Search Results (52)

Background: Rubinstein–Taybi syndrome (RSTS) is characterized by intellectual disability, short stature, distinctive facial dysmorphism, broad thumbs/halluces, hearing loss, congenital heart or renal defects, and cryptorchidism in males. Pathogenic variants in CREBBP (~90% of cases) or EP300 (~10%) underlie the disorder, with ~88% single nucleotide variants (SNVs) and ~12% copy number variants (CNVs) in CREBBP. Materials and Methods: We investigated 17 patients clinically diagnosed with RSTS at a tertiary hospital in Poland. Genetic confirmation was achieved by next-generation sequencing, multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), or Sanger sequencing. Results: Pathogenic variants were identified in CREBBP (13/17, 76%) and EP300 (4/17, 24%). Variant types included frameshift indels (6/17, 35%), missense (4/17, 24%), nonsense (3/17, 18%), splice-site (2/17, 12%), and gross deletions (2/17, 12%). Notably, 13/17 (76%) were novel: ten in CREBBP (c.−49_12del, c.289C>T, c.1093_1096del, c.1094A>G, c.3178A>T, c.3401A>T, c.(3836+1_3837−1)_(4394+1_4395−1)del, c.4133+2T>G, c.4963dup, c.5028_5029dup) and three in EP300 (c.1942C>T, c.3044_3045del, c.4713_4722del). Among the novel CREBBP variants, eight occurred de novo and two had unknown inheritance. Two novel EP300 variants occurred de novo and one was of unknown origin. Conclusions: This first Polish RSTS cohort demonstrates a considerable proportion of gross deletions (12% overall; 15% in CREBBP) and an unexpectedly high rate of novel variants (76%), suggesting possible population-specific differences. These findings underscore the genetic heterogeneity of RSTS and highlight the importance of comprehensive molecular diagnostics and studies in underrepresented populations. Full article

Background: Craniofrontonasal dysplasia (CFND) is an X-linked developmental disorder caused by mutations in the EFNB1 gene located on chromosome Xq13. This gene encodes ephrin-B1, a ligand for Eph receptors, which is involved in cell signaling pathways and the development of the nervous and vascular systems, as well as facial and cranial structures. Paradoxically, the syndrome manifests with greater severity in heterozygous females, whereas hemizygous males typically present with mild or no abnormalities. Methods and Results: We report the case of a late preterm female neonate with dysmorphic features at birth, who subsequently developed necrotizing enterocolitis (NEC) caused by thrombosis of the superior mesenteric artery. Extensive bowel resection led to short bowel syndrome, resulting in cholestatic liver disease, malabsorption, and growth impairment. Array-comparative genomic hybridization (a-CGH) analysis identified a ~791 Kb microduplication at Xq13.1, encompassing the EFNB1 gene, confirming the diagnosis of CFND. She was enrolled in a multidisciplinary follow-up program and, at 2 years of age, presents with marked growth and neurodevelopmental delay. Conclusions: This report describes a rare association between CFND and NEC caused by superior mesenteric artery thrombosis. To the best of our knowledge, no previously reported cases of CFND associated with thrombosis or thrombosis-related conditions, including NEC, have been identified. This is based on a literature review (2004–2025) performed using PubMed and Scopus, and limited to English-language case reports and reviews. Full article

Genetic studies have identified numerous candidate genes for neurodevelopmental disorders associated with intellectual disability (ID) and autism spectrum disorders (ASD). Some genetic anomalies are very rare or challenging to detect, making it essential to validate the presence of gene mutations or copy number variations in additional patients with similar clinical phenotypes. Background/Objectives: Case reports play a crucial role in this process by validating rare variants in phenotypically matched patients, shedding light on novel candidate genes linked to these disorders. Methods: Patients with ID and ASD underwent neurological examinations, brain magnetic resonance imaging (MRI), sleep and wake electroencephalogram (EEG), neuropsychological evaluations, and laboratory tests including molecular analysis for fragile-X syndrome and array comparative genomic hybridization (aCGH). Results: We observed a patient with ID and ASD who carried a microdeletion in Xq22.1 that affects only exon 1 and intron 1 of the Nuclear RNA Export Factor 5 (NXF5) gene. The patient’s phenotypic features overlap with those of the only four previously reported cases of variations involving the same gene. Conclusions: Our findings suggest that NXF5 may play a role in neurodevelopmental disorders and should be considered in the spectrum of X-linked ID associated with ASD. Full article

Background: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases. Methods: Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used. Results: Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder. Conclusions: The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes. Full article

Schizophrenia (SCZ) is a complex mental disorder, whose pathogenesis involves both environmental and genetic factors. Genetic risk is conferred through a combination of common variants and rare mutations, with point mutations and copy number variants (CNVs). Many of the genetic variants associated with SCZ have pleiotropic effects, influencing brain development and being shared with other neurodevelopmental disorders (NDDs), such as intellectual disability (ID). This overlap supports the concept of a neurodevelopmental continuum, suggesting shared genetic risk, at least between SCZ and ID, and most presumably among SCZ and many other NDDs. Here, we describe the case of a male patient whose clinical features align with this hypothesis. He presented cognitive and behavioral impairments preceding psychotic symptoms, further reinforcing the genetic and clinical interaction between SCZ and other NDDs. The patient’s genetic profile was analyzed using array comparative genomic hybridization (a-CGH) and whole-exome sequencing (WES) to investigate the genetic determinants underlying his clinical condition. The genetic testing identified variants in loci associated with both SCZ and NDDs. Our findings highlight the need to integrate genetic assessments into psychiatrists’ clinical practice. Moreover, this report contributes to the current body of evidence supporting the thesis on the neurodevelopmental continuum of SCZ. Full article

Background: Interstitial deletions of chromosome 1q are rare, with about 30 cases reported in the literature. The phenotypical features of the affected subjects described so far include microcephaly, pre- and post-natal growth retardation, psychomotor delays, ear anomalies, brachydactyly, in addition to small hands and feet, and rarely a congenital diaphragmatic hernia (CDH). Case presentation: Here, we report on a neonate with CDH, dysmorphic features, and multiple midline anomalies including a cleft palate, in whom an array-comparative genomic hybridization (a-CGH) analysis allowed the identification of an interstitial deletion of the long arm of chromosome 1. Our patient underwent a surgical correction of CDH on the fourth day of life, while that of cleft palate has been planned to be performed at 12 months. Conclusions: The few subjects suffering such rearrangement reported to date, along with the clinical and genetic profile of the present newborn, show that 1q deletions should be considered within the context of the “interstitial 1q deletion syndrome”. Comparing our case with those described in previous studies, the involved genomic regions and the phenotypic traits are partially overlapping, although the clinical picture of the present patient is among the few ones including a congenital diaphragmatic hernia within the phenotypical spectrum. A more extensive comparative analysis of a larger number of patients with similar genetic profiles may allow for a more precise clinical and genomic characterization of this rare syndrome, and for genotype–phenotype correlations. Full article

Introduction: Invasive prenatal testing with chromosomal microarray analysis after first-trimester screening is a relevant option but there is still debate regarding the indications. Therefore, we evaluated the prevalence of numerical chromosomal aberrations detected by classic karyotype and clinically relevant copy number variants (CNVs) in prenatal samples using array comparative genomic hybridization (aCGH) stratified to NT thickness: <the 95th percentile, the 95th percentile–2.9 mm, 3.0–3.4 mm, 3.5–3.9 mm, 4.0–4.5 mm, and >4.5 mm, and by the presence/absence of associated structural anomalies detected by ultrasonography. Materials and Methods: Retrospective cohort study carried out at two tertiary Polish centers for prenatal diagnosis (national healthcare system) in central and south regions from January 2018 to December 2021. A total of 1746 prenatal samples were received. Indications for invasive prenatal testing included high risk of Down syndrome in the first-trimester combined test (n = 1484) and advanced maternal age (n = 69), and, in 193 cases, other reasons, such as parental request, family history of congenital defects, and genetic mutation carrier, were given. DNA was extracted directly from amniotic fluid (n = 1582) cells and chorionic villus samples (n = 164), and examined with classic karyotype and aCGH. Results: Of the entire cohort of 1746 fetuses, classical karyotype revealed numerical chromosomal aberrations in 334 fetuses (19.1%), and aCGH detected CNV in 5% (n = 87). The frequency of numerical chromosomal aberrations increased with NT thickness from 5.9% for fetuses with NT < p95th to 43.3% for those with NT > 4.5 mm. The highest rate of numerical aberrations was observed in fetuses with NT > 4.5 mm having at least one structural anomaly (50.2%). CNVs stratified by NT thickness were detected in 2.9%, 2.9%, 3.5%, 4.3%, 12.2%, and 9.0% of fetuses with NT < 95th percentile, 95th percentile–2.9 mm, 3.0–3.4 mm, 3.5–3.9 mm, 4.0–4.5 mm, and >4.5 mm, respectively. After exclusion of fetuses with structural anomalies and numerical aberrations, aCGH revealed CNVs in 2.0% of fetuses with NT < 95th percentile, 1.5% with NTp95–2.9 mm, 1.3% with NT 3.0–3.4 mm, 5.4% with NT 3.5–3.9 mm, 19.0% with NT 4.0–4.5 mm, and 14.8% with NT > 4.5 mm. Conclusions: In conclusion, our study indicates that performing aCGH in samples referred to invasive prenatal testing after first-trimester screening provides additional clinically valuable information over conventional karyotyping, even in cases with normal NT and anatomy. Full article

Background: In recent years, preimplantation genetic testing for aneuploidies (PGT-A) has become widespread in assisted reproduction. However, contrary to expectations, PGT-A does not significantly improve the clinical outcomes of assisted reproductive technologies. One of the underlying reasons is the discordance between the PGT-A results and the true chromosomal constitution of the blastocyst. In this case series, we re-examined the PGT-A results in trophectoderm (TE) re-biopsies and in the two isolated blastocyst compartments—the TE and the inner cell mass (ICM). Methods: This study enrolled 23 human blastocysts from 17 couples who were referred for assisted reproduction. The blastocysts were unsuitable for uterine transfer due to the chromosomal imbalance revealed by PGT-A using array comparative genomic hybridization (aCGH) (n = 11) or next-generation sequencing (NGS) (n = 12). The re-examination of the PGT results involved two steps: (1) a TE re-biopsy with subsequent aCGH and (2) blastocyst separation into the TE and the ICM with a subsequent cell-by-cell analysis of each isolated compartment by fluorescence in situ hybridization (FISH) with the DNA probes to chromosomes 13, 16, 18, 21, and 22 as well as to the PGT-A detected imbalanced chromosomes. Results: In 8 out of 23 cases, the PGT-A results were concordant with both the re-biopsy and the isolated TE and ICM analyses. The latter included the diagnoses of full non-mosaic aneuploidies (five cases of trisomies and two cases of monosomies). In one case, the results of PGT-A, aCGH on the TE re-biopsy, and FISH on the isolated TE showed Xp tetrasomy, which contrasted with the FISH results on the isolated ICM, where this chromosomal pathology was not detected. This case was classified as a confined mosaicism. In 4 out of 23 cases, the results were partially discordant. The latter included one case of trisomy 12, which was detected as non-mosaic by PGT-A and the re-biopsy and as mosaic by FISH on the isolated TE and ICM. This case was classified as a true mosaicism with a false negative PGT-A result. In 11 out of 23 cases, the re-examination results were not concordant with the PGT-A results. In one of these discordant cases, non-mosaic tetraploidy was detected by FISH in the isolated TE and ICM, whereas the PGT-A and the TE re-biopsy failed to detect any abnormality, which advocated for their false negative result. In two cases, the re-examination did not confirm full aneuploidies. In eight cases, full or partial mosaic aneuploidies as well as chaotic mosacism were not confirmed in the isolated TE nor the isolated ICM. Thus, in 47.8% of cases, the PGT-A results did not reflect the true chromosomal constitution of a blastocyst. Conclusions: The PGT results may have different prognostic value in the characterization of the chromosomal constitution of a blastocyst. The detected non-mosaic aneuploidies have the highest prognostic value. In stark contrast, most PGT-identified mosaic aneuploidies fail to characterize the true chromosomal constitution of a blastocyst. Once detected, a differential diagnosis is needed. Full article

Examinations of ovarian cancer cells require the ability to identify tumor cells. Array-based comparative genome hybridization (aCGH) on 30 ovarian carcinomas (OC) identified three genomic loci (8q24.23; 17p12; 18q22.3) over- or under-represented in OC. A fluorescence in situ hybridization (FISH) probe of these three loci is intended to identify tumor cells by their signal pattern deviating from a diploid pattern. Human DNA from these three loci is isolated from bacterial artificial chromosomes (BAC), amplified and labeled with fluorescent dyes. After a standard FISH procedure, 71 OC suspensions from primary tumors, three OC cell lines, three lymphocyte suspensions, and one mesenchymal cell line LP-3 are analyzed with a fluorescence microscope. On average, 15% of the lymphocytes deviate from the expected diploid signal pattern, giving a cut-off of 36%. If this value is exceeded, tumor cells are detected. The mesenchymal cell line LP-3 shows only 21% as a negative control. The OC cell lines as positive controls exceed this value at 38%, 67%, and 54%. Of the 71 OC primary cultures, four cases fell below this cut-off as false negatives. In the two-sample t-test, the percentages of conspicuous signal patterns differ significantly. Full article

The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions. Full article

Neurodevelopmental disorders are a group of complex multifactorial disorders characterized by cognitive impairment, communication deficits, abnormal behaviour, and/or motor skills resulting from abnormal neural development. Copy number variants (CNVs) are genetic alterations often associated with neurodevelopmental disorders. We evaluated the diagnostic efficacy of the array-comparative genomic hybridization (a-CGH) method and its relevance as a routine diagnostic test in patients with neurodevelopmental disorders for the identification of the molecular alterations underlying or contributing to the clinical manifestations. In the present study, we analysed 1800 subjects with neurodevelopmental disorders using a CGH microarray. We identified 208 (7%) pathogenetic CNVs, 2202 (78%) variants of uncertain significance (VOUS), and 504 (18%) benign CNVs in the 1800 patients analysed. Some alterations contain genes potentially related to neurodevelopmental disorders including CHRNA7, ANKS1B, ANKRD11, RBFOX1, ASTN2, GABRG3, SHANK2, KIF1A SETBP1, SNTG2, CTNNA2, TOP3B, CNTN4, CNTN5, and CNTN6. The identification of interesting significant genes related to neurological disorders with a-CGH is therefore an essential step in the diagnostic procedure, allowing a better understanding of both the pathophysiology of these disorders and the mechanisms underlying their clinical manifestations. Full article

Autism spectrum disorders (ASDs) encompass a broad group of neurodevelopmental disorders with varied clinical symptoms, all being characterized by deficits in social communication and repetitive behavior. Although the etiology of ASD is heterogeneous, with many genes involved, a crucial role is believed to be played by copy number variants (CNVs). The present study examines the role of copy number variation in the development of isolated ASD, or ASD with additional clinical features, among a group of 180 patients ranging in age from two years and four months to 17 years and nine months. Samples were taken and subjected to array-based comparative genomic hybridization (aCGH), the gold standard in detecting gains or losses in the genome, using a 4 × 180 CytoSure Autism Research Array, with a resolution of around 75 kb. The results indicated the presence of nine pathogenic and six likely pathogenic imbalances, and 20 variants of uncertain significance (VUSs) among the group. Relevant variants were more prevalent in patients with ASD and additional clinical features. Twelve of the detected variants, four of which were probably pathogenic, would not have been identified using the routine 8 × 60 k microarray. These results confirm the value of microarrays in ASD diagnostics and highlight the need for dedicated tools. Full article

Ovarian cancer (OC) cells with homologous recombination deficiency (HRD) accumulate genomic scars (LST, TAI, and LOH) over a value of 42 in sum. PARP inhibitors can treat OC with HRD. The detection of HRD can be done directly by imaging these genomic scars, or indirectly by detecting mutations in the genes involved in HR. We show that HRD detection is also possible using high-resolution aCGH. A total of 30 OCs were analyzed retrospectively with high-resolution arrays as a test set and 19 OCs prospectively as a validation set. Mutation analysis was performed by HBOC TruRisk V2 panel to detect HR-relevant mutations. CNVs were clustered with respect to the involved HR genes versus the OC cases. In prospective validation, the HRD status determined by aCGH was compared with external HRD assessments. Two BRCA mutation carriers did not have HRD. OC could approximately differentiate into two groups with characteristic CNV patterns with different survival rates. Mutation frequencies have a linear regression on the HRD score. Mutations in individual HR-relevant genes do not always indicate HRD. This may depend on the mutation frequency in tumor cells. The aCGH shows the genomic scars of an HRD inexpensively and directly. Full article

Congenital diaphragmatic hernia (CDH) is a major birth anomaly that often occurs with additional non-hernia-related malformations, and is then referred to as CDH+. While the impact of genetic alterations does not play a major role in isolated CDH, patients with CDH+ display mutations that are usually determined via array-based comparative genomic hybridization (aCGH). We analyzed 43 patients with CDH+ between 2012 and 2021 to identify novel specific mutations via aCGH associated with CDH+ and its outcome. Deletions (n = 32) and duplications (n = 29) classified as either pathological or variants of unknown significance (VUS) could be detected. We determined a heterozygous deletion of approximately 3.75 Mb located at 8p23.1 involving several genes including GATA4, NEIL2, SOX7, and MSRA, which was consequently evaluated as pathological. Another heterozygous deletion within the region of 9p23 (9,972,017-10,034,230 kb) encompassing the Protein Tyrosine Phosphatase Receptor Type Delta gene (PTPRD) was identified in 2 patients. This work expands the knowledge of genetic alterations associated with CDH+ and proposes two novel candidate genes discovered via aCGH. Full article

Expanded carrier screening (ECS) means a comprehensive genetic analysis to evaluate an individual’s carrier status. ECS is becoming more frequently used, thanks to the availability of techniques such as next generation sequencing (NGS) and array comparative genomic hybridization (aCGH), allowing for extensive genome-scale analyses. Here, we report the case of a couple who underwent ECS for a case of autism spectrum disorder in the male partner family. aCGH and whole-exome sequencing (WES) were performed in the couple. aCGH analysis identified in the female partner two deletions involving genes associated to behavioral and neurodevelopment disorders. No clinically relevant alterations were identified in the husband. Interestingly, WES analysis identified in the male partner a pathogenic variant in the LPL gene that is emerging as a novel candidate gene for autism. This case shows that ECS may be useful in clinical contexts, especially when both the partners are analyzed before conception, thus allowing the estimation of their risk to transmit an inherited condition. On the other side, there are several concerns related to possible incidental findings and difficult-to-interpret results. Once these limits are defined by the establishment of specific guidelines, ECS may have a greater diffusion. Full article