The Phenotypic Spectrum of 16p11.2 Recurrent Chromosomal Rearrangements

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2024 Aug 29

PMID 39202413

Authors

Anastasios K Mitrakos

Konstantina Kosma

Periklis Makrythanasis

Maria Tzetis

Affiliations

Soon will be listed here.

Abstract

The human 16p11.2 chromosomal region is rich in segmental duplications which mediate the formation of recurrent CNVs. CNVs affecting the 16p11.2 region are associated with an increased risk for developing neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID), as well as abnormal body weight and head circumference and dysmorphic features, with marked phenotypic variability and reduced penetrance. CNVs affecting the 16p11.2 region mainly affect a distal interval of ~220 Kb, between Breakpoints 2 and 3 (BP2-BP3), and a proximal interval of ~593 Kb (BP4-BP5). Here, we report on 15 patients with recurrent 16p11.2 rearrangements that were identified among a cohort of 1600 patients (0.9%) with neurodevelopmental disorders. A total of 13 deletions and two duplications were identified, of which eight deletions included the proximal 16p11.2 region (BP4-BP5) and five included the distal 16p11.2 region (BP2-BP3). Of the two duplications that were identified, one affected the proximal and one the distal 16p11.2 region; however, both patients had additional CNVs contributing to phenotypic severity. The features observed and their severity varied greatly, even between patients within the same family. This article aims to further delineate the clinical spectrum of patients with 16p11.2 recurrent rearrangements in order to aid the counselling of patients and their families.

References

Al-Jawahiri R, Jones M, Milne E . Atypical neural variability in carriers of 16p11.2 copy number variants. Autism Res. 2019; 12(9):1322-1333. DOI: 10.1002/aur.2166. View

DellEdera D, Dilucca C, Allegretti A, Simone F, Lupo M, Liccese C . 16p11.2 microdeletion syndrome: a case report. J Med Case Rep. 2018; 12(1):90. PMC: 5881179. DOI: 10.1186/s13256-018-1587-1. View

Dittwald P, Gambin T, Szafranski P, Li J, Amato S, Divon M . NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits. Genome Res. 2013; 23(9):1395-409. PMC: 3759717. DOI: 10.1101/gr.152454.112. View

Woodbury-Smith M, DAbate L, Stavropoulos D, Howe J, Drmic I, Hoang N . The Phenotypic variability of 16p11.2 distal BP2-BP3 deletion in a transgenerational family and in neurodevelopmentally ascertained samples. J Med Genet. 2023; 60(12):1153-1160. PMC: 10715508. DOI: 10.1136/jmg-2022-108818. View

Bochukova E, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K . Large, rare chromosomal deletions associated with severe early-onset obesity. Nature. 2009; 463(7281):666-70. PMC: 3108883. DOI: 10.1038/nature08689. View

Cardenas-de-la-Parra A, Martin-Brevet S, Moreau C, Rodriguez-Herreros B, Fonov V, Maillard A . Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations. Neuroimage. 2019; 203:116155. DOI: 10.1016/j.neuroimage.2019.116155. View

Sanders S, He X, Willsey A, Ercan-Sencicek A, Samocha K, Cicek A . Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron. 2015; 87(6):1215-1233. PMC: 4624267. DOI: 10.1016/j.neuron.2015.09.016. View

Weiss L, Shen Y, Korn J, Arking D, Miller D, Fossdal R . Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008; 358(7):667-75. DOI: 10.1056/NEJMoa075974. View

Qureshi A, Mueller S, Snyder A, Mukherjee P, Berman J, Roberts T . Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci. 2014; 34(34):11199-211. PMC: 4138332. DOI: 10.1523/JNEUROSCI.1366-14.2014. View

10.

Bijlsma E, Gijsbers A, Schuurs-Hoeijmakers J, van Haeringen A, Fransen van de Putte D, Anderlid B . Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur J Med Genet. 2009; 52(2-3):77-87. DOI: 10.1016/j.ejmg.2009.03.006. View

11.

Poot M . Syndromes Hidden within the 16p11.2 Deletion Region. Mol Syndromol. 2018; 9(4):171-174. PMC: 6103351. DOI: 10.1159/000490845. View

12.

Tzetis M, Kitsiou-Tzeli S, Frysira H, Xaidara A, Kanavakis E . The clinical utility of molecular karyotyping using high-resolution array-comparative genomic hybridization. Expert Rev Mol Diagn. 2012; 12(5):449-57. DOI: 10.1586/erm.12.40. View

13.

Li L, Huang L, Lin S, Luo Y, Fang Q . Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene. Am J Med Genet A. 2017; 173(8):2284-2288. DOI: 10.1002/ajmg.a.38284. View

14.

Sonderby I, Gustafsson O, Doan N, Hibar D, Martin-Brevet S, Abdellaoui A . Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Mol Psychiatry. 2018; 25(3):584-602. PMC: 7042770. DOI: 10.1038/s41380-018-0118-1. View

15.

Kumar R, Karamohamed S, Sudi J, Conrad D, Brune C, Badner J . Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet. 2007; 17(4):628-38. DOI: 10.1093/hmg/ddm376. View

16.

McCarthy S, Makarov V, Kirov G, Addington A, McClellan J, Yoon S . Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009; 41(11):1223-7. PMC: 2951180. DOI: 10.1038/ng.474. View

17.

Bachmann-Gagescu R, Mefford H, Cowan C, Glew G, Hing A, Wallace S . Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med. 2010; 12(10):641-7. DOI: 10.1097/GIM.0b013e3181ef4286. View

18.

Chung W, Roberts T, Sherr E, Snyder L, Spiro J . 16p11.2 deletion syndrome. Curr Opin Genet Dev. 2021; 68:49-56. PMC: 10256135. DOI: 10.1016/j.gde.2021.01.011. View

19.

Oikonomakis V, Kosma K, Mitrakos A, Sofocleous C, Pervanidou P, Syrmou A . Recurrent copy number variations as risk factors for autism spectrum disorders: analysis of the clinical implications. Clin Genet. 2016; 89(6):708-18. DOI: 10.1111/cge.12740. View

20.

Kleinendorst L, van den Heuvel L, Henneman L, van Haelst M . Who ever heard of 16p11.2 deletion syndrome? Parents' perspectives on a susceptibility copy number variation syndrome. Eur J Hum Genet. 2020; 28(9):1196-1204. PMC: 7608422. DOI: 10.1038/s41431-020-0644-6. View