Next-generation sequencing refines the genetic architecture of Greek GnRH-deficient patients

Stamou, Maria; Varnavas, Petros; Plummer, Lacey; Koika, Vasiliki; Georgopoulos, Neoklis A.

doi:10.1530/ec-19-0010

Cited by 10 publications

(5 citation statements)

References 43 publications

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“…Although heterozygous variants of the GNRH1 gene have been reported in the literature, no oligogenic case of GNRH1 has been reported so far, whereas this is not the case for GNRHR [36]. Furthermore, in a recent study applying WES in a large cohort of GnRH deficient Greek patients, no GNRH1 variant was identified either as a monogenic or as an oligogenic cause of CHH [37].…”

Section: Discussionmentioning

confidence: 96%

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

Sertedaki

Tatsi

Vasilakis

et al. 2022

Cells

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Combined pituitary hormone deficiency (CPHD) is characterized by deficiency of growth hormone and at least one other pituitary hormone. Pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus, and/or pituitary have been identified so far to cause genetic forms of CPHD. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology of CPHD due to congenital hypopituitarism employing whole exome sequencing (WES) in two newborn patients, initially tested and found to be negative for PROP1, LHX3, LHX4 and HESX1 pathogenic variants by Sanger sequencing and for copy number variations by MLPA. In this study, the application of WES in these CPHD newborns revealed the presence of three different heterozygous gene variants in each patient. Specifically in patient 1, the variants BMP4; p.Ala42Pro, GNRH1; p.Arg73Ter and SRA1; p.Gln32Glu, and in patient 2, the SOX9; p.Val95Ile, HS6ST1; p.Arg306Gln, and IL17RD; p.Pro566Ser were identified as candidate gene variants. These findings further support the hypothesis that CPHD constitutes an oligogenic rather than a monogenic disease and that there is a genetic overlap between CPHD and congenital hypogonadotropic hypogonadism.

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Section: Discussionmentioning

confidence: 96%

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

Sertedaki

Tatsi

Vasilakis

et al. 2022

Cells

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“…Previous large-scale IGD cohort studies using NGS technologies have demonstrated that numerous genes contribute to the development of IGD (7,13,(37)(38)(39). In a prior study with 130 patients in a Brazilian cohort using targeted gene panel sequencing, about 10% of the patients harbored ANOS1 mutations (7).…”

Section: Discussionmentioning

confidence: 99%

“…Of these, 29.4% (5 of 17) had an intragenic deletion, and one patient (5.8%) had a whole gene deletion (11). In several other studies, the frequency of ANOS1 mutations was either too small or MLPA analysis was not conducted, making it difficult to assess the mutation spectrum of this gene (37,39,42).…”

Section: Discussionmentioning

confidence: 99%

Mutation spectrum and frequency of copy number variations of the ANOS1 gene in patients with Kallmann syndrome or normosmic isolated hypogonadotropic hypogonadism

Kim

Choi

Hwang

et al. 2023

Endocrine Connections

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Objective: This study was performed to investigate the molecular characteristics and frequency of copy number variations (CNVs) of ANOS1 in patients with Kallmann syndrome (KS) or normosmic isolated hypogonadotropic hypogonadism (nIHH) using multiplex ligation-dependent probe amplification (MLPA) analysis and sequencing. Methods: Among 45 patients from 43 independent families, Sanger sequencing, next-generation sequencing (NGS), or microarray was performed in 24 patients from 23 families, and MLPA was performed in 19 patients who did not show rare sequence variants (n = 18) or ANOS1 amplification by PCR (n = 1). Results: Seven patients (4 patients with KS, 1 patient with nIHH, one prepubertal boy with anosmia, and one newborn patient) from 6 families (6/43, 14%) harbored molecular defects in ANOS1 including a nonsense mutation [c.1140G>A (p.W380*)], a frameshift mutation [c.1260del (p.Q421Kfs*61)], a splice site mutation (c.1449+1G>A), an exon 7 deletion, a complete deletion, and 7.9 Mb-sized inversion encompassing ANOS1. The complete deletion of ANOS1 was identified in a neonate with a micropenis and cryptorchidism. Unilateral renal agenesis was found in three patients, whereas only one patient displayed both synkinesia and sensorineural hearing loss. There was no reversal of hypogonadotropic hypogonadism in any patient during 9.1 ± 2.9 years of treatment with testosterone enanthate. Conclusions: Molecular defects in the ANOS1 gene could be identified in 14% of probands including various types of CNVs (3/43, 7.0%). Comprehensive analysis using sequencing and analysis for CNVs is required to detect molecular defects in ANOS1.

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“…Studies have revealed that PROKR2 knockout gene mice exhibit dysplasia of the olfactory bulb, and migration of GnRH neurons fails ( 29 ). Functional loss mutations in PROKR2 have been reported in approximately 5.6% of IHH patients ( 30 ). The 11th nIHH patient carries both c.667T>G and c.892C>T mutations on PROKR2 .…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular features of 40 Chinese patients with idiopathic hypogonadotropic hypogonadism

Wang,

Jiang,

Xia

2023

Transl Androl Urol

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Background Male idiopathic hypogonadotropic hypogonadism (IHH) is a heterogeneous clinical rare genetic disorder that can be divided into two forms: Kallmann syndrome (KS) and olfactory normal IHH (nIHH). Nearly half of unknown pathogenic genes and related pathogenic mechanisms have yet to be explored. Methods Clinical data of 40 IHH patients (22 KS and 18 nIHH) were retrospectively recorded. All patients were diagnosed at the Department of Endocrinology of Jinling Hospital, Jiangsu Provincial People’s Hospital, and the First Affiliated Hospital of the University of Science and Technology of China from 2014 to 2021. The proband genomic DNA (gDNA) was confirmed by whole exome sequencing (WES) and Sanger sequencing. Results Ten new genetic mutations related to IHH in four families and eight sporadic unrelated IHH patients were identified. The total positive detection rate of 40 patients was 30% (nIHH 8/18 + KS 4/22), and the FGFR1 mutation rate accounted for 7.5% (3/40). Mutation rates of ANOS1, CHD7, and KISS1R were 5% (2/40), respectively. The mutation rates of SEMA3E, PROKR2, and SOX10 were 2.5% (1/40), respectively. After analysis by SIFT and PolyPhen-2 software, all missense mutation sites, such as SEMA3E (p.P323S), CHD7 (p.W1785C), PROKR2 (p.Y223D and p.R298C), were harmful; all nonsense mutation sites, such as FGFR1 (p.R661X) and KISS1R (p.R331X, p.Y103X), analyzed were pathogenic by Mutation Taster software. The comparison of MEGA5 software showed that all the variants had extremely high homology among different species and were extremely conservative in evolution. Conclusions The study aims to expand the genotype mutation spectrum of IHH and provide evidence for the follow-up clinical treatment and genetic counseling of the disease.

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Next-generation sequencing refines the genetic architecture of Greek GnRH-deficient patients

Cited by 10 publications

References 43 publications

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

Mutation spectrum and frequency of copy number variations of the ANOS1 gene in patients with Kallmann syndrome or normosmic isolated hypogonadotropic hypogonadism

Clinical and molecular features of 40 Chinese patients with idiopathic hypogonadotropic hypogonadism

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