Evolution of bird sex chromosomes: a cytogenomic approach in Palaeognathae species.

BACKGROUND: Different patterns of sex chromosome differentiation are seen in Palaeognathae birds, a lineage that includes the ratites (Struthioniformes, Rheiformes, Apterygiformes, Casuariiformes, and the sister group Tinamiformes). While some Tinamiform species have well-differentiated W chromosomes, both Z and W of all the flightless ratites are still morphologically undifferentiated. Here, we conducted a comprehensive analysis of the ZW differentiation in birds using a combination of cytogenetic, genomic, and bioinformatic approaches. The whole set of satDNAs from the emu (Dromaius novaehollandiae) was described and characterized. Furthermore, we examined the in situ locations of these satDNAs alongside several microsatellite repeats and carried out Comparative Genomic Hybridizations in two related species: the greater rhea (Rhea americana) and the tataupa tinamou (Crypturellus tataupa). RESULTS: From the 24 satDNA families identified (which represent the greatest diversity of satDNAs ever uncovered in any bird species), only three of them were found to accumulate on the emu's sex chromosomes, with no discernible accumulation observed on the W chromosome. The W chromosomes of both the greater rhea and the emu did not exhibit a significant buildup of either C-positive heterochromatin or repetitive DNAs, indicating their large undifferentiation both at morphological and molecular levels. In contrast, the tataupa tinamou has a highly differentiated W chromosome that accumulates several DNA repeats. CONCLUSION: The findings provide new information on the architecture of the avian genome and an inside look at the starting points of sex chromosome differentiation in birds.

NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy.

BACKGROUND: NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-ß/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects. METHODS: We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with known NODAL variants and CHD from institutional research and clinical cohorts to investigate an allelic series. For those with candidate contributory variants, variant allele confirmation and segregation analysis were studied by Sanger sequencing in available family members. Array comparative genomic hybridization and droplet digital PCR were utilized for copy number variants (CNV) validation and characterization. We performed Human Phenotype Ontology (HPO)-based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. RESULTS: Missense, nonsense, splice site, indels, and/or structural variants of NODAL were identified as potential causes of heterotaxy and other laterality defects in 33 CHD cases. We describe a recurrent complex indel variant for which the nucleic acid secondary structure predictions implicate secondary structure mutagenesis as a possible mechanism for formation. We identified two CNV deletion alleles spanning NODAL in two unrelated CHD cases. Furthermore, 17 CHD individuals were found (16/17 with known Hispanic ancestry) to have the c.778G > A:p.G260R NODAL missense variant which we propose reclassification from variant of uncertain significance (VUS) to likely pathogenic. Quantitative HPO-based analyses of the observed clinical phenotype for all cases with p.G260R variation, including heterozygous, homozygous, and compound heterozygous cases, reveal clustering of individuals with biallelic variation. This finding provides evidence for a genotypic-phenotypic correlation and an allele-specific gene dosage model. CONCLUSION: Our data further support a role for rare deleterious variants in NODAL as a cause for sporadic human laterality defects, expand the repertoire of observed anatomical complexity of potential cardiovascular anomalies, and implicate an allele specific gene dosage model.

Identifying novel disease genes and revealing the pathomechanism of monogenic diseases.

Diseases are caused by genetic and/or environmental factors. It is important to understand the pathomechanism of monogenic diseases that are caused only by genetic factors, especially prenatal- or childhood-onset diseases for pediatricians. Identifying "novel" disease genes and elucidating how genomic changes lead to human phenotypes would develop new therapeutic approaches for rare diseases for which no fundamental cure has yet been established. Genomic analysis has evolved along with the development of analytical techniques, from Sanger sequencing (first-generation sequencing) to techniques such as comparative genomic hybridization, massive parallel short-read sequencing (using a next-generation sequencer or second-generation sequencer) and long-read sequencing (using a next-next generation sequencer or third-generation sequencer). I have been researching human genetics using conventional and new technologies, together with my mentors and numerous collaborators, and have identified genes responsible for more than 60 diseases. Here, an overview of genomic analyses of monogenic diseases that aims to identify novel disease genes, and several examples using different approaches depending on the disease characteristics are presented.

Comparative Genomic Analysis of PEBP Genes in Cucurbits Explores the Interactors of Cucumber CsPEBPs Related to Flowering Time.

The family of phosphatidylethanolamine-binding proteins (PEBPs) participates in various plant biological processes, mainly flowering regulation and seed germination. In cucurbit crops, several PEBP genes have been recognized to be responsible for flowering time. However, the investigation of PEBP family members across the genomes of cucurbit species has not been reported, and their conservation and divergence in structure and function remain largely unclear. Herein, PEBP genes were identified from seven cucurbit crops and were used to perform a comparative genomics analysis. The cucurbit PEBP proteins could be classified into MFT, FT, TFL, and PEBP clades, and further, the TFL clade was divided into BFT-like, CEN-like, and TFL1-like subclades. The MFT-like, FT-like, and TFL-like proteins were clearly distinguished by a critical amino acid residue at the 85th position of the Arabidopsis FT protein. In gene expression analysis, CsaPEBP1 was highly expressed in flowers, and its expression levels in females and males were 70.5 and 89.2 times higher, respectively, than those in leaves. CsaPEBP5, CsaPEBP6, and CsaPEBP7 were specifically expressed in male flowers, with expression levels 58.1, 17.3, and 15.7 times higher, respectively, than those of leaves. At least five CsaPEBP genes exhibited the highest expression during the later stages of corolla opening. Through clustering of time-series-based RNA-seq data, several potential transcription factors (TFs) interacting with four CsaPEBPs were identified during cucumber corolla opening. Because of the tandem repeats of binding sites in promoters, NF-YB (Csa4G037610) and GATA (Csa7G64580) TFs appeared to be better able to regulate the CsaPEBP2 and CsaPEBP5 genes, respectively. This study would provide helpful information for further investigating the roles of PEBP genes and their interacting TFs in growth and development processes, such as flowering time regulation in cucurbit crops.

Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.

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.

The first two whole mitochondrial genomes for the genus Dactylis species: assembly and comparative genomics analysis.

BACKGROUND: Orchardgrass (Dactylis glomerata L.), a perennial forage, has the advantages of rich leaves, high yield, and good quality and is one of the most significant forage for grassland animal husbandry and ecological management in southwest China. Mitochondrial (mt) genome is one of the major genetic systems in plants. Studying the mt genome of the genus Dactylis could provide more genetic information in addition to the nuclear genome project of the genus. RESULTS: In this study, we sequenced and assembled two mitochondrial genomes of Dactylis species of D. glomerata (597, 281 bp) and D. aschersoniana (613, 769 bp), based on a combination of PacBio and Illumina. The gene content in the mitochondrial genome of D. aschersoniana is almost identical to the mitochondrial genome of D. glomerata, which contains 22-23 protein-coding genes (PCGs), 8 ribosomal RNAs (rRNAs) and 30 transfer RNAs (tRNAs), while D. glomerata lacks the gene encoding the Ribosomal protein (rps1) and D. aschersoniana contains one pseudo gene (atp8). Twenty-three introns were found among eight of the 30 protein-coding genes, and introns of three genes (nad 1, nad2, and nad5) were trans-spliced in Dactylis aschersoniana. Further, our mitochondrial genome characteristics investigation of the genus Dactylis included codon usage, sequences repeats, RNA editing and selective pressure. The results showed that a large number of short repetitive sequences existed in the mitochondrial genome of D. aschersoniana, the size variation of two mitochondrial genomes is due largely to the presence of a large number of short repetitive sequences. We also identified 52-53 large fragments that were transferred from the chloroplast genome to the mitochondrial genome, and found that the similarity was more than 70%. ML and BI methods used in phylogenetic analysis revealed that the evolutionary status of the genus Dactylis. CONCLUSIONS: Thus, this study reveals the significant rearrangements in the mt genomes of Pooideae species. The sequenced Dactylis mt genome can provide more genetic information and improve our evolutionary understanding of the mt genomes of gramineous plants.

Chromosome-scale genome assemblies of Himalopsyche anomala and Eubasilissa splendida (Insecta: Trichoptera).

Trichoptera is one of the most evolutionarily successful aquatic insect lineages and is highly valued value in adaptive evolution research. This study presents the chromosome-level genome assemblies of Himalopsyche anomala and Eubasilissa splendida achieved using PacBio, Illumina, and Hi-C sequencing. For H. anomala and E. splendida, assembly sizes were 663.43 and 859.28 Mb, with scaffold N50 lengths of 28.44 and 31.17 Mb, respectively. In H. anomala and E. splendida, we anchored 24 and 29 pseudochromosomes, and identified 11,469 and 10,554 protein-coding genes, respectively. The high-quality genomes of H. anomala and E. splendida provide critical genomic resources for understanding the evolution and ecology of Trichoptera and performing comparative genomics analyses.

MicroRNA copy number alterations in the malignant transformation of pleomorphic adenoma to carcinoma ex pleomorphic adenoma.

OBJECTIVE: This study used array comparative genomic hybridization to assess copy number alterations (CNAs) involving miRNA genes in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA), residual PA, and carcinoma ex pleomorphic adenoma (CXPA). MATERIALS AND METHODS: We analyzed 13 PA, 4 RPA, 29 CXPA, and 14 residual PA using Nexus Copy Number Discovery software. The miRNAs genes affected by CNAs were evaluated based on their expression patterns and subjected to pathway enrichment analysis. RESULTS: Across the groups, we found 216 CNAs affecting 2261 miRNA genes, with 117 in PA, 59 in RPA, 846 in residual PA, and 2555 in CXPA. The chromosome 8 showed higher involvement in altered miRNAs in PAs and CXPA patients. Six miRNA genes were shared among all groups. Additionally, miR-21, miR-455-3p, miR-140, miR-320a, miR-383, miR-598, and miR-486 were prominent CNAs found and is implicated in carcinogenesis of several malignant tumors. These miRNAs regulate critical signaling pathways such as aerobic glycolysis, fatty acid biosynthesis, and cancer-related pathways. CONCLUSION: This study was the first to explore CNAs in miRNA-encoding genes in the PA-CXPA sequence. The findings suggest the involvement of numerous miRNA genes in CXPA development and progression by regulating oncogenic signaling pathways.

Diagnosis and management of congenital hypopituitarism in children.

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic-pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.

Acute Lymphoblastic Leukemia With Near-haploid Karyotype and Philadelphia Chromosome.

BACKGROUND/AIM: In precursor B-cell lineage acute lymphoblastic leukemia (BCP-ALL), leukemic cells harbor genetic abnormalities that play an important role in the diagnosis, prognosis, and treatment. A subgroup of BCP-ALL is characterized by the presence of a Philadelphia (Ph) chromosome and a chimeric BCR::ABL1 gene, whereas in another subgroup, leukemic cells exhibit near-haploidy with chromosome number 24-30. This study presents the third documented case of BCP-ALL in which a near haploid clone concurrently displayed a Ph chromosome/BCR::ABL1. CASE REPORT: Bone marrow cells obtained at diagnosis from a 25-year-old man with BCP-ALL were genetically investigated using G-banding, fluorescence in situ hybridization, and array comparative genomic hybridization. Leukemic cells had an abnormal karyotype 28,X,-Y,+6,+10,+18,+21,+ der(22) t(9;22)(q34;q11)[13]/28,idem, del(10)(q24),der(12) t(1;12) (q21;p13)[2]/46,XY[3], retained heterozygosity of the disomic chromosomes 6, 10, 18, and 21, had breakpoints in introns 1 of ABL1 and BCR, and carried a BCR::ABL1 chimera encoding the 190 kDa BCR::ABL1 protein. CONCLUSION: The coexistence of the BCR::ABL1 chimera and near-haploidy in the same cytogenetic clone suggested a possible synergistic role in leukemogenesis, with the former activating signaling pathways and the latter disrupting gene dosage balance.

Added value of whole-exome and RNA sequencing in advanced and refractory cancer patients with no molecular-based treatment recommendation based on a 90-gene panel.

INTRODUCTION: The objective was to determine the added value of comprehensive molecular profile by whole-exome and RNA sequencing (WES/RNA-Seq) in advanced and refractory cancer patients who had no molecular-based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array-based comparative genomic hybridization (aCGH). MATERIALS AND METHODS: In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90-gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA-Seq. Data from TGP/aCGH were reanalyzed, and together with WES/RNA-Seq, findings were simultaneously discussed at a new molecular tumor board (MTB). RESULTS: After exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3 [1-10]). Out of these 167 relevant molecular alterations, 51 (31%) were common to both TGP/aCGH and WES/RNA-Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA-Seq only, including two fusion transcripts in two patients. A MBTR was provided in 4/50 (8%) patients using the information from TGP/aCGH versus 9/50 (18%) patients using WES/RNA-Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA-Seq. CONCLUSIONS: In advanced and refractory cancer patients in whom no MBTR was recommended from TGP/aCGH, WES/RNA-Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBTR.

Correlation between large rearrangements and patient phenotypes in NF1 deletion syndrome: an update and review.

About 5-10% of neurofibromatosis type 1 (NF1) patients exhibit large genomic germline deletions that remove the NF1 gene and its flanking regions. The most frequent NF1 large deletion is 1.4 Mb, resulting from homologous recombination between two low copy repeats. This "type-1" deletion is associated with a severe clinical phenotype in NF1 patients, with several phenotypic manifestations including learning disability, a much earlier development of cutaneous neurofibromas, an increased tumour risk, and cardiovascular malformations. NF1 adjacent co-deleted genes could act as modifier loci for the specific clinical manifestations observed in deleted NF1 patients. Furthermore, other genetic modifiers (such as CNVs) not located at the NF1 locus could also modulate the phenotype observed in patients with large deletions. In this study, we analysed 22 NF1 deletion patients by genome-wide array-CGH with the aim (1) to correlate deletion length to observed phenotypic features and their severity in NF1 deletion syndrome, and (2) to identify whether the deletion phenotype could also be modulated by copy number variations elsewhere in the genome. We then review the role of co-deleted genes in the 1.4 Mb interval of type-1 deletions, and their possible implication in the main clinical features observed in this high-risk group of NF1 patients.

Incidental detection of familial 8p23.2 microduplication encompassing CSMD1 associated with mosaic 46,XY,t(7;8)(q31.2;p23.1)/46,XY at amniocentesis in a pregnancy with no apparent phenotypic abnormality and a favorable outcome.

OBJECTIVE: We present incidental detection of familial 8p23.2 microduplication encompassing CSMD1 associated with mosaic 46,XY,t(7;8)(q31.2;p23.1)/46,XY at amniocentesis in a pregnancy with no apparent phenotypic abnormality and a favorable outcome. CASE REPORT: A 38-year-old, gravida 2, para 1, phenotypically normal woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY,t(7;8)(q31.2;p23.1)[2]/46,XY[20]. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes and parental bloods revealed the result of a 2.178-Mb 8p23.2 microduplication encompassing CSMD1, or arr 8p23.2 (3,070,237-5,248,586) × 3.0 [GRCh37 (hg19)] in the fetus and the mother. The father did not have such a microduplicaiton. Prenatal ultrasound findings were unremarkable. At 38 weeks of gestation, a 2880-g phenotypically normal male baby was delivered. All the cord blood, umbilical cord and placenta had the karyotype of 46.XY. When follow-up at age six months, the neonate was normal in phenotype and development. CONCLUSION: Mosaicism for a balanced reciprocal translocation with a euploid cell line can be a transient and benign condition. Familial 8p23.2 microduplication encompassing CSMD1 can be associated with a favorable outcome.

Gynecological sarcomas, surgical management: primary, metastatic, and recurrent disease.

Adult-type gynecological soft tissue and visceral sarcomas are rare tumors, with an estimated incidence of 13% of all sarcomas and 4% of all gynecological malignancies. They most often develop in the uterus (83%), followed by the ovaries (8%), vulva and vagina (5%), and other gynecological organs (2%). The objective of this review is to provide an overview of the current management of gynecological sarcomas, according to international guidelines. The management of gynecological sarcomas should follow the recommendations for the management of soft tissue and visceral sarcomas. Centralizing cases in expert centers improves patient survival, both for the diagnostic phase and for multidisciplinary therapeutic management. In the case of pelvic soft tissue sarcomas, a radiological biopsy is essential before any surgical decision is taken. In the case of a myometrial tumour which may correspond to a sarcoma, if conservative surgery such as myomectomy or morcellation is planned, an ultrasound-guided biopsy with pathological analysis including comparative genomic hybridization analysis must be carried out. In all cases, en bloc surgery, without rupture, is mandatory. Many rare histological subtypes require specific surgical management.

Identification of a novel CG307 sub-clade in third-generation-cephalosporin-resistant Klebsiella pneumoniae causing invasive infections in the USA.

Despite the notable clinical impact, recent molecular epidemiology regarding third-generation-cephalosporin-resistant (3GC-R) Klebsiella pneumoniae in the USA remains limited. We performed whole-genome sequencing of 3GC-R K. pneumoniae bacteraemia isolates collected from March 2016 to May 2022 at a tertiary care cancer centre in Houston, TX, USA, using Illumina and Oxford Nanopore Technologies platforms. A comprehensive comparative genomic analysis was performed to dissect population structure, transmission dynamics and pan-genomic signatures of our 3GC-R K. pneumoniae population. Of the 178 3GC-R K. pneumoniae bacteraemias that occurred during our study time frame, we were able to analyse 153 (86 %) bacteraemia isolates, 126 initial and 27 recurrent isolates. While isolates belonging to the widely prevalent clonal group (CG) 258 were rarely observed, the predominant CG, 307, accounted for 37 (29 %) index isolates and displayed a significant correlation (Pearson correlation test P value=0.03) with the annual frequency of 3GC-R K. pneumoniae bacteraemia. Interestingly, only 11 % (4/37) of CG307 isolates belonged to the commonly detected 'Texas-specific' clade that has been observed in previous Texas-based K. pneumoniae antimicrobial-resistance surveillance studies. We identified nearly half of our CG307 isolates (n=18) belonged to a novel, monophyletic CG307 sub-clade characterized by the chromosomally encoded bla SHV-205 and unique accessory genome content. This CG307 sub-clade was detected in various regions of the USA, with genome sequences from 24 additional strains becoming recently available in the National Center for Biotechnology Information (NCBI) SRA database. Collectively, this study underscores the emergence and dissemination of a distinct CG307 sub-clade that is a prevalent cause of 3GC-R K. pneumoniae bacteraemia among cancer patients seen in Houston, TX, and has recently been isolated throughout the USA.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

IMPORTANCE: A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. OBJECTIVE: We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. SETTINGS: We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. RESULTS: One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. CONCLUSIONS AND RELEVANCE: Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

Antenatal description of large 4q13.2q21.23 deletion and outcomes.

BACKGROUND: 4q21 microdeletion syndrome is an emergent non-recurrent genomic disorder characterized by facial dysmorphy, progressive growth retardation, severe intellectual deficit, and absent or severely delayed speech. Deletions occur in clusters along 4q interstitial or terminal regions. 4q chromosomal aberrations are variable in type, size, and breakpoint. Genotype-phenotype correlation is a challenging task. The recurrent antenatal feature associated a posteriori with this syndrome is intrauterine growth retardation. There are very few precise antenatal descriptions of this syndrome. METHODS: We report here the first antenatal history of one of the largest deletion of this region. RESULTS: Our case harbored a 16.9 Mb deletion encompassing 135 protein coding genes including 20 OMIM morbid genes involved in neurological and cognitive abilities. Those breakpoints overlap two clusters of described microdeletion syndromes of cytogenetic band 4q13 and 4q21. CONCLUSION: From the end of the second trimester, set of call signs associated with this syndrome can be completed by: excess of amniotic fluid, mild growth retardation, short long bones, bony anomalies of the extremities, and bulging cheeks. So, emphasis should be placed on the examination of the extremities, and the face during the routine targeted prenatal ultrasound.

First report on chromosomal abnormalities in Eastern Morocco: Identification of a new case of a de novo partial trisomy 13q using single-nucleotide polymorphism array.

BACKGROUND: Chromosomal abnormalities are the main cause of birth defects, intellectual disability, and miscarriages. They contribute to significant human morbidity and infant mortality. Here we report for the first time the chromosomal abnormalities encountered in the population of Eastern Morocco. Furthermore, we describe a new case of a de novo partial trisomy 13q combined with a terminal deletion in an 11-day-old girl. METHODS: From November 2015 to March 2022, 195 patients from the BRO Biobank who were clinically suspected of having chromosomal abnormalities were referred to the cytogenetics laboratory of the Genetics Unit of the Faculty of Medicine and Pharmacy of Oujda for cytogenetic study. Karyotyping analysis was performed on peripheral blood samples using standard R banding techniques. To identify single-nucleotide polymorphism (SNP) and copy number variants (CNVs), Illumina SNP array was used. RESULTS: Among 195 studied cases, 32 (16.4 %) had abnormal karyotypes, of which 12 cases had numerical aberrations while 20 cases had structural aberrations. The most common numerical aberrations were Turner syndrome and Down syndrome followed by Edward, Patau, and Klinefelter syndromes. For structural aberrations, translocations were the most common, followed by derivative chromosomes, inversions, deletions, and an addition on chromosome 13 identified in an 11-day-old girl. To further characterize this addition, SNP array was carried out and revealed a 58.8-Mb duplication in region 13q14.3q34 associated with a 1-Mb deletion in region 13q34. Follow-up parental chromosomes analysis showed normal karyotypes for the parents, confirming that this partial trisomy 13q was de novo. Comparison of the phenotype associated with this novel duplication on chromosome 13q with those previously reported confirmed the considerable variability in the phenotype of the patients with partial trisomy 13q. CONCLUSION: This study provided the first report on chromosomal abnormalities in Eastern Morocco and it enriched the phenotype spectrum of partial trisomy 13q and further confirmed the genotype-phenotype correlations. Furthermore, these findings justify the need to set up microarray comparative genomic hybridization techniques in Morocco for better genetic diagnosis.

Array-Based Comparative Genomic Hybridization for the Detection of Copy Number Alterations in Single Cells.

Comprehensive genome-wide analyses of single cells represent an important tool for clinical applications, such as pre-implantation diagnostic and prenatal diagnosis, as well as for cancer research purpose. For the latter, studies of tumor heterogeneity, circulating tumor cells (CTCs), and disseminated cancer cells (DCCs) require the analysis of single-cell genomes. Here we describe a reliable and robust array-based comparative genomic hybridization (aCGH) protocol based on Ampli 1™ whole genome amplification that allows the detection of copy number alterations (CNAs) in single cancer cells as small as 100 kb.