Molecular Cytogenetics最新文献

Objective: To explore the utility of microarray technology in prenatal diagnosis of nasal bone agenesis or hypoplasia.

Methods: Between July 2018 to October 2023, several cases of abnormal nasal bone development were diagnosed via ultrasound at county and municipal maternal and child health institutes. During this interval, One hundred fetuses underwent prenatal diagnosis at Jinhua Maternal and Child Health Institute, with chromosome microarray analysis (CMA) and karyotyping recommended for intervention. Those declining such diagnostic intervention received non-invasive prenatal screening (NIPS) as an alternative.

Results: Among the 100 pregnant women, 64 underwent invasive prenatal testing, and 15 cases (23.44%) were found to have chromosomal variation Numerical abnormalities accounted for 73.33%, structural abnormalities accounted for 13.33%, and polymorphic variations accounted for 13.33%. Among chromosomally normal fetuses, an additional 5 cases exhibited copy number variations (CNVs), including 1 case of pathological significance. Thirty-six participants received NIPS, and all results were low-risk. Analysis of nasal bone agenesis/hypoplasia was conducted and divided into solitary and non-solitary groups. The pathogenic abnormality rate of CMA in the two groups was 16.28% and 28.57%, respectively, with no statistical significance observed (P > 0.05). However, the pathogenic abnormality rates of CMA + NIPS were 9.09% and 26.09%, respectively, and the difference was statistically significant (P < 0.05).

Conclusion: Fetal nasal bone agenesis or hypoplasia is associated with chromosomal disorders. Notably, non-isolated nasal defects increase the risk of chromosomal alterations. Combined with CMA analysis, alterations caused by microdeletions or microinsertions can be detected. This approach can be used for clinical antenatal evaluation.

Background: Turner syndrome (TS) is a common chromosomal abnormality caused by the complete or partial absence of one X chromosome. It affects approximately 1 in ~ 1,200 to 2,500 female births. In this case report, we examined the clinical details of a 21-year-old female for cytogenetic investigation due to the absence of menarche (primary amenorrhea). Karyotype analysis revealed [46,X, del(X)(q24)[22]/45,X[28]], representing a mosaic form of TS with a novel deletion of the long arm of the X chromosome.

Conclusion: This case demonstrates that TS variants may present with menstrual disorder in the absence of typical dysmorphic features. Further investigation into rare TS variants in females lacking standard features is crucial for understanding genotype-phenotype correlations in TS.

Objective: To explore the clinical and genetic features both spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) diagnosed in a child.

Methods: A child was diagnosed with SMA combined with a duplication of exons 2-20 in the DMD gene at another hospital. Optical genome mapping (OGM) was employed to assess whether the duplication of exons 2-20 in the DMD gene affected its function.

Results: The patient was a 19-month-old boy who presented with delayed motor development and generalised hypotonia. Whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) performed at another hospital indicated that the patient had a hemizygous duplication involving exons 2-20 of the DMD gene, which was maternally inherited. Additionally, the patient had a homozygous deletion of SMN1 exons 7 and 8 (zero copies) and 3 copies of SMN2 exons 7 and 8. Both parents carried one copy of SMN1. Additionally, the mother harboured two copies of SMN2, whereas the father had three copies of SMN2. OGM analysis revealed a tandem duplication of exons 2-20 in the DMD gene in the patient and his mother.

Conclusion: We describe a rare case of a patient with concomitant DMD and SMA. When a patient's phenotype cannot be explained by a single genetic disorder, the possibility of multiple genetic disorders coexisting due to multiple mutations must be considered. OGM is a valuable diagnostic tool for determining the pathogenicity of DMD exon duplications, as it can definitively establish their genomic location and structure.

Background: Congenital heart defects represent a major global health burden, affecting nearly one million newborns annually. Identifying the underlying genetic causes is essential for improved diagnosis, patient management, and genetic counseling.

Patients and methods: We conducted a cytogenetic study integrating conventional karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA 44 K) in 20 Tunisian patients presenting syndromic CHDs and referred to our Genetics Department.

Results and discussion: CMA identified pathogenic copy number variations in four patients. These included an inherited 11 Mb deletion at 9p24.2 together with a 10 Mb duplication of 20pter; a de novo 1.2 Mb deletion at 15q26.2 with an 11 Mb duplication at 2q36.3; a de novo 113 kb deletion at 17q21.32; and a de novo 48 Mb duplication at 8q22. Several CNVs overlapped known deletion/duplication syndromes, some with previously infrequent cardiac involvement. Genotype-phenotype correlations enabled prioritization of CHD relevant genes including DOCK8, HTR2B, KANSL1, ZFPM2, and TRPS1, whose dosage sensitivity and interactions with cardiac developmental pathways may contribute to the observed phenotypes.

Conclusion: This study reinforces the clinical utility of CMA in detecting cryptic chromosomal abnormalities in syndromic CHD. The identified CNVs and gene candidates offer new insights into CHD genetic architecture and support CMA as a first-tier diagnostic tool. These findings highlight the contribution of rare, pathogenic CNVs in syndromic cases and suggest their integration into refined diagnostic and counseling strategies. Further functional studies are necessary to elucidate the roles of these candidates in cardiogenesis.

Background: Xq28 duplications are a significant cause of X-linked intellectual disability (XLID). While the postnatal features of distal Xq28 duplication syndrome are well characterized, the prenatal phenotypes remain poorly defined due to limited data, posing challenges for genetic counseling.

Case presentation: We identified three fetuses carrying 454-558 kb distal Xq28 microduplications through chromosomal microarray analysis (CMA) from 13,084 prenatal cases at our center. The primary indications for diagnosis were abnormal ultrasound findings. Case 1 (male) and case 3 (female) exhibited nasal bone hypoplasia. Case 2 (male) showed increased nuchal translucency (NT) and a persistent right umbilical vein. After genetic counseling, two couples chose to terminate their pregnancies, while one couple continued the pregnancy and delivered a healthy child.

Conclusion: Distal Xq28 duplications would present diverse prenatal phenotypes, ranging from normal to abnormal. Skeletal anomalies are the most common prenatal features in symptomatic fetuses with this duplication. Prenatal diagnosis and genetic counseling are essential for providing clinical guidance to the affected families. The correlation between prenatal ultrasound findings and the distal Xq28 duplications requires further investigation in larger cohorts.

Background: Intrachromosomal insertion is a rare form of structural chromosomal rearrangement that often cannot be accurately delineated by conventional G-banding, making it difficult to predict reproductive outcomes. In clinical practice, such insertions are often misinterpreted as inversions or remain undetected, leading to recurrent segmental imbalances in offspring. We aimed to characterize an unresolved structural rearrangement identified in a family and to clarify its reproductive implications through advanced cytogenetic and molecular analyses.

Methods: Cytogenetic and molecular studies were conducted in a family where the proband exhibited a 17.8 Mb duplication at 9q21.31-q22.33. Although G-banding suggested a parental structural abnormality, its configuration could not be precisely defined. Subsequent preimplantation genetic testing for structural rearrangements (PGT-SR) using shallow whole-genome sequencing was performed on embryos, and further structural characterization was achieved through fluorescence in situ hybridization (FISH) and nanopore long-read sequencing.

Results: PGT-SR identified recurrent segmental imbalances involving the same region as in the proband, including four duplications and one deletion among 13 embryos. FISH and long-read sequencing demonstrated that the paternal rearrangement represented an intrachromosomal inverted insertion, described as ins(9)(q34.13q22.33q21.31). The father was phenotypically normal but transmitted unbalanced gametes generated by recombination between the insertion and original sites, leading to recurrent chromosomal abnormalities.

Conclusions: This case highlights the potential of intrachromosomal insertions, although balanced in carriers, to cause recurrent segmental duplications or deletions in offspring. Comprehensive analysis using FISH and long-read sequencing is essential for accurate diagnosis, appropriate genetic counseling, and informed reproductive decision-making.

Background: Expanded non-invasive prenatal testing (E-NIPT) extends traditional screening for trisomies 21, 18, and 13 to sex-chromosome aneuploidies (SCAs), rare autosomal aneuploidies (RAAs), and 92 pathogenic subchromosomal copy-number-variations (CNV) regions. However, the clinical performance of E-NIPT in large Chinese cohorts has not been fully characterized. This study aimed to assess the diagnostic performance of E-NIPT in a real-world cohort of nearly ten thousand pregnancies.

Methods: In this retrospective cohort study, we reviewed 9,708 consecutive pregnancies screened with E-NIPT at Xuzhou Maternity and Child Health Care Hospital between March 2021 and August 2024. All 192 screen-positive pregnancies were counseled for invasive diagnostic confirmation; 158 underwent chromosomal microarray analysis. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each anomaly category were calculated.

Results: Among 9,708 pregnancies, 192 (1.98%) were screen-positive; overall PPV among confirmed cases was 32.3%. Category-level results were: T21, 28 screen-positive with 26 confirmations and 23 true positives (sensitivity 100%, specificity 99.97%, PPV 88.5%, NPV 100%); T18, 11/10/3 (100%, 99.93%, 30.0%, 100%); T13, 15/13/2 (100%, 99.89%, 15.4%, 100%); SCAs, 37/26/15 (100%, 99.89%, 57.7%, 100%); RAAs, 43/5/1 (100%, 99.96%, 20.0%, 100%); CNVs, 58/48/7 with one false negative (sensitivity 87.5%, specificity 99.58%, PPV 14.6%, NPV 99.99%).

Conclusions: E-NIPT showed excellent apparent sensitivity and high specificity for common trisomies and SCAs, with modest PPV for CNVs and low PPV for RAAs. Positive findings should undergo invasive diagnostic confirmation and genetic counseling to guide management.

Background: Optical genome mapping (OGM) has demonstrated significant potential in detecting structural variations (SVs) and has been comprehensively evaluated both retrospectively and prospectively in prenatal diagnosis. However, obtaining an adequate volume of amniotic fluid (AF) samples for OGM remains challenging due to the diverse detection techniques currently employed in prenatal diagnosis, which can limit the applicability of OGM in this setting. This study seeks to explore enhancements in cell culture techniques and quality control processes for prenatal samples when utilizing OGM in prenatal diagnosis.

Results: OGM successfully analyzed 188 AF samples with a minimum input of 0.225 million cells for ultra-high-molecular-weight DNA extraction. The study provides a comprehensive overview of the mass of chorionic villus samples, the volume of AF used for cell culture, the duration of culture, and the cell yields obtained for OGM. It was demonstrated that reducing the number of cells used for DNA isolation may not significantly decrease DNA quality for OGM with optimal cell viability and may even yield better results than those achieved with recommended cell amounts. This suggests that the current QC standards may be overly stringent, and that variant analysis remains feasible for some samples that do not meet these criteria. Based on the variant data analysis of these samples, standards appropriate for prenatal samples were summarized.

Conclusions: The findings of this study indicate that a reduced volume of AF sample or a shortened cell culture duration can be achieved in prenatal OGM, thereby enhancing the feasibility of employing OGM in prenatal diagnosis and potentially benefiting patients. Furthermore, data QC metrics suitable for prenatal samples may be more tolerant than previously recommended, necessitating further investigation with larger cohorts to establish specific QC standards for prenatal samples.