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BMC Pregnancy and Childbirth

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Open Access 01-12-2024 | Autism Spectrum Disorder | Research

Intrauterine ultrasound phenotyping, molecular characteristics, and postnatal follow-up of fetuses with the 15q11.2 BP1-BP2 microdeletion syndrome: a single-center, retrospective clinical study

Authors: Meiying Cai, Aixiang Lv, Wantong Zhao, Liangpu Xu, Na Lin, Hailong Huang

Published in: BMC Pregnancy and Childbirth | Issue 1/2024

Abstract

Objectives

The 15q11.2 BP1-BP2 microdeletion is associated with neurodevelopmental diseases. However, most studies on this microdeletion have focused on adults and children. Thus, in this study, we summarized the molecular characteristics of fetuses with the 15q11.2 BP1-BP2 microdeletion and their postnatal follow-up to guide prenatal diagnosis.

Methods

Ten thousand fetuses were retrospectively subjected to karyotype analysis and chromosome microarray analysis.

Results

Chromosome microarray analysis revealed that 37 (0.4%) of the 10,000 fetuses had 15q11.2 BP1-BP2 microdeletions. The fragment size of the 15q11.2 BP1-BP2 region was approximately 312–855 kb and encompassed TUBGCP5, CYFIP1, NIPA2, and NIPA1 genes. Twenty-five of the 37 fetuses with this microdeletion showed phenotypic abnormalities. The most common ultrasonic structural abnormality was congenital heart disease, followed by renal dysplasia and Dandy–Walker malformation. The 15q11.2 BP1-BP2 microdeletion was inherited from the father and mother in 6 and 10 cases, respectively, and de novo inherited in 4 cases. In the postnatal follow-up, 16.1% of the children had postnatal abnormalities.

Conclusion

Fetuses with the 15q11.2 BP1-BP2 microdeletion showed high proportions of phenotypic abnormalities, but the specificity of penetrance was low. Thus, fetuses with this syndrome are potentially at a higher risk of postnatal growth/behavioral problems and require continuous monitoring of growth and development.

Rafi SK, Butler MG. The 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Phenotypes. Int J Mol Sci. 2020;21(9):3296.CrossRefPubMedPubMedCentral

Ho KS, Wassman ER, Baxter AL, et al. Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders. Int J Mol Sci. 2016;17(12):2070.CrossRefPubMedPubMedCentral

Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T. Behavioral Differences Among Subjects With Prader-Willi Syndrome and Type I or Type II Deletion and Maternal Disomy. Pediatrics. 2004;113:565–73.CrossRefPubMed

Cooper GM, Coe BP, Girirajan S, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43:838–46.CrossRefPubMedPubMedCentral

Doornbos M, Sikkema-Raddatz B, Ruijvenkamp C, et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet. 2009;52:108–15.CrossRefPubMed

Kovel CD, Trucks H, Helbig I, Sander T. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain. 2010;133(Pt 1):23–32.CrossRefPubMed

Devin M, Merlin GB. The 15q11.2 BP1-BP2 microdeletion syndrome: a review. Int J Mol Sci. 2015;16(2):4068–82.CrossRef

Rosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG. Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med. 2013;15:478–81.CrossRefPubMed

Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST, Working Group of the American College of Medical Genetics Laboratory Quality Assurance C. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13:680–5.CrossRefPubMed

10.

Charney AW, Stahl EA, Green EK, et al. Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases. Biol Psychiat. 2019;86:110–9.CrossRefPubMed

11.

Rudd DS, Axelsen M, Epping EA, Andreasen NC, Wassink TH. A genome-wide CNV analysis of schizophrenia reveals a potential role for a multiple-hit model. Am J Med Genet B. 2014;165B:619–26.CrossRef

12.

Rees E, Walters J, Georgieva L, Isles AR, Kirov G. Analysis of copy number variations at 15 schizophrenia-associated loci. Brit J Psychiat. 2014;204:108–14.CrossRefPubMed

13.

Burnside RD, Pasion R, Mikhail FM, et al. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet. 2011;130:517–28.CrossRefPubMedPubMedCentral

14.

Jiang Y, Zhang Y, Zhang P, et al. NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy. Hum Genet. 2012;131(7):1217–24.CrossRefPubMed

15.

Jähn JA, von Spiczak S, Muhle H, et al. Iterative phenotyping of 15q11.2, 15q13.3 and 16p13.11 microdeletion carriers in pediatric epilepsies. Epilepsy Res. 2014;108(1):109–16.CrossRefPubMed

16.

van der Meer D, Sønderby IE, Kaufmann T, et al. Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition. JAMA psychiatry. 2020;77(4):420–30.CrossRefPubMed

17.

Li X, Shi G, Li Y, Wang B, et al. 15q11.2 deletion is enriched in patients with total anomalous pulmonary venous connection. J Med Genet. 2020;1:1–9.

18.

Riggs ER, Andersen EF, Cherry AM, et al. Correction: 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. 2021;23(11):2230.CrossRefPubMed

19.

Cheng SSW, Chan KYK, Leung KKP, et al. Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong. Am J Med Genet C. 2019;181:196–207.CrossRef

20.

Cox DM, Butler MG. The 15q11.2 BP1-BP2 microdeletion syndrome: a review. Int J Mol Sci. 2015;16:4068–82.CrossRefPubMedPubMedCentral

21.

Butler MG. Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder. J Intellect Disabil Res. 2017;61:568–79.CrossRefPubMedPubMedCentral

22.

Davis KW, Serrano M, Loddo S, et al. Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome. Int J Mol Sci. 2019;20(6):1459.CrossRefPubMedPubMedCentral

23.

Butler MG. Magnesium Supplement and the 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome: A Potential Treatment? Int J Mol Sci. 2019;20(12):2914.CrossRefPubMedPubMedCentral

24.

Goytain A, Hines RM, El-Husseini A, et al. NIPA 1(SPG6), the Basis for Autosomal Dominant Form of Hereditary Spastic Paraplegia, Encodes a Functional Mg2+ Transporter. J Biol Chem. 2007;282:8060–8.CrossRefPubMed

25.

Hildebrand MS, Damiano JA, Mullen SA, et al. Does variation in NIPA2 contribute to genetic generalized epilepsy? Hum Genet. 2014;133:673–4.CrossRefPubMed

26.

Wolf VD, Brison N, Devriendt K, Peeters H. Genetic counseling for susceptibility loci and neurodevelopmental disorders: The del15q11.2 as an example. Am J Med Genet A. 2013;161A(11):2846–54.CrossRefPubMed

27.

Quaresima P, Fesslova V, Farina A, et al. How to do a fetal cardiac scan. Arch Gynecol Obstet. 2023;307(4):1269–76.CrossRefPubMed

28.

Wu XL, Ru L, Fang F, Pan M, Liao C. Chromosome microarray analysis in the investigation of children with congenital heart disease. BMC Pediatr. 2017;17:117.CrossRefPubMedPubMedCentral

29.

Jnch AE, Douard E, Moreau C, Dijck AV, Jacquemont S. Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice. J Med Genet. 2019;56(10):701–10.CrossRef

30.

Stefansson H, Meyer-Lindenberg A, Steinberg S, et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014;505(7483):361–6.CrossRefPubMed

31.

Vanlerberghe C, Petit F, Malan V, et al. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015;58(3):140–7.CrossRefPubMed

32.

Ma R, Deng L, Xia Y, et al. A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies. Sci Rep. 2017;7:44446.CrossRefPubMedPubMedCentral

33.

Lord C, Risi S, DiLavore PS, Shulman C, Thurm A, Pickles A. Autism from 2 to 9 years of age. Arch Gen Psychiat. 2006;63(6):694–701.CrossRefPubMed

34.

Vitrikas K, Savard D, Bucaj M. Developmental Delay: When and How to Screen. Am Fam Physician. 2017;96(1):36–43.PubMed

Title: Intrauterine ultrasound phenotyping, molecular characteristics, and postnatal follow-up of fetuses with the 15q11.2 BP1-BP2 microdeletion syndrome: a single-center, retrospective clinical study
Authors: Meiying Cai
Aixiang Lv
Wantong Zhao
Liangpu Xu
Na Lin
Hailong Huang
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Autism Spectrum Disorder
Published in: BMC Pregnancy and Childbirth / Issue 1/2024
Electronic ISSN: 1471-2393
DOI: https://doi.org/10.1186/s12884-023-06223-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Intrauterine ultrasound phenotyping, molecular characteristics, and postnatal follow-up of fetuses with the 15q11.2 BP1-BP2 microdeletion syndrome: a single-center, retrospective clinical study

Abstract

Objectives

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusion

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