外显子组和基因组测序用于诊断新生儿低张力的遗传基础：一项国际联盟研究。
Exome and Genome Sequencing to Diagnose the Genetic Basis of Neonatal Hypotonia: An International Consortium Study.
作者信息
Morton Sarah U, Costain Gregory, French Courtney E, Wakeling Emma, Szuto Anna, Christodoulou John, Cohn Ronald, Darras Basil T, Wojcik Monica H, D'Gama Alissa M, Dowling James J, Lunke Sebastian, Muntoni Francesco, Raymond Lucy, Rowitch David, Beggs Alan H, Stark Zornitza, Agrawal Pankaj B
机构信息
From the Division of Newborn Medicine (S.U.M., M.H.W., A.M.D.G.), Boston Children's Hospital; Department of Pediatrics (S.U.M., M.H.W., A.M.D.G., A.H.B., P.B.A.), Harvard Medical School; The Manton Center for Orphan Disease Research (S.U.M., M.H.W., A.H.B., P.B.A.), Boston Children's Hospital; The Broad Institute of MIT and Harvard (S.U.M., M.H.W., A.H.B., P.B.A.), Cambridge, MA; Division of Clinical and Metabolic Genetics (G.C., R.C.), The Hospital for Sick Children; Program in Genetics and Genome Biology (G.C.,. R.C., J.J.D.), SickKids Research Institute; Department of Paediatrics (G.C., R.C., J.J.D.), Department of Molecular Genetics (G.C., A.S., J.J.D.), University of Toronto, Ontario, Canada; Division of Genetics and Genomics (C.E.F., M.H.W., A.H.B., P.B.A.), Boston Children's Hospital, MA; North East Thames Regional Genetic Service (E.W., F.M.), Great Ormond Street Hospital Trust, London, United Kingdom; Department of Genetic Counselling (A.S.), The Hospital for Sick Children, Toronto, OntarioN, Canada; Murdoch Children's Research Institute and Department of Paediatrics (J.C., S.L., Z.S.), University of Melbourne, Victoria; Discipline of Child and Adolescent Health (J.C.), Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (B.T.D.), Boston Children's Hospital; Epilepsy Genetics Program (A.M.D.G.), Department of Neurology, Boston Children's Hospital, MA; Division of Neurology (J.J.D.), The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pathology (S.L.), University of Melbourne, Australia; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (F.M.), Great Ormond Street Institute of Child Health, University College London; Departments of Medical Genetics and Paediatrics (L.R., D.R.), University of Cambridge, United Kingdom; Division of Neonatology (D.R.), Department of Pediatrics, UCSF, San Francisco, CA; Australian Genomics Health Alliance (Z.S.); and Division of Neonatology (P.B.A.), Department of Pediatrics, University of Miami and Holtz Children's Hospital, Jackson Health System, FL.
出版信息
Neurology. 2025 Jan 14;104(1):e210106. doi: 10.1212/WNL.0000000000210106. Epub 2024 Dec 19.
BACKGROUND AND OBJECTIVES
Hypotonia is a relatively common finding among infants in the neonatal intensive care unit (NICU). Consideration of genetic testing is recommended early in the care of infants with unexplained hypotonia. We aimed to assess the diagnostic yield and overall impact of exome and genome sequencing (ES and GS).
METHODS
Consecutive infants with hypotonia were identified from research and clinical databases across 5 teaching hospitals in United States, Canada, United Kingdom, and Australia. Inclusion criteria included NICU admission and genetic evaluation. Infants with a known explanation for hypotonia were excluded. Data regarding infant characteristics, genetic testing, and diagnoses were collected. The primary outcome was identification of a molecular diagnosis. Impact on care was a secondary outcome. The Fisher exact and Wilcoxon rank-sum tests were used for statistical analysis.
RESULTS
We identified 147 infants with unexplained hypotonia. The median gestational age was 39 weeks (interquartile range [IQR] 36-42 weeks), 77 (52%) were female, and the median age was 8 days at the time of evaluation (IQR 2-19 days). Eighty (54%) had hypotonia as the main clinical feature while 67 (46%) had additional multisystem involvement. Seventy-five (51%) underwent rapid ES, 44 (30%) rapid GS, 2 (1%) both ES and GS, and 26 (18%) were admitted before ES or GS became available. Of the 121 infants who underwent ES and/or GS, 72 (60%) had the primary outcome of a molecular diagnosis. In addition, 2 infants with mitochondrial genome variants were diagnosed by mitochondrial GS after negative ES, and one infant needed targeted testing to identify a short tandem repeat expansion missed by GS. The proportion diagnosed by ES and GS was not different between infants with hypotonia as the primary finding (37/56, 66%) and infants with multisystemic symptoms (35/65, 54%, odds ratio [OR] 1.7, CI 0.8-3.7, value = 0.20). Testing was more likely to have an impact on care for infants receiving a genetic diagnosis (57/66 vs 14/33, OR 8.4, CI 2.9-26.1, = 1.0E-05).
DISCUSSION
Rapid ES and GS provided a molecular diagnosis for most of the infants with unexplained hypotonia who underwent testing. Further studies are needed to assess the generalizability of these findings as increased access to genetic testing becomes available.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that in unexplained neonatal hypotonia, rapid ES or GS adds diagnostic specificity.
背景与目的
肌张力减退在新生儿重症监护病房（NICU）的婴儿中是相对常见的表现。对于不明原因肌张力减退的婴儿，建议在早期护理中考虑进行基因检测。我们旨在评估外显子组和基因组测序（ES和GS）的诊断率及总体影响。
方法
从美国、加拿大、英国和澳大利亚的5家教学医院的研究和临床数据库中，连续纳入肌张力减退的婴儿。纳入标准包括入住NICU并接受基因评估。已知肌张力减退原因的婴儿被排除。收集有关婴儿特征、基因检测和诊断的数据。主要结局是确定分子诊断。对护理的影响是次要结局。采用Fisher精确检验和Wilcoxon秩和检验进行统计分析。
结果
我们确定了147例不明原因肌张力减退的婴儿。中位胎龄为39周（四分位间距[IQR]36 - 42周），77例（52%）为女性，评估时的中位年龄为8天（IQR 2 - 19天）。80例（54%）以肌张力减退为主要临床特征，67例（46%）有其他多系统受累。75例（51%）接受了快速ES，44例（30%）接受了快速GS，2例（1%）同时接受了ES和GS，26例（18%）在ES或GS可用之前就已入院。在接受ES和/或GS的121例婴儿中，72例（60%）获得了分子诊断这一主要结局。此外，2例线粒体基因组变异的婴儿在ES结果为阴性后通过线粒体GS被诊断出来，1例婴儿需要进行靶向检测以识别GS遗漏的短串联重复序列扩增。以肌张力减退为主要表现的婴儿（37/56，66%）和有多系统症状的婴儿（35/65，54%）通过ES和GS诊断的比例没有差异（优势比[OR]1.7，CI 0.8 - 3.7，P值 = 0.20）。检测对接受基因诊断的婴儿的护理更可能产生影响（57/66对14/33，OR 8.4，CI 2.9 - 26.1，P = 1.0E - 05）。
讨论
快速ES和GS为大多数接受检测的不明原因肌张力减退婴儿提供了分子诊断。随着基因检测的可及性增加，需要进一步研究以评估这些发现的普遍性。
证据分级
本研究提供了IV级证据，即在不明原因的新生儿肌张力减退中，快速ES或GS增加了诊断特异性。
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