Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption

Sanctis, Luisa De; Giachero, Federica; Mantovani, Giovanna; Weber, Giovanna; Salerno, Mariacarolina; Baroncelli, Giampiero I.; Elli, M. F.; Matarazzo, Patrizia; Waśniewska, Małgorzata; Mazzanti, Laura; Scirè, Giuseppe; Tessaris, Daniele

doi:10.1186/s13052-016-0310-3

Cited by 19 publications

(34 citation statements)

References 39 publications

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“…By contrast, patients with PHP1B show abnormal patterns of methylation in the DMRs associated with the GNAS complex locus 45,47,[86][87][88]101,143,[151][152][153][154] . A methylation defect can be classified as partial or complete and can affect one or multiple DMRs within 20q13 (reF.…”

Section: Molecular Diagnosismentioning

confidence: 92%

“…GNAS shows differential methylation at four distinct DMRs: one paternally methylated-DMR (GNAS-NESP:TSS-DMR) and three maternally methylated-DMRs (GNAS-AS1:TSS-DMR, GNAS-XL:Ex1-DMR and GNAS A/B:TSS-DMR, according to the current nomenclature 156 ). Loss of methylation at GNAS A/B:TSS-DMR is detected in all patients with PHP1B 45,47,[86][87][88]101,143,[151][152][153][154] .…”

Section: Molecular Diagnosismentioning

confidence: 97%

“…In PHP and related disorders, the fifth, fourth and third metacarpal and the first and fourth distal phalanges are the most affected bones of the hand 85 ; metatarsals are often shortened as well. 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).…”

Section: The Definition Of Pth Resistance Is As Followsmentioning

confidence: 99%

“…In brief, PHP1A is caused by inactivating variants on the maternal allele of the GNAS gene within exons 1-13 (referring sequences NG_016194.1/NM_001077488.1 and LRG_1051), including both point mutations and rare gene rearrangements 16,23,27,41,45,86,88,97,112,122,[143][144][145][146][147][148] ( Supplementary Fig. 1b).…”

Section: Molecular Diagnosismentioning

confidence: 99%

“…If a female carries the STX16 or NESP/AS deletion, each of her descendants has a 50% risk of inheriting the genetic defect, and if the descendant inherits the defect, he or she will present with a methylation defect affecting only GNAS A/B:TSS-DMR or the complete GNAS locus (depending on the inherited deletion) 18 . In both cases, the descendant will develop PHP1B 45,47,[86][87][88]101,143,[151][152][153][154] . Although translocations of chromosome 20 resulting in UPD(20)pat are very rare, parental karyotyping is recommended to establish the risk of recurrence.…”

Section: Genetic Counsellingmentioning

confidence: 99%

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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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Section: Molecular Diagnosismentioning

confidence: 92%

Section: Molecular Diagnosismentioning

confidence: 97%

Section: The Definition Of Pth Resistance Is As Followsmentioning

confidence: 99%

Section: Molecular Diagnosismentioning

confidence: 99%

Section: Genetic Counsellingmentioning

confidence: 99%

See 3 more Smart Citations

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

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

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Pseudohypoparathyroidism

Linglart¹,

Levine²,

Jüppner³

2018

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

Snanoudj

Molin

Colson

et al. 2019

Journal of Bone and Mineral Research

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Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding G s α. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The motherspecific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of G s α in oocyte biology or embryogenesis, with implications for genetic counseling.

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Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption

Cited by 19 publications

References 39 publications

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

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

Pseudohypoparathyroidism

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

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