Looks Can Be Deceiving: Diagnostic Power of Exome Sequencing in Debunking 15q11.2 Copy Number Variations

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2024 Nov 27

PMID 39596641

Authors

Camilla Meossi

Alessia Carrer

Claudia Ciaccio

Laura Pezzoli

Lidia Pezzani

Rosa Maria Silipigni

Francesca L Sciacca

Romano Tenconi

Silvia Esposito

Arianna De Laurentiis

Chiara Pantaleoni

Paola Marchisio

Federica Natacci

Stefano DArrigo

Maria Iascone

Donatella Milani

Affiliations

Soon will be listed here.

Abstract

: The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.2 CNVs. : We enrolled 35 probands with 15q11.2 microdeletions or microduplications from two genetic centers between January 2021 and January 2023. Chromosomal Microarray Analysis (CMA) and ES were performed with written consent obtained from all parents. Pathogenic variants were classified according to ACMG guidelines. : CMA identified additional pathogenic CNVs in 3 of 35 children (9%). Subsequent ES revealed likely pathogenic or pathogenic variants in 11 of 32 children (34%). Notably, a higher percentage of isolated autism spectrum disorder (ASD) diagnoses was observed in patients without other CNVs or point mutations ( = 0.019). : The ES analysis provided a diagnostic yield of 34% in this pediatric cohort with 15q11.2 CNVs. While the study does not dismiss the contribution of the CNV to the clinical phenotype, the findings suggest that ES may uncover the underlying causes of neurodevelopmental disorders. Continuous monitoring and further genetic testing are recommended for all 15q11.2 CNV carriers to optimize clinical management and familial counseling.

References

Chu F, Shaw S, Lee C, Lo L, Hsu J, Hung T . Adverse Perinatal and Early Life Outcomes following 15q11.2 CNV Diagnosis. Genes (Basel). 2021; 12(10). PMC: 8535766. DOI: 10.3390/genes12101480. View

Pezzani L, Marchetti D, Cereda A, Caffi L, Manara O, Mamoli D . Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy. Am J Med Genet A. 2018; 176(12):2867-2871. DOI: 10.1002/ajmg.a.40635. View

Meossi C, Carrer A, Ciaccio C, Estienne M, Silipigni R, Sciacca F . Clinical features and magnesium levels: Novel insights in 15q11.2 BP1-BP2 copy number variants. J Intellect Disabil Res. 2023; 67(7):679-689. DOI: 10.1111/jir.13038. View

Williams S, Nakev A, Guo H, Frain S, Tenin G, Liakhovitskaia A . Association of congenital cardiovascular malformation and neuropsychiatric phenotypes with 15q11.2 (BP1-BP2) deletion in the UK Biobank. Eur J Hum Genet. 2020; 28(9):1265-1273. PMC: 7608352. DOI: 10.1038/s41431-020-0626-8. View

Maya I, Perlman S, Shohat M, Kahana S, Yacobson S, Tenne T . Should We Report 15q11.2 BP1-BP2 Deletions and Duplications in the Prenatal Setting?. J Clin Med. 2020; 9(8). PMC: 7463673. DOI: 10.3390/jcm9082602. View

Maver A, cuturilo G, Kovanda A, Miletic A, Peterlin B . Rare missense TUBGCP5 gene variant in a patient with primary microcephaly. Eur J Med Genet. 2018; 62(12):103598. DOI: 10.1016/j.ejmg.2018.12.003. View

Locke D, Segraves R, Nicholls R, Schwartz S, Pinkel D, Albertson D . BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications. J Med Genet. 2004; 41(3):175-82. PMC: 1735707. DOI: 10.1136/jmg.2003.013813. View

Rafi S, Butler M . The 15q11.2 BP1-BP2 Microdeletion () Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Phenotypes. Int J Mol Sci. 2020; 21(9). PMC: 7246448. DOI: 10.3390/ijms21093296. View

Hashemi B, Bassett A, Chitayat D, Chong K, Feldman M, Flanagan J . Deletion of 15q11.2(BP1-BP2) region: further evidence for lack of phenotypic specificity in a pediatric population. Am J Med Genet A. 2015; 167A(9):2098-102. DOI: 10.1002/ajmg.a.37134. View

10.

Boen R, Kaufmann T, Frei O, van der Meer D, Djurovic S, Andreassen O . No signs of neurodegenerative effects in 15q11.2 BP1-BP2 copy number variant carriers in the UK Biobank. Transl Psychiatry. 2023; 13(1):61. PMC: 9938862. DOI: 10.1038/s41398-023-02358-w. View

11.

Chai J, Locke D, Greally J, Knoll J, Ohta T, Dunai J . Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am J Hum Genet. 2003; 73(4):898-925. PMC: 1180611. DOI: 10.1086/378816. View

12.

Baldwin I, Shafer R, Hossain W, Gunewardena S, Veatch O, Mosconi M . Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families. Int J Mol Sci. 2021; 22(4). PMC: 7914695. DOI: 10.3390/ijms22041660. View

13.

Cafferkey M, Ahn J, Flinter F, Ogilvie C . Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome. Am J Med Genet A. 2014; 164A(8):1916-22. DOI: 10.1002/ajmg.a.36554. View

14.

Srivastava S, Love-Nichols J, Dies K, Ledbetter D, Martin C, Chung W . Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019; 21(11):2413-2421. PMC: 6831729. DOI: 10.1038/s41436-019-0554-6. View

15.

Davis K, Serrano M, Loddo S, Robinson C, Alesi V, Dallapiccola B . Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome. Int J Mol Sci. 2019; 20(6). PMC: 6470921. DOI: 10.3390/ijms20061459. View

16.

Burnside R, Pasion R, Mikhail F, Carroll A, Robin N, Youngs E . Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet. 2011; 130(4):517-28. PMC: 6814187. DOI: 10.1007/s00439-011-0970-4. View

17.

Kreiman B, Boles R . State of the Art of Genetic Testing for Patients With Autism: A Practical Guide for Clinicians. Semin Pediatr Neurol. 2020; 34:100804. DOI: 10.1016/j.spen.2020.100804. View

18.

Rosenfeld J, Coe B, Eichler E, Cuckle H, Shaffer L . Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med. 2012; 15(6):478-81. PMC: 3664238. DOI: 10.1038/gim.2012.164. View

19.

Rosina E, Pezzani L, Apuril E, Pezzoli L, Marchetti D, Bellini M . Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study. Mol Genet Genomic Med. 2023; 12(1):e2316. PMC: 10767581. DOI: 10.1002/mgg3.2316. View

20.

Chaste P, Sanders S, Mohan K, Klei L, Song Y, Murtha M . Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2. Autism Res. 2014; 7(3):355-62. PMC: 6003409. DOI: 10.1002/aur.1378. View