SHOX far-downstream copy-number variations involving cis-regulatory nucleotide variants in two sisters with Leri-Weill dyschondrosteosis.
Adolescent
Child
Child, Preschool
DNA Copy Number Variations
/ genetics
Dwarfism
/ diagnostic imaging
Female
Gene Expression Regulation
/ genetics
Gene Frequency
Gene Regulatory Networks
/ genetics
Genotype
Growth Disorders
/ diagnostic imaging
Haploinsufficiency
/ genetics
Haplotypes
/ genetics
Humans
Male
Mutation
Osteochondrodysplasias
/ diagnostic imaging
Pedigree
Polymorphism, Single Nucleotide
/ genetics
Short Stature Homeobox Protein
/ genetics
Siblings
SHOX
Leri-Weill dyschondrosteosis
copy-number variation
haploinsufficiency
single nucleotide polymorphism
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
28
03
2019
revised:
27
05
2019
accepted:
11
06
2019
pubmed:
23
6
2019
medline:
4
8
2020
entrez:
23
6
2019
Statut:
ppublish
Résumé
SHOX haploinsufficiency leading to Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature typically results from intragenic mutations or copy-number variations (CNVs) involving SHOX and/or its putative enhancer regions that are distributed in the genomic interval between 400 kb and 840 kb from Xpter/Ypter. Here, we report two sisters with LWD, who carried a deletion in the far-downstream region of SHOX. The 0.62 Mb deletion contained 50 single nucleotide polymorphisms (SNPs) and short insertions and deletions (indels), whose genotypes were linked to SHOX expression levels in the Genotype-Tissue Expression portal. Notably, most of these SNPs/indels accumulated within a ~20 kb interval that was positioned ~900 kb away from Xpter/Ypter. These SNPs/indels showed similar minor allele frequencies, indicating that they reside within a haplotype block. The ~20 kb interval was not evolutionarily conserved; however, it was associated with the previously determined peak of chromosome conformation capture profiling (4C)-seq. Importantly, the deletion in the present cases partially overlapped with CNVs of three previous cases with skeletal deformity and/or short stature. The results indicate that far-downstream CNVs constitute rare genetic causes of SHOX haploinsufficiency. These CNVs possibly impair SHOX expression through copy-number changes of a human-specific cis-regulatory haplotype block. This notion awaits further validation.
Identifiants
pubmed: 31228230
doi: 10.1002/ajmg.a.61275
doi:
Substances chimiques
SHOX protein, human
0
Short Stature Homeobox Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1778-1782Subventions
Organisme : JCR Pharmaceuticals
Pays : International
Informations de copyright
© 2019 Wiley Periodicals, Inc.