Prenatal detectives: a 10.42 Mb homozygous chromosome 6 segment with a normal baby

When a routine blood test flags a possible chromosomal problem in an unborn baby, most families brace for the worst. But a new case report from China shows how modern genomic detective work can turn a frightening screening result into a reassuring story. A 29-year-old mother, pregnant with her second child, was referred for invasive testing after non-invasive prenatal testing (NIPT) suggested a high probability of an extra copy of chromosome 11. What her medical team found instead was something far more unusual: a long stretch of chromosome 6 in which the fetus was homozygous at virtually every variant, yet the baby, born at term, developed completely normally.

The case, published in Frontiers in Genetics by Dandan Li of Shiyan Maternal and Child Health Hospital and colleagues, centers on a phenomenon known as a run of homozygosity, or ROH. These are long, uninterrupted segments of the genome in which the two homologous chromosomes carry identical alleles, as if the same ancestral haplotype had been inherited from both parents. ROH can arise from several causes, including parental consanguinity, population genetic drift, positive selection, or chromosomal events such as uniparental disomy, in which both copies or a portion of a chromosome pair are inherited from a single parent. Distinguishing among these origins is the central challenge of prenatal counseling for such findings.

The mother underwent amniocentesis at 18 weeks of gestation. Conventional G-banded karyotyping of cultured amniocytes at 550-band resolution revealed a normal female karyotype of 46,XX, with no numerical or structural abnormalities of chromosome 11. Chromosomal microarray analysis, using a high-density chip with roughly 550,000 non-polymorphic markers and 200,000 SNP markers spaced at an average interval of about 1.7 kilobases, likewise found no copy-number changes involving chromosome 11. The initial NIPT finding was therefore classified as a false positive, a well-documented occurrence that can stem from confined placental mosaicism, maternal copy-number variants, circulating maternal tumor DNA, or simple technical noise.

But the microarray did reveal something unexpected: a copy-neutral 10.42 megabase run of homozygosity spanning chromosome 6q25.3q27, corresponding to positions 157,776,570 through 168,194,615 on the GRCh37 reference genome. Because neither ROH nor uniparental disomy alters chromosome copy number or gross architecture, conventional cytogenetic karyotyping cannot detect them. SNP-based microarray can identify regions of homozygosity, but it only reliably detects isodisomy, the form of uniparental disomy in which two identical copies are inherited from one parent. Heterodisomy, in which two different copies from one parent are inherited, requires different tools entirely.

To resolve the parental origin of the homozygous segment, the team turned to trio-based whole-exome sequencing, comparing fetal, maternal, and paternal genotypes across the entire interval. The logic is elegant. If a fetus is homozygous for an allele while the father is wild-type and the mother carries it, that pattern supports maternal uniparental disomy. The reverse supports paternal disomy. But if the fetus is homozygous and both parents are heterozygous, or one parent is homozygous and the other carries the same allele, the genotype is compatible with biparental inheritance and does not support uniparental disomy. Across the 10.42 megabase interval, the team identified 66 informative SNPs, every one of which was consistent with one allele contributed by each parent. No informative SNP showed fetal homozygosity with one parent being wild-type for the fetal allele, formally excluding segmental uniparental disomy of chromosome 6.

The distinction matters enormously for chromosome 6, which harbors known imprinted loci. Full-chromosome maternal uniparental disomy of chromosome 6 has been associated with intrauterine growth restriction, preterm birth, and variable neurodevelopmental phenotypes, while paternal disomy or segmental paternal disomy involving the 6q24 imprinting control region causes transient neonatal diabetes mellitus. Critically, the well-characterized 6q24 imprinted region lies proximal to the 6q25.3q27 segment reported here. Upon review of curated imprinted gene databases, the 10.42 megabase interval does not overlap any established, clinically relevant imprinted genes or imprinting-control regions, meaning any theoretical phenotypic risk from segmental disomy limited to this region would arise predominantly from unmasking autosomal-recessive pathogenic variants rather than from disrupted genomic imprinting.

The homozygous segment contains several clinically relevant genes, including ARID1B, WTAP, DLL1, TBP, SYNJ2, TIAM2, PHF10, MAP3K4, and PSMB1, none of which are well-documented imprinted loci. Pathogenic variants in several of these genes are linked to developmental disorders. Trio-based exome sequencing found no pathogenic or likely pathogenic homozygous variants associated with autosomal-recessive disease within the interval. The genome-wide homozygosity profile showed only this single discrete segment, with no additional autosomal runs of homozygosity, a pattern inconsistent with the multiple, widely distributed segments typically observed in offspring of consanguineous couples. Instead, the team concluded, the most parsimonious explanation is that a shared ancestral haplotype present in the general population was inherited independently from each parent, consistent with population-level shared ancestry rather than cryptic parental relatedness. The parents, a 29-year-old woman and her 32-year-old husband, are non-consanguineous.

Prenatal ultrasound did identify one finding: a single umbilical artery, classified as isolated because no other structural malformations, facial dysmorphisms, cardiac anomalies, renal anomalies, or intrauterine growth restriction were detected. After genetic counseling, the parents decided to continue the pregnancy. At 40 weeks and 2 days of gestation, a 3,450-gram female infant was born via vaginal delivery, with Apgar scores of 9, 10, and 10 at one, five, and ten minutes. A complete physical examination was normal. At the six-month follow-up, comprehensive pediatric evaluation showed all growth indices within normal age-matched reference values, with motor, social-communicative, visual-auditory, and neurological performances consistent with expected developmental milestones.

The authors are careful to note that important residual genetic risks remain even after excluding uniparental disomy and identifiable homozygous pathogenic variants. Whole-exome sequencing primarily targets coding exons and splice-site boundaries and cannot reliably detect deep-intronic variants, distant regulatory-element variants, repeat expansions, certain complex structural variants, or low-level somatic mosaicism. It also does not assess DNA methylation status, so epigenetic abnormalities including imprinting defects cannot be fully ruled out by short-read exome sequencing alone. And although isolated single umbilical artery is most often a benign incidental finding, it carries a weak statistical association with subtle developmental risks that cannot be entirely excluded prenatally. The team found no compelling molecular evidence supporting a causal link between the biparentally inherited segment and the single umbilical artery.

For prenatal counselors encountering runs of homozygosity on the long arm of chromosome 6, the case offers a clear framework: differentiate biparental inheritance from segmental uniparental disomy given the imprinting potential of chromosome 6, integrate multiple lines of evidence rather than relying on a single molecular test, and recommend long-term postnatal follow-up even when prenatal findings appear benign. The authors argue that combining NIPT, detailed prenatal ultrasound, karyotype analysis, chromosomal microarray, whole-exome sequencing, and genetic counseling will prove a more accurate risk assessment for the prenatal diagnosis of both runs of homozygosity and uniparental disomy. In an era when whole-exome trios are increasingly routine in clinical genetics, this case adds to a limited but growing literature showing that large homozygous segments can, in the right circumstances, carry no clinical consequence at all.

Subject of Research: Prenatal diagnosis of a homozygous chromosome 6q25.3q27 segment

Article Title: Case Report: Prenatal diagnosis and genetic counseling for a homozygous segment spanning chromosome 6q25.3q27 with normal phenotype

Article References: Li, D., Hu, J., Wu, J., & Bian, X. (2026). Case Report: Prenatal diagnosis and genetic counseling for a homozygous segment spanning chromosome 6q25.3q27 with normal phenotype. Frontiers in Genetics, 17, Article 1935109. https://doi.org/10.3389/fgene.2026.1935109

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1935109

Keywords: runs of homozygosity, uniparental disomy, chromosomal microarray, whole-exome sequencing, prenatal diagnosis, genetic counseling, chromosome 6, NIPT, Case, Report, Prenatal, diagnosis