Distal 5q duplications are associated with Hunter–McAlpine syndrome, a chromosomal disorder characterized by growth retardation, microcephaly, developmental delay, intellectual disability, and dysmorphic features. The clinical spectrum remains incompletely defined because of the variability in the size and gene content of the reported duplications, as well as the frequent presence of additional chromosomal imbalances. We report a distal 5 q duplication (5q34–> qter) concomitant with a terminal Yq deletion (Yq11.223–> qter) and provide a review of the literature. We describe an 11-year-old boy with growth retardation, microcephaly, developmental delay, moderate intellectual disability, severe speech impairment, behavioral abnormalities, dysmorphic features, dental anomalies, and bilateral fifth-finger clinodactyly. Karyotyping showed additional material on the long arm of chromosome Y. Array comparative genomic hybridization identified an approximately 20 Mb duplication of 5q34–> qter and an approximately 34 Mb terminal deletion of Yq11.223–> qter. Fluorescent in situ hybridization confirmed translocation of distal chromosome 5 material onto the Y chromosome and the loss of the terminal Yq region. Parental analyses were normal, indicating a de novo rearrangement. The deleted Yq region encompassed the AZFc interval, including the DAZ gene cluster, as well as part of the distal AZFb region. The present case represents a distal 5q duplication due to a derivative Y chromosome resulting from a de novo t(Y;5) translocation, and, to our knowledge, the first reported case of Hunter–McAlpine syndrome associated with loss of the DAZ gene cluster. Combined with a structured review of the literature, this study expands the phenotypic and cytogenetic spectrum of Hunter–McAlpine syndrome.
Marker chromosomes (MCs) are structurally abnormal chromosomes that can be detected by standard cytogenetic banding techniques but their precise structure and origin cannot be fully determined by these methods alone. These abnormal chromosomes can be present as supernumerary chromosomes in an otherwise normal karyotype or replace a normal chromosome in a structurally abnormal karyotype. MCs can originate from any of the 24 chromosomes, which makes genotype-phenotype correlation a challenge in clinical diagnosis and genetic counseling for MCs carriers. In this study, we combined cytogenetic and molecular diagnostic techniques to determine the origin of MCs. By correlating the associated genomic variations with clinical phenotypes, we aimed to provide preliminary evidence-based medical guidance for individuals carrying MCs. We retrospectively reviewed 15 cases of marker chromosomes (MCs) identified by conventional cytogenetic testing among 9,733 individuals at our center. A subset of these cases was further analyzed by single nucleotide polymorphism (SNP) array to determine the precise origin, size, and genomic content of the MCs. In this cohort, 15 carriers of marker chromosomes (MCs) were identified, including 13 with mosaic and 2 with non-mosaic karyotypes. Seven of these patients underwent molecular analysis. Of these, SNP array revealed that five carried MCs derived from the X/Y chromosomes. In one case, a duplicated fragment at 11p11.12q12.2 was identified, whereas in another, no copy number variations (CNVs) were detected by SNP array. The clinical phenotypes of the eight postnatal MC carriers were diverse, ranging from asymptomatic to severe growth and developmental delay. Observed manifestations included short stature, primary amenorrhea, and infertility. Marker chromosomes (MCs) exhibit substantial genetic and clinical heterogeneity. The combined use of karyotyping and SNP array analysis effectively determined their chromosomal origin and facilitated the assessment of their pathogenic potential. Clinical outcomes were found to be strongly associated with the structure, chromosomal origin, and mosaic ratio of the MCs. This integrated diagnostic approach enables more accurate genotype-phenotype correlation and facilitates informed genetic counseling for affected individuals.
GM1 gangliosidosis is a rare genetic disorder that affects lysosomes. It is caused by variants in the GLB1 gene, which leads to a lack of the enzyme β-galactosidase. The infantile form (Type I) is the most severe. It begins in the first months of life and has a poor prognosis. We report two cases of infantile GM1 gangliosidosis from two consanguineous families.Patient I, evaluated at 9 months, showed developmental delays that began at 3 months, along with distinct physical features and significantly reduced levels of β-galactosidase enzyme activity. Patient II, also evaluated at 4 months, presented with severe neurological symptoms, cherry-red spots, and hepatosplenomegaly. This patient also harbored a novel homozygous variant c.169T > C, p.(Tyr57His) in the GLB1 gene not previously reported. These cases show the range of symptoms in infantile GM1 gangliosidosis and provide new genetic information by identifying a novel pathogenic variant. Early diagnosis through enzyme testing and genetic analysis is vital for advising families and developing prevention strategies in high-risk groups.
The coexistence of 46,XX/46,XY cells in cultured amniotic fluid sample is not uncommon. The vast majority of these cases are the result of contamination by maternal cells in an otherwise normal male fetus. However, this finding might be true chimera or mosaicism, which can be associated with sexual ambiguity. Conventional cytogenetic study could not exclude these abnormalities. Here, we present a case of 46,XX/46,XY at amniocentesis and ascertained a mosaicism by postnatal single nucleotide polymorphism (SNP) array in a phenotypic male newborn. A fetus of a 37-year-old nulliparous woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Chromosome analysis of the first and second samples revealed a mixture of 46,XX and 46,XY cell lines. Prenatal ultrasound examination showed normal male genitalia. After birth, peripheral blood samples were analyzed by karyotyping, fluorescence in situ hybridization (FISH), SNP array, and short tandem repeat (STR) analysis. These studies confirmed 46,XX/46,XY mosaicism in a phenotypically normal male newborn. Our case is the second report of 46,XX/46,XY mosaicism noted by prenatal cytogenetic study and confirmed by postnatal SNP array with normal male genitalia. When encountering XX/XY in prenatal diagnosis, SNP array is a useful tool to distinguish maternal cell contamination from chimera or mosaicism. Detailed prenatal ultrasound for the genitalia is required for the prediction of prognosis. The fetus may have a favorable outcome without ultrasound abnormalities.
Abstract Duplication of 6p is a rare genetic syndrome of which about 25% have one or more congenital cardiac defects including cardiac septal defects, pulmonary artery hypoplasia and patent ductus arteriosus. We present the first case of a fetus with functional single ventricle and persistent truncus arteriosus during prenatal diagnosis whose genomic analysis revealed a novel pure duplication of 6p25.2-p22.3. The duplication fragment was confirmed to be associated with intrachromosomal insertion from mother via chromosome karyotype. The presentation of this case aims to expand the existing knowledge regarding this rare condition and facilitate its diagnosis in the future. Based on the comparison of cases with 6p duplication syndrome, we notice that the 6p terminal region, especially at 6p25.1 to 6p25.2, could be the critical region associated with heart complications or anomalies of the pulmonary arteries. The duplication of the potential modifier genes, RIPK1 and FARS2, were proposed to be attributed to heart defects in our study and should be further researched.
Dandy-Walker malformation (DWM) is a condition characterized by a cyst in the posterior cranial fossa contiguous with the fourth ventricle, combined with complete or partial agenesis of the cerebellar vermis; and elevation of the cerebellar tentorium, torcular Herophili, and transverse sinuses. DWM has been linked to specific genetic variants, with pathogenic or likely pathogenic variants reported in FOXC1, ZIC1, and ZIC4. Variants in the TUBB2B and TUBB3 genes are associated with abnormalities in tubulin, leading to cerebellar hypoplasia. In our study, three patients diagnosed with DWM underwent whole-genome analysis using next-generation sequencing, and two were found to have heterozygous variants in the tubulinopathy-associated genes TUBB2B and TUBB3, respectively. These findings indicate that some cases previously diagnosed as DWM may fall under the spectrum of tubulinopathies associated with cerebellar hypoplasia.
To report a rare prenatal case of paternal uniparental isodisomy of chromosome 3 (upd(3)pat) associated with isolated intrauterine growth restriction (IUGR). Expanded non‑invasive prenatal screening (NIPS) in a 19‑year‑old woman indicated a duplication on chromosome 3q. Amniocentesis was performed for karyotyping, chromosomal microarray analysis (CMA), and trio whole‑exome sequencing (WES). Copy number variation sequencing (CNV-seq) was performed for the validation of the placental tissue postpartum. Karyotype was normal (46,XY). CMA revealed a whole-chromosome region of homozygosity (ROH) on chromosome 3, and WES confirmed upd(3)pat with no recessive pathogenic variants. Third‑trimester ultrasound showed IUGR. A male infant weighing 2,450 g was delivered at 38 weeks with normal birth examination. CNV-seq confirmed trisomy 3 on the fetal side of the placenta. Follow-up assessment at 2.5 years of age showed unremarkable neurodevelopmental outcomes. NIPS is a screening rather than a diagnostic test and all positive findings must be confirmed by invasive diagnostic procedures. Trisomy rescue can lead to coexistence of UPD3 with confined placental mosaicism (CPM). A multimodal approach incorporating karyotyping, CMA, trio‑WES, and CNV‑seq is essential for resolving discordant findings. This study expands the limited prenatal literature on upd(3)pat and highlights the critical importance of comprehensive genetic testing for accurate diagnosis and genetic counseling.
The Plebeia group, including Plebeia, Lestrimelitta, and Friesella, requires clearer taxonomic resolution. Plebeia is the polyphyletic: species in clade II are more closely related to Friesella and Lestrimelitta than to their congeners in clade I, which are more restricted to the Amazon biome, and Central and North America. Molecular cytogenetic studies in Meliponini have shown the important role of heterochromatin in karyotypic evolution and species diversification. In this study, we compared heterochromatic repetitive sequences in the Plebeia group to better understand its evolutionary patterns and diversification. For this, we hybridized a probe of highly and moderately repetitive DNA from the Friesella schrottkyi genome (here called FSch-C0t probe) onto the chromosomes of F. schrottkyi, Lestrimelitta limao, and some Plebeia species from clade II to investigate whether repetitive sequences constituting heterochromatin are shared among species. Additionally, we mapped the microsatellite (GA)n in four Plebeia species from clade II as a control experiment, as it typically shows general euchromatic hybridization patterns in stingless bees. The FSch-C0t probe labeled all heterochromatin in F. schrottkyi and was restricted to the centromeric heterochromatin in analyzed Plebeia species from clade II, indicating the sharing of repetitive sequences in part of the heterochromatin between these two genera. However, the FSch-C0t did not yield signals in the AT-rich regions of L. limao, which likely correspond to heterochromatin, suggesting a variation in the heterochromatic composition compared to that of F. schrottkyi and analyzed Plebeia species from clade II. In addition, FSch-C0t signals were detected in some terminal regions of the chromosomes in Plebeia spp. and L. limao, potentially corresponding to telomeric sequences. Microsatellite (GA)n was located on one of the chromosomal arms in the euchromatic regions of the four Plebeia taxa, following a trend reported for other Meliponini. Our data reveal a dynamic evolution of heterochromatic composition in the Plebeia group, with hypotheses regarding its diversification discussed in light of available phylogenies.
To define the genomic architecture of Y‑chromosome ectopy in a child with 46,XX testicular disorders of sex development (DSD) and illustrate the complementary roles of low‑coverage CNV sequencing (CNV‑seq) and optical genome mapping (OGM). A one‑and‑a‑half‑year‑old child with male phenotype, unfused scrotum, and hypospadias underwent clinical assessment and Doppler ultrasound, karyotyping, whole‑exome sequencing (WES), CNV‑seq, and OGM. CNV‑seq data were aligned to GRCh37; OGM maps were aligned to GRCh38 with T2T‑CHM13 consulted for Y display. Coordinates were harmonized for interpretation. FISH and long‑range PCR targeting the full SRY locus were not performed. Ultrasound showed bilateral scrotal testes, with no uterus or ovarian tissue. Karyotype was 46,XX, inv(9)(p12q13). CNV-seq identified called losses at Xp22.33 (287,328–3,605,487) and within Yp11.31–p11.2 (2,649,472–6,065,425) and Yp11.2 (7,270,527–9,599,178). OGM resolved a derivative X containing an insertion of Yp sequence at Xp22.33, with three re-join events in Yp11.2, including a deleted interval ( 6.2–7.3 Mb) and a local inversion ( 7.3–9.9 Mb); the call was ogm[GRCh38] der(X)(Ypter_Yp11.2::Yp11.2::Xp22.33_Xqter)(Ypter_6248448::9915169_7362950::3618476_Xqter). Harmonized coordinates indicate that the retained Yp11.3 interval includes SRY and is inserted into der(Xp22.33), supporting SRYpositive 46,XX testicular DSD on a coordinate basis. The Xp22.33 deletion supports counseling regarding SHOX haploinsufficiency–related growth surveillance. CNV-seq and OGM deliver nonredundant, genomewide dosage and architectural resolution that localizes the insertion site, defines breakpoint orientation, and provides counseling-relevant information beyond karyotype and WES. The coordinate-based inference of SRY and PAR1 involvement demonstrates a practical framework for integrating structural genomics into DSD diagnostics.
Abstract Background This study aimed to analyze chromosomal characteristics and copy number variations (CNVs) in fetuses with ventriculomegaly (VM), thereby comparing genetic features between the isolated VM group and the non-isolated VM. Simultaneously evaluate the efficacy of karyotyping and CNV analysis in prenatal diagnosis of fetuses with VM. Methods This retrospective cross-sectional study included 78 fetuses diagnosed with VM at the Prenatal Diagnosis Center, National Hospital of Obstetrics and Gynecology, the Clinical Genetics Center, Hanoi Medical University Hospital, and the Prenatal Diagnosis Center, Hanoi Obstetrics and Gynecology Hospital from January 2023 to December 2024. Genetic testing methods included conventional karyotyping and CNV analysis. Results Chromosomal abnormalities were detected in 14.1% (11/78) of cases by karyotyping, while CNVs were identified in 17.9% (14/78). CNVs were significantly more frequent in the non-isolated VM group compared to the isolated group (29.4% vs. 9.1%, p = 0.02). Both methods concordantly detected six cases of aneuploidy. Three cases of microdeletions/duplications were detected by CNV analysis, while karyotyping revealed no abnormalities. An additional four cases with chromosomal structural abnormalities detected by karyotyping had their deletion/duplication segments precisely characterized for size and location through CNV analysis. Conclusion Genetic testing using amniotic fluid samples should be considered an essential component in the prenatal diagnostic approach to VM. Non-isolated VMs exhibit significantly higher CNV risk than isolated VMs. CNV analysis enhances diagnostic efficacy for genetic abnormalities compared to karyotyping, while simultaneously facilitating genetic variant classification, thereby providing more detailed information for prognostic assessment. The combined approach of karyotyping and CNV analysis improves the detection rate of genetic abnormalities, supporting enhanced genetic counseling and superior pregnancy management.
Adult T-lymphoblastic leukemia often harbors cryptic structural variants that remain undetected by standard cytogenetic and targeted molecular testing, limiting precise risk stratification and therapeutic planning. This case is notable for the use of optical genome mapping (OGM) to uncover multiple disease-defining and likely oncogenic genomic alterations in an adult patient with newly diagnosed T-lymphoblastic leukemia. The report highlights how comprehensive structural variant profiling can refine prognosis and identify clinically meaningful aberrations that would otherwise be missed in routine practice. A 29-year-old man presented with fever, chills, dyspnea, headache, petechiae, and was found to have pancytopenia. Bone marrow biopsy showed a hypercellular marrow with approximately 95
Abstract Background Isodicentric Y chromosomes [idic(Y)] are frequently detected in patients with disorders of sex development (DSDs). However, prenatal cases are rarely reported. We performed comprehensive prenatal diagnostic evaluations in three fetuses with mosaic idic(Y) and followed up on pregnancy outcomes to explore the genotype-phenotype correlation. Methods Amniotic fluid cells from three fetuses were subjected to karyotyping and chromosomal microarray analysis (CMA), with confirmation by fluorescence in situ hybridization (FISH) and real-time quantitative PCR (qPCR). Subsequently, parental karyotypes were analyzed using peripheral blood samples to assess inheritance (de novo vs. inherited). Results All three fetuses exhibited mosaic 45,X with idic(Y) karyotypes, which exhibited distinct breakpoints (Yp11.32, Yq11.221, and Yq11.223). Two fetuses had additional 46,XY cell lines. The SRY gene was retained in all cases. In Fetus 1, the AZF region was intact, whereas in Fetus 2 and Fetus 3, AZFb + c and AZFc were deleted. Fetus 1 was born alive following genetic counseling. Notably, a right adrenal neuroblastoma was detected during late gestation and successfully resected postnatally. The other two pregnant women elected for pregnancy termination. Conclusion The integration of multiple technologies is essential for accurate prenatal diagnosis in cases of mosaic idic(Y). Our findings, including the rare association with neuroblastoma, contribute new insights into the phenotypic spectrum of this condition. Long-term follow-up and multidisciplinary clinical management are crucial for optimizing outcomes in live-born patients.
To report the prenatal diagnosis and follow-up of a fetus with mosaic tetrasomy 9p without obvious abnormal clinical manifestations. A fetus diagnosed with mosaic T9p at Shaoxing Maternal and Child Health Hospital in February 2022 was selected as the study subject. The amniotic fluid karyotype was 47,XY,+i(9)(p10)[3]/46,XY[97]. CNV-seq revealed a 70.56 Mb copy number gain in 9p24.3q21.11 (mosaicism at 6
Abstract Background Partial trisomy 21 is a rare chromosomal aberration that can provide unique insights into genotype-phenotype correlations in Down syndrome (DS). While non-invasive prenatal testing (NIPT) has become a widely used screening tool for common aneuploidies, its sensitivity is limited in cases of low-level mosaicism or partial duplications. We report a de novo partial trisomy 21 encompassing the entire Down syndrome critical region (DSCR) that escaped NIPT. Case presentation A 38-year-old first gravida underwent NIPT for evaluation of fetal trisomies 13, 18 or 21 as well as monosomy X, which showed normal results. Ultrasound at 19 + 5 weeks of gestation revealed polyhydramnios and a left-sided fetal hydrothorax, prompting amniocentesis. By karyotyping, a derivative chromosome 21 carrying additional material on the p-arm was identified. PCR-based microsatellite analysis, FISH and array-based studies on amniotic cells characterized the attached material as a de novo terminal duplication of 11.8 Mb of chromosome 21q22.12q22.3, fully encompassing the DSCR and without evidence of mosaicism. Comprehensive genetic counselling was provided, and the pregnancy was electively terminated at 24 weeks of gestation. Postmortem examination of the fetus revealed phenotypic features consistent with Down syndrome. In contrast to the non-mosaic duplication observed in amniotic fluid cells, post-termination tissue analysis demonstrated placental mosaicism, comprising predominantly a normal male cell line and a chromosomal aberrant male cell line with partial duplication of 21q22.12q22.3 in 28% of interphase nuclei in short-term cultured chorionic villi. This constellation likely explains the normal NIPT result. Conclusion This case illustrates the limitations of NIPT in detecting partial trisomies and low-grade placental mosaicism. It emphasizes the importance of further invasive prenatal investigations when results of ultrasound and NIPT are discrepant and it contributes to the understanding of genotype-phenotype correlations in partial trisomy 21. Clinicians should be aware that partial duplications of 21q22 can produce a full DS phenotype despite unremarkable NIPT results. This case highlights the challenges of technical choices in prenatal diagnostics and emphasizes the need for careful interpretation of screening tests and targeted counselling.
Genetic defects account for a substantial proportion of severe male infertility, yet standard diagnostic methods such as karyotyping and multiplex PCR for Y-chromosomal microdeletions fail to detect all clinically relevant abnormalities. We investigated 51 rigorously pre-selected men with confirmed non-obstructive azoospermia (NOA), all presenting with normal karyotype or balanced chromosomal rearrangement, negative Y-microdeletion PCR results, no CFTR mutations, and no recognized environmental, infectious, endocrine, or metabolic causes of spermatogenic failure. Genome-wide CNV detection was performed using Agilent GenetiSure Cyto 4 × 180 K array CGH (GRCh38). Clinically relevant CNVs were identified in 6/51 men (11.8
Chronic myeloid leukemia (CML) is defined by the presence of the BCR::ABL1 fusion gene resulting from the t(9;22)(q34;q11.2) translocation. In addition to this primary rearrangement, secondary chromosomal abnormalities involving chromosomes 9 and 22 may arise during clonal evolution and influence disease progression and response to therapy. Pericentric inversion of chromosome 9 is usually regarded as a constitutional variant. However, when acquired in CML, particularly involving the derivative chromosome 9, it represents a rare secondary abnormality whose biological and clinical significance remains poorly defined. We report the case of a 37 year old woman diagnosed with chronic phase CML following investigation of marked hyperleukocytosis. Fluorescence in situ hybridization (FISH) confirmed the presence of the BCR::ABL1 fusion in more than 90
To explore the utility of microarray technology in prenatal diagnosis of nasal bone agenesis or hypoplasia. 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. Among the 100 pregnant women, 64 underwent invasive prenatal testing, and 15 cases (23.44
18p deletion syndrome (OMIM #146390) displays a variable clinical spectrum due to differences in deletion size, position, and penetrance. While several classical phenotypes have been linked to specific genomic regions, many genotype-phenotype correlations remain elusive. Here we present a 30-year-old female patient with the classical features of 18p deletion syndrome, along with reproductive endocrine abnormalities, including elevated prolactin levels and diminished ovarian reserve. Chromosomal microarray revealed a 13.85 Mb deletion at 18p (arr[GRCh37]18p11.32p11.21(136,228_13,986,303)x1). To better delineate the clinical and molecular cytogenetic findings associated with monosomy 18p and explore genotype–phenotype correlations, we also reviewed 41 reported cases (including the present case) with confirmed genomic deletions indexed in the PubMed database between 2010 and 2025. The results showed that terminal deletions were most common (66
BACKGROUND: T/myeloid mixed-phenotype acute leukemias (MPAL-T/M) is a type of rare and high-risk acute leukemia that carries both T- and myeloid- lineage markers. The diagnosis of MPAL requires integration of clinical, immunophenotypic, and genetic information. Optical Genome Mapping (OGM) technology is a particularly powerful tool to profile genome-wide variants and locate complex chromosomal rearrangements that may guide diagnosis and risk stratification in MPAL-T/M. CASE PRESENTATION: We report two MPAL-T/M cases with comprehensive clinical, immunophenotype, and genetic results. A shared chromosomal rearrangement between chromosomes 14q32 and 16q24, t(14;16)(q32;q24), was detected in both leukemias. The t(14;16) has breakpoints 500-900 kb downstream to the BCL11B gene on chromosome 14, and within or near LINC01081 on chromosome 16, juxtaposing BCL11B enhancer to a novel gene on chromosome 16. In addition, both leukemias were positive for WT1 mutations and negative for FLT3-ITD. CONCLUSION: These cases represent the first report of recurrent translocation, t(14;16), in MPAL-T/M. The t(14;16) with these breakpoints is consistent with the juxtaposition of BCL11B enhancer to a novel gene on chromosome 16, similar to BCL11B::TLX3 in T-ALL. This report highlights the clinical relevance of OGM in identifying critical gene rearrangement that creates enhancer hijacking in the diagnosis of MPAL-T/M. These discoveries, along with further chromatin topology and gene expression studies, may provide a new window into the underlying biology of these aggressive leukemias.
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. 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.
