澳大利亚基因组学线粒体旗舰项目：一项提供线粒体诊断的国家计划。

The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses.

作者信息

Rius Rocio, Compton Alison G, Baker Naomi L, Balasubramaniam Shanti, Best Stephanie, Bhattacharya Kaustuv, Boggs Kirsten, Boughtwood Tiffany, Braithwaite Jeffrey, Bratkovic Drago, Bray Alessandra, Brion Marie-Jo, Burke Jo, Casauria Sarah, Chong Belinda, Coman David, Cowie Shannon, Cowley Mark, de Silva Michelle G, Delatycki Martin B, Edwards Samantha, Ellaway Carolyn, Fahey Michael C, Finlay Keri, Fletcher Janice, Frajman Leah E, Frazier Ann E, Gayevskiy Velimir, Ghaoui Roula, Goel Himanshu, Goranitis Ilias, Haas Matilda, Hock Daniella H, Howting Denise, Jackson Matilda R, Kava Maina P, Kemp Madonna, King-Smith Sarah, Lake Nicole J, Lamont Phillipa J, Lee Joy, Long Janet C, MacShane Mandi, Madelli Evanthia O, Martin Ellenore M, Marum Justine E, Mattiske Tessa, McGill Jim, Metke Alejandro, Murray Sean, Panetta Julie, Phillips Liza K, Quinn Michael C J, Ryan Michael T, Schenscher Sarah, Simons Cas, Smith Nicholas, Stroud David A, Tchan Michel C, Tom Melanie, Wallis Mathew, Ware Tyson L, Welch AnneMarie E, Wools Christine, Wu You, Christodoulou John, Thorburn David R

机构信息

Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia; The University of Melbourne, Melbourne, VIC, Australia.

The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.

出版信息

Genet Med. 2025 Jan;27(1):101271. doi: 10.1016/j.gim.2024.101271. Epub 2024 Sep 19.

DOI:10.1016/j.gim.2024.101271

PMID:39305161

Abstract

PURPOSE

Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.

METHODS

A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.

RESULTS

Diagnostic yield was 55% (n = 77) with variants in nuclear (n = 37) and mtDNA (n = 18) MD genes, as well as phenocopy genes (n = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.

CONCLUSION

Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.

摘要

目的

线粒体疾病（MD）患者家庭常常要经历漫长的诊断过程和侵入性检测，但仍有许多人未得到分子诊断。由临床医生、诊断和研究科学家组成的澳大利亚基因组学线粒体旗舰项目开展了一项全国性前瞻性研究，以确定使用血液样本进行单例基因组测序的诊断效用。

方法

采用改良奈梅亨标准（MNC）招募了140名疑似患有MD的儿童和成人，并将他们随机分为外显子组+线粒体DNA（mtDNA）测序组或基因组测序组。

结果

诊断率为55%（n = 77），在核MD基因（n = 37）、mtDNA MD基因（n = 18）以及表型模拟基因（n = 22）中发现了变异。无论疾病起病情况如何，在77%的诊断中确定了核基因病因。儿童起病病例的诊断率（71%）高于成人起病病例（31%），非欧洲血统儿童（78%）与欧洲血统儿童（67%）的诊断率相当。对于儿童，较高的MNC评分与诊断率提高以及表型模拟基因诊断减少相关。此外，3名成年患者在骨骼肌中发现了mtDNA缺失，最初在血液中未检测到。