Systematic Analysis of Copy Number Variants of Uncertain Significance Partially Overlapping with the Haploinsufficient or Triplosensitive Genes in Clinical Testing

Overview

Journal Ann Med

Publisher Informa Healthcare

Specialty General Medicine

Date 2023 Nov 2

PMID 37917952

Authors

Ran Zhou

Jiao Jiao

Yan Wang

Lulu Meng

Yiming Li

Yiyun Xu

Ping Hu

Zhengfeng Xu

Affiliations

Soon will be listed here.

Abstract

Copy number variants of uncertain significance (VUS) has brought much distress for patients and great counselling challenges for clinicians. Of these, a special type of VUS (HT-VUS), harbouring one or both breakpoints within the established haploinsufficient or triplosensitive genes, were considered to be more likely to cause clinical effects compared with other types of VUS. We retrospectively evaluated the properties and clinical significance of those HT-VUS samples in clinical testing for chromosome microarray analysis (CMA). A total of 7150 samples were selected for HT-VUS screening, and 75 (1.05%) subjects with 75 HT-VUS were found. The majority of these HT-VUS were heterozygous duplications and chromosome X had the most HT-VUS. The prevalence of HT-VUS was 0.90% (28/3116) for prenatal low-risk samples, 1.18% (26/2196) for prenatal high-risk samples, 1.37% (10/728) for postnatal samples and 0.99% (11/1110) for early pregnancy loss samples. However, the incidence of HT-VUS was not statistically different between different groups. HT-VUS (deletions or duplications) involving introns and HT-VUS (duplications) including terminal coding exons (either the first or last exons) might be clinically neutral. Our study will be helpful for both interpretation and genetic counselling in the future.

References

Hollenbeck D, Williams C, Drazba K, Descartes M, Korf B, Rutledge S . Clinical relevance of small copy-number variants in chromosomal microarray clinical testing. Genet Med. 2016; 19(4):377-385. DOI: 10.1038/gim.2016.132. View

Manning M, Hudgins L . Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010; 12(11):742-5. PMC: 3111046. DOI: 10.1097/GIM.0b013e3181f8baad. View

Buchanan J, Chitayat D, Kolomietz E, Lee H, Scherer S, Speevak M . Prenatal genomic microarray and sequencing in Canadian medical practice: towards consensus. J Med Genet. 2015; 52(9):585-6. DOI: 10.1136/jmedgenet-2015-103223. View

Mullegama S, Rosenfeld J, Orellana C, van Bon B, Halbach S, Repnikova E . Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. Eur J Hum Genet. 2013; 22(1):57-63. PMC: 3865402. DOI: 10.1038/ejhg.2013.67. View

Rehm H, Berg J, Brooks L, Bustamante C, Evans J, Landrum M . ClinGen--the Clinical Genome Resource. N Engl J Med. 2015; 372(23):2235-42. PMC: 4474187. DOI: 10.1056/NEJMsr1406261. View

Miller D, Adam M, Aradhya S, Biesecker L, Brothman A, Carter N . Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010; 86(5):749-64. PMC: 2869000. DOI: 10.1016/j.ajhg.2010.04.006. View

Mansfield P, Constantino J, Baldridge D . MYT1L: A systematic review of genetic variation encompassing schizophrenia and autism. Am J Med Genet B Neuropsychiatr Genet. 2020; 183(4):227-233. PMC: 7605444. DOI: 10.1002/ajmg.b.32781. View

Marcou C, Pitel B, Hagen C, Boczek N, Rowsey R, Baughn L . Limited diagnostic impact of duplications <1 Mb of uncertain clinical significance: a 10-year retrospective analysis of reporting practices at the Mayo Clinic. Genet Med. 2020; 22(12):2120-2124. DOI: 10.1038/s41436-020-0932-0. View

Kearney H, Thorland E, Brown K, Quintero-Rivera F, South S . American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011; 13(7):680-5. DOI: 10.1097/GIM.0b013e3182217a3a. View

10.

Tsuchiya K, Shaffer L, Aradhya S, Gastier-Foster J, Patel A, Rudd M . Variability in interpreting and reporting copy number changes detected by array-based technology in clinical laboratories. Genet Med. 2009; 11(12):866-73. DOI: 10.1097/GIM.0b013e3181c0c3b0. View

11.

Mullegama S, Elsea S . Intragenic MBD5 familial deletion variant does not negatively impact MBD5 mRNA expression. Mol Cytogenet. 2014; 7(1):80. PMC: 4243375. DOI: 10.1186/s13039-014-0080-9. View

12.

Cosemans N, Vandenhove L, Vogels A, Devriendt K, Van Esch H, Van Buggenhout G . The clinical relevance of intragenic deletions. J Med Genet. 2020; 57(5):347-355. DOI: 10.1136/jmedgenet-2019-106448. View

13.

Lowther C, Speevak M, Armour C, Goh E, Graham G, Li C . Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression. Genet Med. 2016; 19(1):53-61. PMC: 4980119. DOI: 10.1038/gim.2016.54. View

14.

Rooney Riggs E, Andersen E, Cherry A, Kantarci S, Kearney H, Patel A . Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2019; 22(2):245-257. PMC: 7313390. DOI: 10.1038/s41436-019-0686-8. View

15.

Lou S, Lomborg K, Lewis C, Riedijk S, Petersen O, Vogel I . "It's probably nothing, but…" Couples' experiences of pregnancy following an uncertain prenatal genetic result. Acta Obstet Gynecol Scand. 2020; 99(6):791-801. DOI: 10.1111/aogs.13813. View

16.

Tadros S, Wang R, Waters J, Waterman C, Collins A, Collinson M . Inherited 2q23.1 microdeletions involving the locus. Mol Genet Genomic Med. 2017; 5(5):608-613. PMC: 5606852. DOI: 10.1002/mgg3.316. View

17.

Wein N, Vulin A, Falzarano M, Szigyarto C, Maiti B, Findlay A . Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat Med. 2014; 20(9):992-1000. PMC: 4165597. DOI: 10.1038/nm.3628. View

18.

De Wel B, Willaert S, Nadaj-Pakleza A, Aube-Nathier A, Testelmans D, Buyse B . Respiratory decline in adult patients with Becker muscular dystrophy: A longitudinal study. Neuromuscul Disord. 2021; 31(3):174-182. DOI: 10.1016/j.nmd.2020.12.010. View

19.

Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A . High-resolution copy number variation analysis of schizophrenia in Japan. Mol Psychiatry. 2016; 22(3):430-440. DOI: 10.1038/mp.2016.88. View

20.

Wang Y, Li Y, Chen Y, Zhou R, Sang Z, Meng L . Systematic analysis of copy-number variations associated with early pregnancy loss. Ultrasound Obstet Gynecol. 2019; 55(1):96-104. DOI: 10.1002/uog.20412. View