Prenatal diagnosis and genetic counseling of a de novo 10q11.21q11.23 duplication associated with a normal phenotype

Abstract

Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. Unbalanced chromosome abnormalities are either gains or losses of large genomic regions that do not or only minimally clinically affect the individual. Noninvasive prenatal testing (NIPT) is widely used in the screening of common fetal chromosome aneuploidy. One example is the duplication of 10q11.21q11.23, which includes the 10q11.2 region. This region contains a complex set of low-copy repeats that may lead to various genomic alterations through non-allelic homologous recombination. In this report, we present a case of a de novo 10q11.21q11.23 duplication with a normal phenotype. This case may be helpful for prenatal diagnosis and genetic counseling. A combination of NIPT, prenatal ultrasound, karyotype analysis, copy number variation sequencing, and genetic counseling is helpful for the prenatal diagnosis of CNVs.

Introduction

Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. Unbalanced chromosome abnormalities (UBCAs) are either gains or losses of large genomic regions, but the affected person is not or only minimally clinically affected. UBCAs are often simply cytogenetically visible CNVs. ¹ CNVs and UBCAs identified in prenatal cases need to be carefully considered and correctly interpreted regarding their potential harmfulness. The literature on CNVs and UBCAs is extensive and not always straightforward, which poses a challenge for genetic counseling.

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 help identify structural and numerical chromosome abnormalities. Copy number variation sequencing (CNV-seq) uses the power of a next-generation sequencing platform in which fragmented genomic DNA across all chromosomes are sequenced. Then, with the help of bioinformatics tools, an abundant number of chromosome variations can be identified. ³

Case presentation

In 2021, a gravida 1 para 0 woman in her late 20 s underwent amniocentesis at 18 weeks of gestation after the additional report of expanded non-invasive prenatal testing (NIPT-plus) revealed a 6.22-megabase (Mb) duplication from 10q11.21 to 10q11.23. Her husband was in his early 30s. There was no family history of birth defects or genetic diseases. G-banding karyotype analysis was performed on cultured amniocytes and parental blood samples. CNV-seq was also performed on uncultured amniocytes.

Chromosomal G-banding revealed a karyotype of 46,XX (Figure 1). The CNV-seq platform used was the NextSeq 550AR platform (Annoroad Technology, Beijing, China), which can cover whole-chromosome aneuploidies, large-scale deletions/duplications, and genome-wide CNVs. The platform can typically detect CNVs ranging from 100 kb to several Mb. CNV-seq analysis detected a 6.02-Mb chromosomal duplication in the region of 10q11.21q11.23, which is to be reported as seq[hg19]dup(10)(q11.21q11.23)chr10:g.46100000_52120000dup (Figure 2). We then performed both CNV-seq and chromosomal G-banding on peripheral blood samples from both parents. Their karyotypes and CNV-seq were normal (Figure 3: the pedigree table of the family). Ultrasound examination showed no dysmorphisms or intrauterine growth restriction (IUGR) in the fetus. At 23 weeks of gestation, the fetus had an estimated weight of 650 g, abdominal circumference of 19.1 cm, head circumference of 21.5 cm, femur length of 4.2 cm, and heart rate of 148 bpm. ⁴ After genetic counseling, the parents decided to continue the pregnancy.

Figure 1.

46,XX karyotype.

Figure 2.

Copy number variation sequencing (CNV-seq) detected a 6.02-Mb chromosomal duplication in the region of 10q11.21q11.23: seq[hg19]dup(10)(q11.21q11.23)chr10:g.46100000_52120000dup.

Figure 3.

Pedigree table of the family. II-1: the carrier of the de novo 10q11.21q11.23 duplication.

At 39 weeks of gestation, the expectant mother gave birth vaginally to a female baby. The baby’s growth parameters at birth were in the normal ranges, with Apgar scores of 9/9/10. A complete physical examination of the baby showed normal results. At the 24-month checkup, the baby was developing normally.

The reporting of this study conforms to CARE guidelines. ⁵

Discussion

The proximal 10q abnormalities included the 10q11.2 region, which contained a complex set of low-copy repeats (LCRs) that may lead to various genomic alterations through non-allelic homologous recombination (NAHR). ⁶ These duplications have been described as being associated with a wide range of cognitive and behavioral phenotypes, including mild-to-moderate developmental delay, postnatal growth retardation, microcephaly, dysmorphic features, and autism spectrum disorders.^6–7 Although the causes of autism are unknown, clinical genetic studies have provided strong evidence in favor of the involvement of genetic factors in its etiology. 10q11.21q11.23 duplication could represent a CNV that predisposes an individual to autism. ⁸

Proximal 10q duplication is often derived from a balanced translocation in a parent or inherited from a carrier (father or mother) with a normal phenotype, with part of this duplication being a de novo mutation. ⁹

The chromosomal duplication of 10q11.21q11.23 contains 32 genes, which are all triplo-insensitive genes. Specifically, these genes encode morphogenetic proteins and regulators of cell growth and differentiation (growth differentiation factor 2 (GDF2)), signal transducers (mitogen-activated protein kinase 8 (MAPK8)), and enzymes (choline acetyltransferase (CHAT)).

GDF2 plays important roles in the differentiation of cholinergic central nervous system neurons and skeletal morphogenesis. ¹⁰ The severe phenotype potentially arises because this region includes major genetic information that affects physical development or from the duplication significantly altering the expression patterns of the corresponding genes.

In this case, the karyotypes and CNV-seq of the parents were normal. During pregnancy, there were no dysmorphisms or IUGR in the fetus. At the 2-year follow-up, the baby did not have an abnormal phenotype nor exhibited any evidence of developmental delay. We will continue to monitor her growth and development in the future.

Some reports in the literature^6–10 have presented cases with similar, but not the same, breakpoints as this case. However, the cases with a similar duplication all resulted in abnormal phenotype or developmental delay. Unlike these cases, our case did not have an abnormal phenotype or exhibit signs of developmental delay.

Conclusion

Here, we presented a case of a de novo 10q11.21q11.23 duplication that was likely caused by NAHR between LCRs associated with a normal phenotype. This case may be helpful for prenatal diagnosis and genetic counseling. When examining CNVs and UBCAs, the database and recent literature should be consulted to provide patients with the latest genotype-phenotype correlation information.

Chromosomal microdeletions and microduplications are difficult to detect by conventional cytogenetics. NIPT is widely used for the screening of common fetal chromosome aneuploidy, but cannot detect a small change (less than 1 Mb) of the fetal (placental) fraction. A combination of NIPT, prenatal ultrasound, karyotype analysis, CNV-seq, and genetic counseling is helpful for the prenatal diagnosis of CNVs. ¹¹

Ethics statement

This research was approved by the Ethics Committee of Renmin Hospital of Shiyan (Approval No. 20231229). All patient guardians provided written informed consent for the study.