A rare splice-site variant in cardiac troponin-T (TNNT2): The need for ancestral diversity in genomic reference datasets

The underrepresentation of different ancestry groups in large genomic datasets creates difficulties in interpreting the pathogenicity of monogenic variants. Genetic testing for individuals with non-European ancestry results in higher rates of uncertain variants and a greater risk of misclassification. We report a rare variant in the cardiac troponin T gene, TNNT2; NM_001001430.3: c.571-1G>A (rs483352835) identified via research-based whole exome sequencing in two unrelated probands of Oceanian ancestry with cardiac phenotypes. The variant disrupts the canonical splice acceptor site, activating a cryptic acceptor and resulting in an in-frame deletion (p.Gln191del). The variant is rare in gnomAD v4.0.0 (13/780,762; 0.002%), with the highest frequency in South Asians (5/74,486; 0.007%) and has 16 ClinVar assertions (13 diagnostic clinical laboratories classify as variant of uncertain significance). There are at least 28 reported cases, many with Oceanian ancestry and diverse cardiac phenotypes. Indeed, among Oceanian-ancestry-matched datasets, the allele frequency ranges from 2.9-8.8%, and is present in 2/4 (50%) Indigenous Australian alleles in Genome Asia 100K, with one participant being homozygous. With Oceanians deriving greater than 3% of their DNA from archaic genomes, we found c.571-1G>A in Vindija and Altai Neanderthal, but not the Altai Denisovan, suggesting an origin post Neanderthal divergence from modern humans 130-145 thousand years ago. Based on these data, we classify this variant as benign, and conclude it is not a monogenic cause of disease. Even with ongoing efforts to increase representation in genomics, we highlight the need for caution in assuming rarity of genetic variants in largely European datasets. Efforts to enhance diversity in genomic databases remain crucial. ### Competing Interest Statement JI receives research grant support from Bristol Myers Squibb unrelated to this work. CC is an employee of and has stock options in Genome Medical. VP receives research support from BioMarin Inc. and serves as consultant and/or scientific advisor for BioMarin, Inc. and Lexeo Therapeutics. All other authors report no conflicts of interest. ### Funding Statement JI is the recipient of a National Heart Foundation of Australia Future Leader Fellowship (#106732). RDB is the recipient of a New South Wales Health Cardiovascular Disease Senior Scientist Grant. CS is the recipient of a National Health and Medical Research Council (NHMRC) Investigator Grant (#2016822) and a New South Wales Health Cardiovascular Disease Clinician Scientist Grant. This study uses data from the Pacific Islands Rheumatic Heart Disease Genetics Network. Funding was provided, in part, by a New South Wales (NSW) Health Cardiovascular Research Capacity Program early-mid career research grant, the British Heart Foundation (PG/14/26/30509; www.bhf.org.uk), the Medical Research Council UK (Fellowship G1100449; www.mrc.ac.uk), and the British Medical Association (Josephine Lansdell Grant; www.bma.org.uk). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was obtained in accordance with policies applicable at Royal Prince Alfred Hospital Sydney Local Health District Human Research Ethics Committee (X15-0089 and X17-0350) for the original two patients, who provided written informed consent, and for collection of de-identified summary data from clinical laboratories and research centers used to inform variant prioritization and classification. Ethical approval for other summary case data including written informed consent from participants was granted by Melbourne Health Human Research Ethics Committee and New Zealand Ethics Committee. Ethical approval with a waiver of consent was granted by Stanford School of Medicine, USA; Pennsylvania University Medical Center, USA. All other data were in the public domain. 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