Association of GNAS imprinting defects and deletions of chromosome 2 in two patients: Clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3

F. M. Elli, L. Desanctis, M. A. Maffini, P. Bordogna, D. Tessaris, A. Pirelli, M. Arosio, A. Linglart, G. Mantovani

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. Results: The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. Conclusions: For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.

Original languageEnglish
Article number2
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 7 2019

Fingerprint

Chromosomes, Human, Pair 2
Pseudohypoparathyroidism
Brachydactyly
Modifier Genes
Genes
Phenotype
Pseudohypoparathyroidism Type 1B
Albright's hereditary osteodystrophy
Parathyroid Hormone
Epigenomics
Methylation
Chromosomes
Hormones
Imprinting (Psychology)

Keywords

  • 2q37
  • AHO
  • GNAS
  • Imprinting
  • iPPSD
  • Methylation defect
  • Modifier gene
  • PHP-1B

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

Association of GNAS imprinting defects and deletions of chromosome 2 in two patients : Clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3. / Elli, F. M.; Desanctis, L.; Maffini, M. A.; Bordogna, P.; Tessaris, D.; Pirelli, A.; Arosio, M.; Linglart, A.; Mantovani, G.

In: Clinical Epigenetics, Vol. 11, No. 1, 2, 07.01.2019.

Research output: Contribution to journalArticle

@article{c747fe56309646c9ab406d13f9eb70d8,
title = "Association of GNAS imprinting defects and deletions of chromosome 2 in two patients: Clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3",
abstract = "Background: The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. Results: The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. Conclusions: For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.",
keywords = "2q37, AHO, GNAS, Imprinting, iPPSD, Methylation defect, Modifier gene, PHP-1B",
author = "Elli, {F. M.} and L. Desanctis and Maffini, {M. A.} and P. Bordogna and D. Tessaris and A. Pirelli and M. Arosio and A. Linglart and G. Mantovani",
year = "2019",
month = "1",
day = "7",
doi = "10.1186/s13148-018-0607-8",
language = "English",
volume = "11",
journal = "Clinical Epigenetics",
issn = "1868-7075",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Association of GNAS imprinting defects and deletions of chromosome 2 in two patients

T2 - Clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3

AU - Elli, F. M.

AU - Desanctis, L.

AU - Maffini, M. A.

AU - Bordogna, P.

AU - Tessaris, D.

AU - Pirelli, A.

AU - Arosio, M.

AU - Linglart, A.

AU - Mantovani, G.

PY - 2019/1/7

Y1 - 2019/1/7

N2 - Background: The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. Results: The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. Conclusions: For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.

AB - Background: The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. Results: The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. Conclusions: For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.

KW - 2q37

KW - AHO

KW - GNAS

KW - Imprinting

KW - iPPSD

KW - Methylation defect

KW - Modifier gene

KW - PHP-1B

UR - http://www.scopus.com/inward/record.url?scp=85059694220&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059694220&partnerID=8YFLogxK

U2 - 10.1186/s13148-018-0607-8

DO - 10.1186/s13148-018-0607-8

M3 - Article

C2 - 30616679

AN - SCOPUS:85059694220

VL - 11

JO - Clinical Epigenetics

JF - Clinical Epigenetics

SN - 1868-7075

IS - 1

M1 - 2

ER -