Maternal Balanced Translocation Behind Recurrent Fetal Holoprosencephaly in Case Report

Researchers at Gansu Provincial Maternity and Child-care Hospital in Lanzhou, China, have reported a case in which a single chromosomal rearrangement carried by a mother appears to explain nine consecutive unsuccessful pregnancies, including three affected by the severe brain malformation holoprosencephaly. The retrospective case report, published in Frontiers in Genetics, describes how prenatal genetic testing of the woman’s last two pregnancies revealed an unbalanced chromosomal inheritance pattern traceable to her own balanced translocation between chromosomes 3 and 13.

The 31-year-old woman had conceived nine pregnancies naturally, and every one of them ended either in a first-trimester miscarriage or in the termination of a pregnancy marked by fetal structural abnormalities. Both she and her partner were healthy and unrelated, with no exposure to toxins or radiation, although the family had a history of recurrent miscarriages. The turning point came in her fifth pregnancy in 2021, when a 12-week nuchal translucency scan showed fetal holoprosencephaly, cystic hygroma, and generalized skin edema, leading to a termination without any genetic testing. Subsequent pregnancies also ended in miscarriage.

In her eighth pregnancy in 2023, another 12-week scan detected cystic hygroma and an abnormal cardiac structure, later confirmed at 15 weeks as cystic hygroma, pleural effusion, and a single ventricle. This time the clinical team pursued prenatal diagnosis. Copy number sequencing identified a duplication in the q27.2 to q29 region of fetal chromosome 3, reported as chr3:g.185220000-197840000, and a deletion in the q31.3 to q34 region of chromosome 13, reported as chr13:g.93320000-115100000. Karyotyping of the fetus indicated a chromosomal composition of 46,XY,del(13)(q31). The mother’s own karyotype was then determined to be 46,XX,t(3;13)(q27;q31), while her husband’s karyotype was normal.

In her ninth pregnancy in 2024, a 12-week scan again revealed cystic hygroma, generalized skin edema, and holoprosencephaly. After labor was induced, trophoblast whole-exome sequencing performed at an external facility identified a duplication of approximately 12.74 Mb at chromosome 3q27.2-q29 and a heterozygous deletion of approximately 21.78 Mb at chromosome 13q31.3-q34, findings consistent with the fetal test results from 2023. The study received approval from the hospital’s ethics committee, and the authors note that the 3q duplication was not visible by conventional G-banding because of its subtelomeric location and the resolution limits of karyotyping, which typically detects imbalances larger than about 5 to 10 Mb.

The key to explaining the recurrent holoprosencephaly lies in the deleted segment of chromosome 13. According to the report, the deletion at 13q31.3-q34 encompasses 71 protein-coding genes, including the entire ZIC2 gene, a well-established causative gene for holoprosencephaly. ZIC2 encodes a zinc finger transcription factor essential for early forebrain development, particularly in cell signaling and pattern formation during embryogenesis. Haploinsufficiency of ZIC2, resulting from the chr13q deletion in this case, is known to cause holoprosencephaly along with associated phenotypes such as intellectual disability, craniofacial dysmorphisms, and neural tube defects. The authors argue that this genotype-phenotype correlation accounts for the recurrent fetal holoprosencephaly observed in the family.

The duplicated segment on chromosome 3 presents a more complicated picture. The report states that the 12.62 Mb duplication at 3q27.2-q29 encompasses 69 protein-coding genes. Although the region includes the locus for 3q29 microduplication syndrome, which typically spans about 1.6 Mb, the duplication in this family is considerably larger. Phenotypes associated with large 3q duplications are variable and can include intellectual disability, microcephaly, and congenital heart defects, and the authors note that fetal cardiac structural abnormalities were observed in one instance, while acknowledging that the early gestational age at the time of ultrasound may have limited the certainty of that diagnosis.

Holoprosencephaly itself is described in the report as a severe developmental anomaly of the brain resulting from the failure of forebrain vesicle division during fetal development, characterized by incomplete midline separation between the telencephalon and diencephalon. Chromosomal abnormalities such as trisomy 13 and trisomy 18, along with copy number variations, are implicated in its pathogenesis, and more than 20 genes have been linked to the condition, with SHH, ZIC2, TGIF, and SIX3 identified as the primary causative genes. The authors add that ultrasonic diagnosis of holoprosencephaly in the first trimester is relatively straightforward, marked by an indistinct anterior brain midline, absence of the choroid plexus butterfly sign, a single ventricle, and fused thalami, and that trisomy 13 is the chromosomal abnormality most frequently associated with the condition.

Carriers of balanced translocations typically appear phenotypically normal because no significant genetic material is lost, but they face a substantially elevated risk of spontaneous abortion, with reported rates as high as 57.8 percent for reciprocal translocation carriers and 43.6 percent for Robertsonian translocation carriers, according to the report. Current clinical guidelines, including those from ESHRE and ASRM, recommend comprehensive genetic evaluation for couples with a history of two or more miscarriages or a pregnancy affected by severe fetal malformations, typically including parental karyotyping to identify balanced structural rearrangements. For carriers identified through this process, preimplantation genetic testing for structural rearrangements, performed on embryos created via in vitro fertilization, is recommended as a key reproductive option because it is specifically designed to distinguish embryos with a normal karyotype, those carrying the balanced translocation, and those with unbalanced chromosomal content. The authors emphasize that this differs from preimplantation genetic testing for aneuploidy, which screens for whole-chromosome gains or losses but is not optimized to detect the segmental imbalances produced by a parental translocation.

The case illustrates the cost of delayed genetic evaluation. The woman experienced multiple miscarriages without genetic testing of the aborted tissues, and only after her eighth pregnancy did interventional prenatal diagnosis reveal the chromosomal imbalances, followed by high-resolution banding karyotype analysis that identified her balanced translocation. The authors write that the absence of timely genetic counseling led to nine consecutive unsuccessful pregnancies, imposing a significant physical and psychological burden, and that had fetal genetic testing been performed after the second miscarriage, followed by preimplantation genetic testing to select embryos, it might have reduced subsequent miscarriages and stillbirths and potentially altered the clinical outcome. They conclude that after two or more consecutive embryonic arrests, timely genetic testing of abortus tissues is recommended to determine the etiology, and that couples identified as balanced translocation carriers should be offered genetic counseling that includes the option of preimplantation genetic screening to reduce the risk of miscarriage and stillbirth. As a single retrospective case report, the findings describe one family’s experience rather than a general outcome, but the authors present it as a clear demonstration of why karyotype analysis and related genetic tests are considered imperative in cases of recurrent miscarriage and abnormal fetal structures.

Subject of Research: Genetic diagnosis of recurrent holoprosencephaly caused by a parental balanced chromosomal translocation

Article Title: Case Report: Genetic diagnosis and counseling for recurrent holoprosencephaly: a case of parental balanced translocation

Article References: Ge, T., Zhang, C., Hao, Y., Cheng, S., Zhou, B., Wang, X., Cao, Y., & Lin, X. (2026). Case Report: Genetic diagnosis and counseling for recurrent holoprosencephaly: a case of parental balanced translocation. Frontiers in Genetics, 17, Article 1761076. https://doi.org/10.3389/fgene.2026.1761076

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1761076

Keywords: holoprosencephaly, balanced translocation, recurrent miscarriage, chromosome 3, chromosome 13, ZIC2, copy number variation, prenatal diagnosis, genetic counseling, preimplantation genetic testing, case report, karyotype