scholarly journals Defects in GnRH Neuron Migration/Development and Hypothalamic-Pituitary Signaling Impact Clinical Variability of Kallmann Syndrome

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 868
Author(s):  
Małgorzata Kałużna ◽  
Bartłomiej Budny ◽  
Michał Rabijewski ◽  
Jarosław Kałużny ◽  
Agnieszka Dubiel ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Gene Panel ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Pituitary Development ◽  
Targeted Ngs ◽  
Uncertain Significance ◽  
Next Generation Sequencing Ngs

Kallmann syndrome (KS) is a combination of isolated hypogonadotropic hypogonadism (IHH) with olfactory dysfunction, representing a heterogeneous disorder with a broad phenotypic spectrum. The genetic background of KS has not yet been fully established. This study was conducted on 46 Polish KS subjects (41 males, 5 females; average age: 29 years old). The studied KS patients were screened for defects in a 38-gene panel with next-generation sequencing (NGS) technology. The analysis revealed 27 pathogenic and likely pathogenic (P/LP) variants, and 21 variants of uncertain significance (VUS). The P/LP variants were detected in 20 patients (43.5%). The prevalence of oligogenic P/LP defects in selected genes among KS patients was 26% (12/46), whereas the co-occurrence of other variants was detected in 43% (20 probands). The examined KS patients showed substantial genotypic and phenotypic variability. A marked difference in non-reproductive phenotypes, involving defects in genes responsible for GnRH neuron development/migration and genes contributing to pituitary development and signaling, was observed. A comprehensive gene panel for IHH testing enabled the detection of clinically relevant variants in the majority of KS patients, which makes targeted NGS an effective molecular tool. The significance of oligogenicity and the high incidence of alterations in selected genes should be further elucidated.

scholarly journals The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

2021 ◽  
Vol 22 (17) ◽  
pp. 9425
Author(s):  
Roberto Oleari ◽  
Valentina Massa ◽  
Anna Cariboni ◽  
Antonella Lettieri
Keyword(s):  
Phenotypic Variability ◽  
Hypogonadotropic Hypogonadism ◽  
Neuroendocrine Cells ◽  
Delayed Puberty ◽  
Neuronal System ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Gnrh Neurons ◽  
Genes Encoding ◽  
Functional Relevance

Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.

scholarly journals A Targeted Gene Panel for Circulating Tumor DNA Sequencing in Neuroblastoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Flora Cimmino ◽  
Vito Alessandro Lasorsa ◽  
Simona Vetrella ◽  
Achille Iolascon ◽  
Mario Capasso
Keyword(s):  
Ad Hoc ◽  
Circulating Tumor Dna ◽  
Gene Panel ◽  
Liquid Biopsies ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variation ◽  
Targeted Ngs ◽  
Molecular Landscape ◽  
Next Generation Sequencing Ngs ◽  
Tumor Biopsies

BackgroundLiquid biopsies do not reflect the complete mutation profile of the tumor but have the potential to identify actionable mutations when tumor biopsies are not available as well as variants with low allele frequency. Most retrospective studies conducted in small cohorts of pediatric cancers have illustrated that the technology yield substantial potential in neuroblastoma.AimThe molecular landscape of neuroblastoma harbors potentially actionable genomic alterations. We aimed to study the utility of liquid biopsy to characterize the mutational landscape of primary neuroblastoma using a custom gene panel for ctDNA targeted sequencing.MethodsTargeted next-generation sequencing (NGS) was performed on ctDNA of 11 patients with primary neuroblastoma stage 4. To avoid the detection of false variants, we used UMIs (unique molecular identifiers) for the library construction, increased the sequencing depth and developed ad hoc bioinformatic analyses including the hard filtering of the variant calls.ResultsWe identified 9/11 (81.8%) patients who carry at least one pathogenic variation. The most frequently mutated genes were KMT2C (five cases), NOTCH1/2 (four cases), CREBBP (three cases), ARID1A/B (three cases), ALK (two cases), FGFR1 (two cases), FAT4 (two cases) and CARD11 (two cases).ConclusionsWe developed a targeted NGS approach to identify tumor-specific alterations in ctDNA of neuroblastoma patients. Our results show the reliability of our approach to generate genomic information which can be integrated with clinical and pathological data at diagnosis.

scholarly journals Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

2018 ◽  
Vol 127 (08) ◽  
pp. 538-544 ◽  
Author(s):  
Ja Hye Kim ◽  
Go Hun Seo ◽  
Gu-Hwan Kim ◽  
Juyoung Huh ◽  
Il Tae Hwang ◽  
...  
Keyword(s):  
Massively Parallel Sequencing ◽  
Diagnostic Yield ◽  
Hypogonadotropic Hypogonadism ◽  
Cost Effective ◽  
Kallmann Syndrome ◽  
Gene Panel ◽  
Sequence Variants ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Gene Panel Sequencing ◽  
Panel Sequencing

Abstract Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified either as Kallmann syndrome (KS) with anosmia or normosmic idiopathic hypogonadotropic hypogonadism (nIHH) and caused by mutations in more than 30 different genes. Recent advances in next-generation sequencing technologies have revolutionized the identification of causative genes by using massively parallel sequencing of multiple samples. This study was performed to establish the genetic etiology of IGD using a targeted gene panel sequencing of 69 known human IGD genes. Methods This study included 28 patients with IGD from 27 independent families. Exomes were captured using customized SureSelect kit (Agilent Technologies) and sequenced on the Miseq platform (Illumina, Inc.), which includes a 163,269 bp region spanning 69 genes. Results Four pathogenic and six likely pathogenic sequence variants were identified in 11 patients from 10 of the 27 families (37%) included in the study. We identified two known pathogenic mutations in CHD7 and PROKR2 from two male patients (7.4%). Novel sequence variants were also identified in 10 probands (37%) in CHD7, SOX3, ANOS1, FGFR1, and TACR3. Of these, while eight variants (29.6%) were presumed to be pathogenic or likely pathogenic, the remaining two were classified as variants of uncertain significance. Of the two pre-pubertal males with anosmia, one harbored a novel heterozygous splice site variant in FGFR1. Conclusions The overall diagnostic yield was 37% of the patients who had undergone targeted gene panel sequencing. This approach enables rapid, cost-effective, and comprehensive genetic screening in patients with KS and nIHH.

scholarly journals Author response: Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism

2019 ◽  
Author(s):  
Samuel Andrew Malone ◽  
Georgios E Papadakis ◽  
Andrea Messina ◽  
Nour El Houda Mimouni ◽  
Sara Trova ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Author Response ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
And Function

scholarly journals DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development

2017 ◽  
Vol 27 (2) ◽  
pp. 359-372 ◽  
Author(s):  
Justine Bouilly ◽  
Andrea Messina ◽  
Georgios Papadakis ◽  
Daniele Cassatella ◽  
Cheng Xu ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Congenital Hypogonadotropic Hypogonadism

scholarly journals BTK, NUTM2A, and PRPF19 Are Novel KMT2A Partner Genes in Childhood Acute Leukemia

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 924
Author(s):  
Elena Zerkalenkova ◽  
Svetlana Lebedeva ◽  
Aleksandra Borkovskaia ◽  
Olga Soldatkina ◽  
Olga Plekhanova ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Residual Disease ◽  
Chromosomal Rearrangements ◽  
Strong Impact ◽  
Acute Leukemias ◽  
Dna And Rna ◽  
Targeted Ngs ◽  
Childhood Acute Leukemia ◽  
Next Generation Sequencing Ngs ◽  
The Given

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with acute leukemias, especially in infants. KMT2A is rearranged with a big variety of partner genes and in multiple breakpoint locations. Detection of all types of KMT2A rearrangements is an essential part of acute leukemia initial diagnostics and follow-up, as it has a strong impact on the patients’ outcome. Due to their high heterogeneity, KMT2A rearrangements are most effectively uncovered by next-generation sequencing (NGS), which, however, requires a thorough prescreening by cytogenetics. Here, we aimed to characterize uncommon KMT2A rearrangements in childhood acute leukemia by conventional karyotyping, FISH, and targeted NGS on both DNA and RNA level with subsequent validation. As a result of this comprehensive approach, three novel KMT2A rearrangements were discovered: ins(X;11)(q26;q13q25)/KMT2A-BTK, t(10;11)(q22;q23.3)/KMT2A-NUTM2A, and inv(11)(q12.2q23.3)/KMT2A-PRPF19. These novel KMT2A-chimeric genes expand our knowledge of the mechanisms of KMT2A-associated leukemogenesis and allow tracing the dynamics of minimal residual disease in the given patients.

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