Errors in Genome Sequencing Result Disclosures: A Randomized Controlled Trial Comparing Neonatology Non-Genetics Healthcare Professionals and Genetic Counselors.

PURPOSE: We compared the rate of errors in genome sequencing (GS) result disclosures by genetic counselors (GC) and trained non-genetics healthcare professionals (NGHP) in SouthSeq, a randomized trial utilizing GS in critically ill infants. METHODS: Over 400 recorded GS result disclosures were analyzed for major and minor errors. We used Fisher's exact test to compare error rates between GCs and NGHPs and performed a qualitative content analysis to characterize error themes. RESULTS: Major errors were identified in 7.5% of disclosures by NGHPs and in no disclosures by GCs. Minor errors were identified in 32.1% of disclosures by NGHPs and in 11.4% of disclosures by GCs. While most disclosures lacked errors, NGHPs were significantly more likely to make any error than GCs for all result types (positive, negative, or uncertain). Common major error themes include omission of critical information, overstating a negative result, and overinterpreting an uncertain result. The most common minor error was failing to disclose negative secondary findings. CONCLUSION: Trained NGHPs made clinically significant errors in GS result disclosures. Characterizing common errors in result disclosure can illuminate gaps in education to inform the development of future genomics training and alternative service delivery models.

Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

Rare and potentially pathogenic variants in hydroxycarboxylic acid receptor genes identified in breast cancer cases.

BACKGROUND: Three genes clustered together on chromosome 12 comprise a group of hydroxycarboxylic acid receptors (HCARs): HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently, HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify germline variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer risk. METHODS: Two different cohorts of breast cancer cases were investigated, the Alabama Hereditary Cancer Cohort and The Cancer Genome Atlas, which were analyzed through nested PCRs/Sanger sequencing and whole-exome sequencing, respectively. All datasets were screened for rare, non-synonymous coding variants. RESULTS: Variants were identified in both breast cancer cohorts, some of which appeared to be associated with breast cancer BC risk, including HCAR1 c.58C > G (p.P20A), HCAR2 c.424C > T (p.R142W), HCAR2 c.517_518delinsAC (p.G173T), HCAR2 c.1036A > G (p.M346V), HCAR2 c.1086_1090del (p.P363Nfs*26), HCAR3 c.560G > A (p.R187Q), and HCAR3 c.1117delC (p.Q373Kfs*82). Additionally, HCAR2 c.515C > T (p.S172L), a previously identified loss-of-function variant, was identified. CONCLUSIONS: Due to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation and their consequences on treatment strategies. Additional studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.