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

Sertedaki, Amalia; Tatsi, Elizabeth‐Barbara; Vasilakis, Ioannis Anargyros; Fylaktou, Irene; Nikaina, Eirini; Iacovidou, Nicoletta; Siahanidou, Tania; Kanaka‐Gantenbein, Christina

doi:10.3390/cells11132088

Cited by 6 publications

(6 citation statements)

References 66 publications

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“…The major challenge is to identify pathogenic variants in cases with isolated PSIS. As shown here and elsewhere [ 18 , 37 , 38 ], in such individuals the diagnostic yield is currently very low.…”

Section: Discussionmentioning

confidence: 75%

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

Brauner,

Bignon-Topalovic,

Bashamboo

et al. 2023

PLoS ONE

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Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by an absent or ectopic posterior pituitary, absent or interrupted pituitary stalk and anterior pituitary hypoplasia on magnetic resonance imaging (MRI), as well in some cases a range of heterogeneous somatic anomalies. The triad can be incomplete. Here, we performed exome sequencing on 16 sporadic patients, aged 0.4 to 13.7 years diagnosed with isolated or complex PSIS. Growth hormone deficiency was isolated in 10 cases, or associated with thyrotropin deficiency in 6 others (isolated (2 cases), associated with adrenocorticotropin deficiency (1 case), gonadotropins deficiency (1 case), or multiple deficiencies (2 cases)). Additional phenotypic anomalies were present in six cases (37.5%) including four with ophthalmic disorders. In 13 patients variants were identified that may contribute to the phenotype. However, only a single individual carried a variant classified as pathogenic. This child presented with the typical clinical presentation of Okur-Chung neurodevelopmental syndrome due to a CSNK2A1 missense variant. We also identified variants in the holoprosencephaly associated genes GLI2 and PTCH1. A likely pathogenic novel splice site variant in the GLI2 gene was observed in a child with PSIS and megacisterna magna. In the remaining 11 cases 26 variants in genes associated with pituitary development or function were identified and were classified of unknown significance. Compared with syndromic forms the diagnostic yield in the isolated forms of PSIS is low. Although we identified rare or novel missense variants in several hypogonadotropic hypogonadism genes (e.g. FGF17, HS6ST1, KISS1R, CHD7, IL17RD) definitively linking them to the PSIS phenotype is premature. A major challenge remains to identify pathogenic variants in cases with isolated PSIS.

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Section: Discussionmentioning

confidence: 75%

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

Brauner,

Bignon-Topalovic,

Bashamboo

et al. 2023

PLoS ONE

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“…If NGS were performed on a larger number of CPHD cases, it could lead to the identification of causative genes. The possibility cannot be ruled out that monogenetic diseases and oligogenic abnormalities may be associated with the disease ( 65 ). Moreover, the results of a recent study revealed copy-number variants in several genes that might contribute to the formation of CPHD ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing

et al. 2022

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Combined pituitary hormone deficiency (CPHD) is not a rare disorder, with a frequency of approximately 1 case per 4,000 live births. However, in most cases, a genetic diagnosis is not available. Furthermore, the diagnosis is challenging because no clear correlation exists between the pituitary hormones affected and the gene(s) responsible for the disorder. Next-generation sequencing (NGS) has recently been widely used to identify novel genes that cause (or putatively cause) CPHD. This review outlines causative genes for CPHD that have been newly reported in recent years. Moreover, novel variants of known CPHD-related genes (POU1F1 and GH1 genes) that contribute to CPHD through unique mechanisms are also discussed in this review. From a clinical perspective, variants in some of the recently identified causative genes result in extra-pituitary phenotypes. Clinical research on the related symptoms and basic research on pituitary formation may help in inferring the causative gene(s) of CPHD. Future NGS analysis of a large number of CPHD cases may reveal new genes related to pituitary development. Clarifying the causative genes of CPHD may help to understand the process of pituitary development. We hope that future innovations will lead to the identification of genes responsible for CPHD and pituitary development.

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“…Using this approach, our 1080 signals were found to be proximal to 10,341 genes, of which 660 'high-confidence AAM genes' were identified as the highest-scoring gene at a locus and with at least two lines of evidence (Supplementary Figure 10 & Supplementary Table 18; top-scoring genes at each of the 1080 loci are also listed in Supplementary Table 19). High-confidence AAM genes include established components of the HPG axis that are disrupted in rare monogenic disorders of puberty (CADM1, CHD4, CHD7, FEZF1, GNRH1, KISS1, SPRY4, TAC3, TACR3, TYRO3) 39 , and other recently reported candidate genes (PLEKHA5, TBX3, ZNF462) 40,41 . Other AAM genes have recognised roles in sex hormone secretion and gametogenesis (ACVR2A, CYP19A1, HSD17B7, INHBA, INHBB, MC3R, PCSK2) 42 , are disrupted in rare monogenic disorders of multiple pituitary hormone deficiency (OTX2, SOX2, SOX3, SST) 43 , monogenic obesity (BDNF, LEPR, MC4R, NTRK2, PCSK1, SH2B1) 44 or syndromes characterised by hypogonadism (Noonan Syndrome: BRAF, SOS1; Bardet-Biedl Syndrome: BBS4; Prader-Willi/Angelman Syndrome: NDN, SNRPN, UBE3A) 45,46,47,48 .…”

Section: Implicating Aam Genes Through Variant To Gene Mapping Approa...mentioning

confidence: 99%

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Kentistou

Kaisinger

Stankovic

et al. 2023

Preprint

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Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants inZNF483which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination ofin silicovariant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptorGPR83, which we demonstrate amplifies signaling ofMC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

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

Cited by 6 publications

References 66 publications

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

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