genetics conference presentation in 2022. D. James Stavropoulos reported having stocks or stock options in Phenotips. The authors have indicated that they have no other conflicts of interest regarding the content of this article., (Copyright © 2023. Published by Elsevier Inc.)

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme involved in over 400 cellular reactions. During embryogenesis, mammals synthesize NAD de novo from dietary l -tryptophan via the kynurenine pathway. Biallelic, inactivating variants in three genes encoding enzymes of this biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder HAAO and four families with biallelic variants in KYNU. These patients present similarly with multiple malformations of the heart, kidney, vertebrae, and limbs, of variable severity. We show that each variant identified in these patients results in loss-of-function, revealed by a significant reduction in NAD levels via yeast genetic complementation assays. For the first time, missense mutations are identified as a cause of malformation and shown to disrupt enzyme function. These missense and frameshift variants cause moderate to severe NAD deficiency in yeast, analogous to insufficient synthesized NAD in patients. We hereby expand the genotypic and corresponding phenotypic spectrum of Congenital NAD Deficiency Disorder., (© 2021 Wiley Periodicals LLC.)