ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2022
Targeted Long-Read Sequencing Identifies a Retrotransposon Insertion as a Cause of Altered GNAS Exon A/B Methylation in a Family With Autosomal Dominant Pseudohypoparathyroidism Type 1b (PHP1B).
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 29 citations in OpenAlex.
- A maternal exon H splice-site variant leading to pseudohypoparathyroidism type 1B with broad methylation defects in GNAS-differentially methylated regions.Clinical epigenetics · 2026Article
- Proof-of-principle: nanopore adaptive sampling enables full blood group genome analysis and resolution of hybrid alleles.Blood advances · 2026Article
- A comprehensive long-read sequencing system to assess DNA methylation at differentially methylated regions and imprinting-disorder-related genes.Genome medicine · 2025Article
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Splice-modulating antisense oligonucleotides targeting a pathogenic intronic variant in adult polyglucosan body disease correct mis-splicing and restore enzyme activity in patient cells.Nucleic acids research · 2025Article
- Bidirectional disruption ofProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Evolution of genome-wide methylation profiling technologies.Genome research · 2025Review
- Expanding Upon Genomics in Rare Diseases: Epigenomic Insights.International journal of molecular sciences · 2024Review
- Recurrent small variants in NESP55/NESPAS associated with broad GNAS methylation defects and pseudohypoparathyroidism type 1B.JCI insight · 2024Article
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
- Addressing Technical Pitfalls in Pursuit of Molecular Factors That Mediate Immunoglobulin Gene Regulation.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
- Local read haplotagging enables accurate long-read small variant calling.Nature communications · 2024Article
- Long-read next-generation sequencing for molecular diagnosis of pediatric endocrine disorders.Annals of pediatric endocrinology & metabolism · 2024Article
- GNAS AS2 methylation status enables mechanism-based categorization of pseudohypoparathyroidism type 1B.JCI insight · 2024Article
- Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review.NPJ genomic medicine · 2024Review
- Pseudohypoparathyroidism: complex disease variants with unfortunate names.Journal of molecular endocrinology · 2024Review
- Whole-genome long-read sequencing downsampling and its effect on variant-calling precision and recall.Genome research · 2023Article
- Local read haplotagging enables accurate long-read small variant calling.bioRxiv : the preprint server for biology · 2023Article
- Applications of long-read sequencing to Mendelian genetics.Genome medicine · 2023Review
- Implementation of Nanopore sequencing as a pragmatic workflow for copy number variant confirmation in the clinic.Journal of translational medicine · 2023Article
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
Abstract
Pseudohypoparathyroidism type Ib (PHP1B) is characterized predominantly by resistance to parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia. These laboratory abnormalities are caused by maternal loss-of-methylation (LOM) at GNAS exon A/B, which reduces in cis expression of the stimulatory G protein α-subunit (Gsα). Paternal Gsα expression in proximal renal tubules is silenced through unknown mechanisms, hence LOM at exon A/B reduces further Gsα protein in this kidney portion, leading to PTH resistance. In a previously reported PHP1B family, affected members showed variable LOM at exon A/B, yet no genetic defect was found by whole-genome sequencing despite linkage to GNAS. Using targeted long-read sequencing (T-LRS), we discovered an approximately 2800-bp maternally inherited retrotransposon insertion nearly 1200 bp downstream of exon XL not found in public databases or in 13,675 DNA samples analyzed by short-read whole-genome sequencing. T-LRS data furthermore confirmed normal methylation at exons XL, AS, and NESP and showed that LOM comprising exon A/B is broader than previously thought. The retrotransposon most likely causes the observed epigenetic defect by impairing function of a maternally derived NESP transcript, consistent with findings in mice lacking full-length NESP mRNA and in PHP1B patients with deletion of exon NESP and adjacent intronic sequences. In addition to demonstrating that T-LRS is an effective strategy for identifying a small disease-causing variant that abolishes or severely reduces exon A/B methylation, our data demonstrate that this sequencing technology has major advantages for simultaneously identifying structural defects and altered methylation. © 2022 American Society for Bone and Mineral Research (ASBMR).
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