Detection of Hypomethylation Syndrome among Patients with Epigenetic Alterations at the<i>GNAS</i>Locus

Pérez-Nanclares, Gustavo; Romanelli, Valeria; Mayo, Sonia; Garin, Intza; Zazo, Celia; Fernández-Rebollo, Eduardo; Martı́nez, Francisco; Lapunzina, Pablo; Nanclares, Guiomar Pérez de

doi:10.1210/jc.2012-1081

Cited by 38 publications

(41 citation statements)

References 42 publications

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“…9,12,20,21 No additional epigenetic changes were observed, including those involved in Beckwith-Wiedemann syndrome, a pediatric overgrowth disorder that is a common cause of macroglossia. 22 In contrast to patients with PHP1A, who are typically of short stature, patients with sporadic PHP1B are of normal height or taller.…”

Section: Discussionmentioning

confidence: 99%

Case Report of GNAS Epigenetic Defect Revealed by a Congenital Hypothyroidism

et al. 2015

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Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to the parathyroid hormone (PTH). PHP type 1A includes multihormone resistance syndrome, Albright's hereditary osteodystrophy, and obesity and is caused by mutations in GNAS exon 1 through 13. PHP type 1B (PHP1B), caused by epigenetic changes in the GNAS locus, was initially described as an isolated resistance to PTH. Epigenetic changes in GNAS have also been reported in patients who display mild Albright's hereditary osteodystrophy or mild thyroid-stimulating hormone (TSH) resistance without mutation of GNAS. Here we report a case of PHP caused by epigenetic changes in GNAS in a patient with congenital hypothyroidism. The patient was referred for a positive newborn screening for hypothyroidism (TSH 50 mIU/L). She exhibited severe clinical features of congenital hypothyroidism. The thyroid was in place, and etiologic explorations were negative. TSH was normalized under L-thyroxin, and the symptoms disappeared, except for a macroglossia. In childhood, PHP was suspected in addition to elevated PTH, obesity, brachydactyly, and a rounded face. Sequencing, methylation analysis, and large deletion research were performed in GNAS. No genetic mutations were found. Methylation analysis revealed a broad epigenetic defect without deletion in GNAS consistent with sporadic PHP1B. The multilocus methylation analysis were negative. This finding expands the known onsets of PHP1B and emphasizes the need for a new PHP classification system. This case report has important consequences for the etiologic diagnosis of congenital hypothyroidism because it adds a new cause of the disease.

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Section: Discussionmentioning

confidence: 99%

Case Report of GNAS Epigenetic Defect Revealed by a Congenital Hypothyroidism

et al. 2015

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“…3) genetic analysers, and analysed using the GeneMapper v.4.1, PeakScanner v.1.0 (Applied Biosystems, Foster City, CA, USA) and Coffalyser v.9.4 (MRC-Holland) softwares, as described previously. 29 Pyrosequencing. Standard bisulphite PCR using commercial or home-made primers targeting DMRs at NESP55, AS, XLas and exon A/B were used for amplification (see Supplementary Table 1).…”

Section: Methylation Detectionmentioning

confidence: 99%

European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study

et al. 2014

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on behalf of the EuroPHP Consortium 12Pseudohypoparathyroidism is a rare endocrine disorder that can be caused by genetic (mainly maternally inherited inactivating point mutations, although intragenic and gross deletions have rarely been reported) or epigenetic alterations at GNAS locus. Clinical and molecular characterization of this disease is not that easy because of phenotypic, biochemical and molecular overlapping features between both subtypes of the disease. The European Consortium for the study of PHP (EuroPHP) designed the present work with the intention of generating the standards of diagnostic clinical molecular (epi)genetic testing in PHP patients. With this aim, DNA samples of eight independent PHP patients carrying GNAS genetic and/or epigenetic defects (three patients with GNAS deletions, two with 20q uniparental disomy and three with a methylation defect of unknown origin) without GNAS point mutations were anonymized and sent to the five participant laboratories for their routine genetic analysis (methylation-specific (MS)-MLPA, pyrosequencing and EpiTYPER) and interpretations. All laboratories were able to detect methylation defects and, after the data analysis, the Consortium compared the results to define technical advantages and disadvantages of different techniques. To conclude, we propose as first-level investigation in PHP patients copy number and methylation analysis by MS-MLPA. Then, in patients with partial methylation defect, the result should be confirmed by single CpG bisulphite-based methods (ie pyrosequencing), whereas in case of a complete methylation defect without detectable deletion, microsatellites or SNP genotyping should be performed to exclude uniparental disomy 20.

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“…Brachydactyly develops over time and might not be evident in early life, except in patients with acrodysostosis 6,35,86 . The frequency and severity of brachydactyly vary among the different disorders: 70-80% in PHP1A 51 , 15-33% in PHP1B 46,51,70,[87][88][89][90][91][92][93] and all patients with acrodysostosis 5,6,14,15,20,[62][63][64][94][95][96] (Table 1). However, brachydactyly is not specific to PHP and related disorders and can be found in patients with, for example, tricho-rhino-phalangeal syndrome, brachydactyly mental retardation syndrome or Turner syndrome (Table 2).…”

Section: The Definition Of Pth Resistance Is As Followsmentioning

confidence: 99%

“…The average level of TSH is 5.3 ± 4.7 mUI/l (4.8 ± 3.4 mUI/l and 5.4 ± 5.2 mUI/l in autosomal dominant PHP1B and sporadic PHP1B, respectively), ranging from 0.8 mUI/l to 50.0 mUI/l (reFs 36,44,[46][47][48][49]51,53,54,87,89,91,102,105,131,143,153,164,166,169,178,200,[206][207][208][209][210] ).…”

Section: Management Of Tsh Resistancementioning

confidence: 99%

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

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Pseu do hy popar ath yroi dism (PHP) and related disorders are associated with a spectrum of abnormal physical characteristics as well as neurocognitive and endocrine abnormalities that are caused primarily by molecular defects that impair hormonal signalling via receptors that are coupled, through the α-subunit of the stimulatory G protein (G s α), to activation of adenylyl cyclase (Fig. 1). 6,7,20,48 * Abstract | This Consensus Statement covers recommendations for the diagnosis and management of patients with pseu do hy popar ath yroi dism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency , hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

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Detection of Hypomethylation Syndrome among Patients with Epigenetic Alterations at theGNASLocus

Abstract: Our work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS.

Cited by 38 publications

References 42 publications

Case Report of GNAS Epigenetic Defect Revealed by a Congenital Hypothyroidism

Case Report of GNAS Epigenetic Defect Revealed by a Congenital Hypothyroidism

European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

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