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Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b

Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b
Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b
Pseudohypoparathyroidism (PHP) is caused by reduced expression of genes within the GNAS cluster, resulting in parathormone resistance. The cluster contains multiple imprinted transcripts, including the stimulatory G protein α subunit (Gs-α) and NESP55 transcript preferentially expressed from the maternal allele, and the paternally expressed XLas, A/B and antisense transcripts. PHP1b can be caused by loss of imprinting affecting GNAS A/B alone (associated with STX16 deletion), or the entire GNAS cluster (associated with deletions of NESP55 in a minority of cases). We performed targeted genomic next-generation sequencing (NGS) of the GNAS cluster to seek variants and indels underlying PHP1b. Seven patients were sequenced by hybridisation-based capture and fourteen more by long-range PCR and transposon-mediated insertion and sequencing. A bioinformatic pipeline was developed for variant and indel detection. In one family with two affected siblings, and in a second family with a single affected individual, we detected maternally inherited deletions of 40 and 33 bp, respectively, within the deletion previously reported in rare families with PHP1b. All three affected individuals presented with atypically severe PHP1b; interestingly, the unaffected mother in one family had the detected deletion on her maternally inherited allele. Targeted NGS can reveal sequence changes undetectable by current diagnostic methods. Identification of genetic mutations underlying epigenetic changes can facilitate accurate diagnosis and counselling, and potentially highlight genetic elements critical for normal imprint setting
1018-4813
494-499
Rezwan, Faisal I.
203f8f38-1f5d-485b-ab11-c546b4276338
Poole, Rebecca L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Prescott, Trine
eaae01bc-c17c-49ed-8c4f-a32d92564f0b
Walker, Joanna M.
750ad47d-dffa-4d23-af9a-600b66ced87e
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Rezwan, Faisal I.
203f8f38-1f5d-485b-ab11-c546b4276338
Poole, Rebecca L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Prescott, Trine
eaae01bc-c17c-49ed-8c4f-a32d92564f0b
Walker, Joanna M.
750ad47d-dffa-4d23-af9a-600b66ced87e
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a

Rezwan, Faisal I., Poole, Rebecca L., Prescott, Trine, Walker, Joanna M., Temple, I. Karen and Mackay, Deborah J.G. (2015) Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b. European Journal of Human Genetics, 23 (4), 494-499. (doi:10.1038/ejhg.2014.133).

Record type: Article

Abstract

Pseudohypoparathyroidism (PHP) is caused by reduced expression of genes within the GNAS cluster, resulting in parathormone resistance. The cluster contains multiple imprinted transcripts, including the stimulatory G protein α subunit (Gs-α) and NESP55 transcript preferentially expressed from the maternal allele, and the paternally expressed XLas, A/B and antisense transcripts. PHP1b can be caused by loss of imprinting affecting GNAS A/B alone (associated with STX16 deletion), or the entire GNAS cluster (associated with deletions of NESP55 in a minority of cases). We performed targeted genomic next-generation sequencing (NGS) of the GNAS cluster to seek variants and indels underlying PHP1b. Seven patients were sequenced by hybridisation-based capture and fourteen more by long-range PCR and transposon-mediated insertion and sequencing. A bioinformatic pipeline was developed for variant and indel detection. In one family with two affected siblings, and in a second family with a single affected individual, we detected maternally inherited deletions of 40 and 33 bp, respectively, within the deletion previously reported in rare families with PHP1b. All three affected individuals presented with atypically severe PHP1b; interestingly, the unaffected mother in one family had the detected deletion on her maternally inherited allele. Targeted NGS can reveal sequence changes undetectable by current diagnostic methods. Identification of genetic mutations underlying epigenetic changes can facilitate accurate diagnosis and counselling, and potentially highlight genetic elements critical for normal imprint setting

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e-pub ahead of print date: 9 July 2014
Published date: April 2015
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 366803
URI: http://eprints.soton.ac.uk/id/eprint/366803
ISSN: 1018-4813
PURE UUID: 7144215e-7112-45b3-8afe-8e5088ad8330
ORCID for Faisal I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 11 Jul 2014 07:59
Last modified: 21 Nov 2021 03:08

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Contributors

Author: Faisal I. Rezwan ORCID iD
Author: Rebecca L. Poole
Author: Trine Prescott
Author: Joanna M. Walker
Author: I. Karen Temple ORCID iD

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