Prenatal diagnosis and genetic counseling of a paternally inherited microduplication 18q11.1 to 18q11.2 in a Chinese family

doi:10.21203/rs.3.rs-1948717/v1

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Case Report

Prenatal diagnosis and genetic counseling of a paternally inherited microduplication 18q11.1 to 18q11.2 in a Chinese family

https://doi.org/10.21203/rs.3.rs-1948717/v1

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Background: Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. Chromosomal imbalances of several megabasepair in size are normally deleterious for the carrier. Still, rarely reported are so-called “unbalanced chromosome abnormalities” (UBCAs), which are either gains or losses or equally large genomic regions, but the affected person is not or only minimally clinically affected. The knowledge of such UBCAs is imperative also in chromosomal microarray analysis (CMA) or noninvasive prenatal testing (NIPT).

Case presentation: A paternally inherited dup(18)(q11.1q11.2) was identified in a over two generations in a Chinese family. The affected region encompasses 25 genes, among which GATA6 is expressed in fetal endothelial cells and mesodermal cells. GATA6 duplications and /or mutations have been seen in cases with congenital heart disease but also non-affected individuals, suggesting incomplete penetrance and variable expressivity.

Conclusions: Duplications in the region of chromosome 18q11 have been rare reported previously in clinically healthy persons. Here a further family with an UBCA in 18q11 is added to the literature, suggesting a careful genetic counselling in comparable, especially prenatal cases.

chromosomal microarray analysis (CMA)

microduplication 18q11.1 to 18q11.2

prenatal diagnosis

unbalanced chromosome abnormality (UBCA)

Besides whole chromosome gains or losses, microdeletions and microduplications are in the focus of prenatal diagnostics ^[1]. Nowadays especially noninvasive prenatal testing (NIPT) is widely used in the screening of common fetal chromosome aneuploidy ^[2].

Conventional karyotyping provides an overview of the entire genome and can identify structural and numerical chromosome abnormalities. Chromosomal microarray analysis (CMA) is a method using array technology to detect chromosome abnormalities spanning less than 5Mb ^[3].

Besides clearly disease causing chromosomal imbalances there are also rare cases of euchromatic variants ^[4] and also the unbalanced chromosome abnormalities (UBCAs) ^[5]. Euchromatic variants do not cause clinical symptoms and are often nothing else than cytogenetically visible copy number variants (CNVs), while UBCAs are gains or losses of euchromatic material in the size of megabasepairs, where according to sheer size of the imbalance a severe phenotype would have to be expected. Still, in cases characterized as having a UBCA, severe phenotypes remain missing, and carrier of an UBCA show no or only minor symptoms ^[5].

Here we report the characterization of a two-generation family with an in GTG-banding cryptic UBCA in 18q11.1 to 18q11.2 of 5.3 Mb in size. The first hint towards that came from NIPT.

A 41-year-old, gravida 1, para 0 pregnant woman underwent amniocentesis at 18 weeks of gestation because result of a genome wide NIPT screening gave a hint for a 5.3 Mb microduplication encompassing 18q11.1 to 18q11.2. Her husband was 45 years old and no family history of birth defects or genetic diseases was reported. The cytogenetic analysis of the cultured amniocytes revealed a normal male karyotype of 46,XY (Fig. 1). CMA of DNA derived from uncultured amniocytes was performed using Affymetrix CytoScan 750K chip, which included 550k nonpolymorphic markers and 200k single-nucleotide polymorphism markers. CMA confirmed the presence of the 5.3-Mb chromosomal duplication, which is to be reported according to International System of Cytogenomic Nomenclature 2020 (ISCN 2020) [6] as arr[GRCh37] 18q11.1q11.2(18,540,000_23,840,000)x3 (Fig. 2).

Parental karyotypes were done and were 46,XX and 46,XY, respectively. However, in CMA the father had the same duplication in 18q as the fetus. Ultrasound examination showed no intrauterine growth restrictions (IUGRs) or congenital malformations except absence of right kidney in the fetus. A comprehensive physical examination of the parents, especially the father showed no abnormalities. After genetic counseling, the parents decided to continue the pregnancy. At 40 weeks of gestation, the mother gave birth vaginally to a male baby. The baby's growth parameters at birth were in the normal ranges. The Apgar scores were 9/10/10. The results of complete physical examination were normal except absence of right kidney. At 36-month follow-up, the baby was developing normally (intelligence quotient, IQ = 110).

Duplications about the region of chromosome 18q11 have been rare reported previously in clinically healthy persons. According to the literature ^[7–10] yet only four cases(in one family) are reported. Here two cases with clearly characterized size of 5.3 Mb is added to the literature. In this family, the fetus and the father have the same duplication, and they both have normal phenotype except absence of right kidney in the fetus. We haven't been able to confirm whether the absence of right kidney in the fetus is related to the chromosomal duplication. This highlights the necessity to be careful in hasty conclusions about the potential impact of gains or losses as detected in NIPT or CMA analyses. Without a parental genetic test and best also a GTG-banding the nature and impact of a detected imbalance cannot be interpreted reliably.

Still it is interesting and needs further investigations that the in the reported family duplication region in 18q11.1q11.2 encompasses 25 genes as ROCK1, GREB1L, ABHD3, ANKRD29, AQP4, CABLES1, CABRY, CHST9, CTAGE1, ESCO1, GATA6, IMPACT, KCTD1, LAMA3, MIB1, NPC1, OSBPL1A, PBBP8, RIOK3, RP11, SNRPD1, SS18, TAF4B, TMEM241 and TTC39C. In these 25 genes, genetic alterations of ROCK1, ABHD3, ANKRD29, CABLES1 and CTAGE1, including deletion, methylation, and point mutations, are directly involved in the development of human cancer and other diseases ^[11–13].

GATA6 is expressed in fetal endothelial cells and mesodermal cells. GATA6 duplications and /or mutations have been seen in cases with congenital heart disease but also non-affected individuals, suggesting incomplete penetrance and variable expressivity ^[14].

With this report it is highlighted that (sub)chromosomal imbalances like microduplication in 18q11.1q11.2 may show great variability concerning phenotypic consequences. CNVs and UBCA identified in prenatal cases need careful considerations and correct interpretation if those are harmless or harmful variants from the norm. Overall, cases like the present remind that parental testing is always necessary, also in cases of imbalances being megabasepairs in size, not to miss UBCAs and terminate a potentially healthy offspring. Our case can be helpful for prenatal diagnosis and genetic counseling. Chromosomal microdeletions and microduplications are difficult to detect by conventional cytogenetics. Combination of prenatal ultrasound, karyotype analysis, CMA and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications ^[15].

Ethics approval and consent to participate

This study was approved by the ethics committee of the Wuhan Hospital of Traditional Chinese Medicine. All patient guardians gave informed consent to the study.

Consent for publication

All patient guardians gave informed consent to the publication of this manuscript.

Availability of data and materials

Please contact the corresponding author for data requests.

Conflicts of interest

The authors have no conflicts of interest relevant to this manuscript.

Funding declaration

There was no funding available for this study.

Authors’ Contribution

Juan Chen is responsible for clinical diagnosis and treatment.

Ying Zhang is responsible for pathological examination.

Mingxi Zhang is responsible for genetic testing and thesis writing.

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No competing interests reported.

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You are reading this latest preprint version

Prenatal diagnosis and genetic counseling of a paternally inherited microduplication 18q11.1 to 18q11.2 in a Chinese family

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