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Purpose: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing., Methods: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project., Results: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return of results at no cost. We summarize the psychosocial or medical implications of these genetic diagnoses. Thus far, ES provided molecular diagnoses for 18 out of 60 (30%) of Texome participants. Plus, in 11 out of 60 (18%) participants, a partial or probable diagnosis was identified. Overall, 5 participants had a change in medical management., Conclusion: To date, the Texome Project has recruited a racially, ethnically, and socioeconomically diverse cohort. The diagnostic rate and medical impact in this cohort support the need for expanded access to genetic testing and services. The Texome Project will continue reducing barriers to genomic care throughout the future study years., Competing Interests: Conflict of Interest Lilei Zhang owns equity and consults for Pelagos Pharmaceuticals, Inc. Scott McLean is a medical consultant for Face2Gene. Baylor College of Medicine (BCM) and Miraca Holdings Inc have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs genetic testing and derives revenue. Pengfei Liu is an employee of BCM and derives support through a professional services agreement with BG. All other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Genome sequencing (GS) may shorten the diagnostic odyssey for patients, but clinical experience with this assay in nonresearch settings remains limited. Texas Children's Hospital began offering GS as a clinical test to admitted patients in 2020, providing an opportunity to study GS utilization, possibilities for test optimization, and testing outcomes., Methods: We retrospectively reviewed GS orders for admitted patients for a nearly 3-year period from March 2020 through December 2022. We gathered anonymized clinical data from the electronic health record to answer the study questions., Results: The diagnostic yield over 97 admitted patients was 35%. The majority of GS clinical indications were neurologic or metabolic (61%) and most patients were in intensive care (58%). Tests were often characterized as candidates for intervention/improvement (56%), frequently because of redundancy with prior testing. Patients receiving GS without prior exome sequencing (ES) had higher diagnostic rates (45%) than the cohort as a whole. In 2 cases, GS revealed a molecular diagnosis that is unlikely to be detected by ES., Conclusion: The performance of GS in clinical settings likely justifies its use as a first-line diagnostic test, but the incremental benefit for patients with prior ES may be limited., Competing Interests: Conflict of Interest The authors declare no conflicts of interest. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications., Methods: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and relatives categorized on the basis of cascade testing completion., Results: Among the 3723 positive ES results across both laboratories, 426 relatives of 282 probands completed cascade testing (uptake = 7.6%). An average of 1.5 relatives (SD = 0.9) were tested per proband. Of the 426 relatives tested, 200 had a variant of interest detected (variant detection yield = 47.0%)., Conclusion: In our real-world data analysis, a small proportion of probands with a positive ES result subsequently had relatives complete cascade testing at the same laboratory. However, approximately half of the tested relatives received a clinically significant result that could have implications for clinical management or reproductive planning. Additional research on ways to increase cascade testing uptake is warranted., Competing Interests: Conflict of Interest H.S.S. and H.S. declare no conflict of interest. J.S. and M.T. are salaried employees at Ambry Genetics, a Konica Minolta, Inc company. Baylor College of Medicine and Miraca Holdings Inc have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs genetic testing and derives revenue. P.L. is an employee of Baylor College of Medicine and derives support through a professional services agreement with Baylor Genetics., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: Little is known about how Medicaid coverage policies affect access to genetic tests for pediatric patients. Building upon and extending a previous analysis of prior authorization requests (PARs), we describe expected coverage of genetic tests submitted to Texas Medicaid and the PAR and diagnostic outcomes of those tests., Methods: We retrospectively reviewed genetic tests ordered at 3 pediatric outpatient genetics clinics in Texas. We compared Current Procedural Terminology (CPT) codes with the Texas Medicaid fee-for-service schedule (FFSS) to determine whether tests were expected to be covered by Medicaid. We assessed completion and diagnostic yield of commonly ordered tests., Results: Among the 3388 total tests submitted to Texas Medicaid, 68.9% (n = 2336) used at least 1 CPT code that was not on the FFSS and 80.7% (n = 2735) received a favorable PAR outcome. Of the tests with a CPT code not on the FFSS, 60.0% (n = 1400) received a favorable PAR outcome and were completed and 20.5% (n = 287) were diagnostic. The diagnostic yield of all tests with a favorable PAR outcome that were completed was 18.7% (n = 380/2029)., Conclusion: Most PARs submitted to Texas Medicaid used a CPT code for which reimbursement from Texas Medicaid was not guaranteed. The frequency with which clinically indicated genetic tests were not listed on the Texas Medicaid FFSS suggests misalignment between genetic testing needs and coverage policies. Our findings can inform updates to Medicaid policies to reduce coverage uncertainty and expand access to genetic tests with high diagnostic utility., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene., Methods: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants., Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function., Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability., Competing Interests: Conflict of Interest S.V.M., T.B.P., and M.J.G.S. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity., Methods: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes., Results: We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1., Conclusion: We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums., Competing Interests: Conflict of Interest Baylor College of Medicine and Miraca Holdings Inc have formed a joint venture with shared ownership and governance of Baylor Genetics, formerly the Baylor Miraca Genetics Laboratories, which performs chromosomal microarray analysis and clinical exome sequencing. J.L., W.Z., L.W., V.P., A.D., H.Da., L.M., F.X., W.B., P.L., and C.M.E. are employees of Baylor College of Medicine and derive support through a professional services agreement with Baylor Genetics. J.R.L. serves on the Scientific Advisory Board of the Regeneron Genetics Center and has stock ownership in 23andMe. All other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency., Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24., Results: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease., Conclusion: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

Purpose: Genetic testing is an important diagnostic tool in pediatric genetics clinics, yet many patients face barriers to testing. We describe the outcomes of prior authorization requests (PARs) for genetic tests, one indicator of patient access to clinically recommended testing, in pediatric genetics clinics., Methods: We retrospectively reviewed PARs for genetic tests (n = 4,535) recommended for patients <18 years of age (n = 2,798) by pediatric medical geneticists at two children's hospitals in Texas, 2017-2018. We described PAR outcomes, accompanying diagnostic codes, and diagnostic yield., Results: The majority (79.9%) of PARs received a favorable outcome. PARs submitted to public payers were more likely to receive a favorable outcome compared with private payers (85.5% vs. 70.3%, respectively; p < 0.001). No diagnostic codes were associated with higher likelihood of PAR approval for exome sequencing. Among the 2,685 tests approved and completed, 522 (19.4%) resulted in a diagnosis., Conclusion: Though there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.