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PubMed2025

Comprehensive chromosomal abnormality detection: integrating CNV-Seq with traditional karyotyping in prenatal diagnostics.

BACKGROUND: This study aimed to evaluate the efficacy of copy number variation sequencing (CNV-Seq) in detecting chromosomal abnormalities in prenatal diagnosis, comparing its performance with traditional karyotype analysis. METHODS: A retrospective analysis was conducted on 1001 prenatal samples collected between April 2021 and December 2023. Samples were analyzed using both CNV-Seq and karyotype analysis. The detection rates of chromosomal abnormalities were compared between the two methods across various prenatal diagnostic indications. Clinical follow-up was performed to assess pregnancy outcomes. RESULTS: CNV-Seq detected chromosomal abnormalities in 89 of 1,001 cases (8.9%), compared to 50 cases (5.0%) identified by traditional karyotyping. CNV-Seq not only detected all abnormalities identified by karyotyping, including common aneuploidies such as trisomy 21 and sex chromosome abnormalities, but also uncovered 53 additional pathogenic submicroscopic CNVs associated with 33 known syndromes. The detection rates of CNV-Seq were significantly higher in high-risk groups, such as those identified by non-invasive prenatal testing (HR-NIPT) and maternal serum screening (HR-MSS), demonstrating superior sensitivity and accuracy in prenatal diagnostics. CONCLUSION: CNV-Seq demonstrated superior sensitivity in detecting chromosomal abnormalities, particularly submicroscopic alterations, compared to traditional karyotyping. The study highlights the potential of CNV-Seq as a valuable tool in prenatal diagnostics, offering improved detection of genetic abnormalities and guiding clinical decision-making. However, a combined approach using both CNV-Seq and karyotype analysis is recommended for comprehensive prenatal genetic screening.

Humans↗
PubMed2025

Effective detection of 148 cases chromosomal mosaicism by karyotyping, chromosomal microarray analysis and QF-PCR in 32,967 prenatal diagnoses.

BACKGROUND: Detection of mosaicism has always been difficult in prenatal diagnosis, which is to assess the value of karyotyping combined with three different molecular genetic tests for prenatal diagnosis. Retrospective review of chromosomal mosaicism (CM) was conducted in 32,967 pregnant women from January 2015 to December 2022. METHODS: A total of 148 fetuses diagnosed with chromosomal mosaicism by karyotyping with copy number variant sequencing (CNV-seq)/ chromosomal microarray analysis (CMA) and quantitative fluorescent polymerase chain reaction (QF-PCR) were selected, and the results from three the methods were compared and further analyzed. The χ2 test for multiple group rates was for the 5 clinical prenatal diagnostic indication groups was used to do multiple comparison tests for statistical analysis. Inconsistent results between methods were identified and further analyzed. RESULTS: A total of 148 CM cases was detected (0.45%, 148/32967), of which karyotyping was detected in combination with CMA in 73 cases (73/85), with CNV-seq in 5 cases (5/11), and with QF-PCR in 35 cases (35/52) and the mosaic conformity rates of the three methods compared with karyotyping were 85.9% (CMA), 67.3% (QF-PCR), and 45.5% (CNV-seq), respectively. There were 49 cases of autosomal mosaicism (49/148, 33.1%) and 99 cases of sex CM (99/148, 66.9%). There were 9 cases of small supernumerary marker chromosome (sSMC)with CMA detection clarified the origin of chromosome fragments. The non-invasive prenatal testing (NIPT) group and the ultrasound abnormality group had the highest detection rates, accounting for 35.1% and 22.3%. CONCLUSIONS: In chromosomal mosaicism, there are inconsistent results between different detection methods. Therefore, karyotyping combined with CMA/CNV-seq and FISH methods significantly improves the detection rate of chromosomal mosaicism and also confirms experimental data in the literature, which is of great value for prenatal diagnosis.

Humans↗
PubMed2026

Prenatal diagnosis and genetic counseling of a de novo 10q11.22q11.23 duplication associated with a normal development at 12 months of age.

BACKGROUND: Copy number variants are an important source of genomic variations, ranging from pathogenic to benign. The 10q11.22q11.23 region contains complex low-copy repeats that predispose to recurrent deletions and duplications via nonallelic homologous recombination. While some reports associate duplications of this region with developmental delay, intellectual disability, and autism spectrum disorders, emerging evidence suggests that such duplications may also be observed in phenotypically normal individuals, indicating incomplete penetrance and variable expressivity. CASE PRESENTATION: A 35-year-old pregnant woman with an unremarkable obstetric history underwent amniocentesis at 20 weeks of gestation. Conventional karyotyping and copy number variation sequencing (CNV-seq) were performed. CNV-seq revealed a de novo 4.56 Mb duplication at 10q11.22q11.23. The duplication was classified as a variant of uncertain significance. After extensive genetic counseling, the parents elected to continue the pregnancy. At 40 weeks of gestation, a female infant was delivered by cesarean section with normal birth parameters. A comprehensive physical examination at birth revealed no abnormalities. At the 12-month follow-up, the infant demonstrated normal growth parameters and age-appropriate neurodevelopmental milestones, with no evidence of dysmorphic features, developmental delay, or other clinical concerns. CONCLUSION: This report describes a prenatal case of a de novo 10q11.22q11.23 duplication with a normal development at 12 months of age. Our findings contribute to the growing body of literature suggesting that duplications in this pericentromeric region may exhibit incomplete penetrance and variable expressivity, and in some cases, may represent benign familial or de novo variants without apparent clinical consequences.

10q11.22q11.23 duplication↗
PubMed2024

Genetic analysis of partial duplication of the long arm of chromosome 16.

BACKGROUND: Pure partial trisomy 16q12.1q22.1 is a rare chromosome copy number variant (CNV). The primary clinical phenotypes associated with this syndrome include abnormal facial morphology, global developmental delay (GDD), short stature, and reported predisposing factors for atypical behavior, autism, the development of learning disabilities, and neuropsychiatric disorders. The dosage-sensitive genes associated with partial trisomy are not disclosed preventing to establish a genotype-phenotype correlation. METHODS: We report a case of a Chinese patient diagnosed with GDD and an abnormal facial shape, who was found to have partial trisomy 16 through karyotyping and high-throughput sequencing analysis. Karyotype and CNV tracing analyses were also conducted on the biological parents of the patient to assess for any chromosomal structural abnormalities. Additionally, we included 29 patients with pure partial trisomy 16q, reported in the DECIPHER database and the literature. We and performed a genotype-phenotype correlation analysis. RESULTS: The proband, a 2-year-old female, was found to have a de novo 21.96 Mb duplication located between 16q12.1q22.1, with no other deletions observed on other chromosomes, indicating a pure partial trisomy of 16q. Through genotype and phenotype analysis of 29 individuals, we found that patients with the duplicated region located at the distal region of 16q may exhibit more severe symptoms than those with duplication at the proximal region; however, no relationship was identified between phenotype and the size of the duplicated segment. CONCLUSION: We report, for the first time, a patient with partial trisomy 16q validated by multiple genetic tests, including CNV-seq, whole exome sequencing (WES), and karyotyping. It is speculated that partial trisomy of 16q may be associated with continuous gene duplication. However, functional studies are necessary to identify the causative gene or critical region linked to duplication syndrome of chromosome 16q.

Child, Preschool↗
PubMed2026

Xp21 contiguous gene deletion syndrome presenting as congenital adrenal hypoplasia: molecular diagnosis and clinical re-evaluation of a pedigree.

OBJECTIVE: To investigate the molecular etiology in a male child clinically suspected of congenital adrenal hyperplasia (CAH) with negative conventional genetic testing, and to elucidate the genetic characteristics of his pedigree. METHODS: Clinical data from the proband and his family members were collected. Molecular diagnostics proceeded sequentially: initial targeted CAH testing (CYP21A2 and POR sequencing/MLPA, plus targeted NR0B1 CNV analysis) was followed by whole-exome sequencing coupled with genome-wide CNV analysis. RESULTS: The proband presented with neonatal cyanosis and hyperpigmentation. Laboratory tests showed markedly elevated ACTH (354.68 pmol/L) and low aldosterone (57.24 pg/mL). Molecular genetic testing identified a hemizygous deletion of approximately 4.44 Mb at Xp21.3-p21.1 (chrX:g.27080000_31520000), encompassing the NR0B1, GK, IL1RAPL1, and DMD genes. CNV-seq confirmed that the mother carried a heterozygous deletion of 4.38 Mb in the same region, while the father and four maternal aunts showed normal genotypes. CONCLUSION: This study ultimately diagnosed the proband with Xp21 contiguous gene deletion syndrome. The adrenal insufficiency resulted from X-linked congenital adrenal hypoplasia (AHC) due to NR0B1 haploinsufficiency, rather than CAH. These findings highlight the considerable clinical overlap between AHC and CAH, indicating that CNV analysis of the Xp21 region should be included in the diagnostic workup for male infants with suspected CAH but negative routine genetic testing. This provides a basis for the precise diagnosis and genetic counseling of such patients.

Humans↗
PubMed2026

Identification of novel HUWE1 variants in Turner-type X-linked intellectual disability.

OBJECTIVE: To characterize the clinical phenotypes and identify the genetic etiology in four unrelated families affected by Turner-type X-linked intellectual disability (XLID). METHODS: Peripheral blood samples were collected from four probands and their parents. Genomic DNA was extracted, and a comprehensive genetic analysis was performed using trio-based Whole Exome Sequencing (WES) combined with low-pass Copy Number Variation sequencing (CNV-seq). Candidate variants were subsequently validated via Sanger sequencing. RESULTS: Genetic analysis identified distinct variants in the HUWE1 across the four families. Specifically, four distinct HUWE1 variants were identified across the families: a hemizygous c.10034 > T (p.Lys3345Met) in Family 1; a heterozygous c.9209G > A (p.Arg3070His) in Family 2; a heterozygous c.12688T > C (p.Phe4230Leu) in Family 3; and a hemizygous c.9070G > A (p.Ala3024Thr) in Family 4. In accordance with ACMG guidelines, the novel variants in Families 1, 3, and 4 were classified as "Likely Pathogenic" (PS2 + PM2_Supporting + PP2 + PP3). In contrast, the previously reported variant in Family 2 was categorized as "Pathogenic" based on the criteria PS2 + PM2_Supporting + PM5 + PP2 + PP3_Moderate. All probands were clinically diagnosed with Turner-type XLID. CONCLUSIONS: This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID. These findings are of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.

Humans↗
PubMed2026

A Novel Splice Variant in the COL1A1 Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. METHODS: Candidate variants were identified and verified through trio whole-exome sequencing (trio-WES), copy number variation sequencing (CNV-seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI-C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype-phenotype spectrum was performed. RESULTS: Trio-WES revealed a novel heterozygous variant in the C-terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II-2) and her foetus (III-1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C-terminal variants. CONCLUSIONS: This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C-terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.

Female↗