Rare Pseudoautosomal Copy-number Variations Involving SHOX And/or Its Flanking Regions in Individuals with and Without Short Stature

Overview

Journal J Hum Genet

Specialty Genetics

Date 2015 Jun 5

PMID 26040210

Citations 17

Authors

Maki Fukami

Yasuhiro Naiki

Koji Muroya

Takashi Hamajima

Shun Soneda

Reiko Horikawa

Tomoko Jinno

Momori Katsumi

Akie Nakamura

Yumi Asakura

Masanori Adachi

Tsutomu Ogata

Susumu Kanzaki

Affiliations

Soon will be listed here.

Abstract

Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3'-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father-daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.

Citing Articles

Mild phenotypes in patients with different deletions in the 3' enhancer region of SHOX.

Miranda V, Sabeh P, Seiltgens C, Molidperee S, Janelle C, Lemyre E Eur J Hum Genet. 2024; .

PMID: 38914686 DOI: 10.1038/s41431-024-01646-3.

Variations in Idiopathic Short Stature in North India and a Review of Cases from Asian Countries.

Srivastava P, Tyagi A, Bamba C, Kumari A, Kaur H, Seth S J Clin Res Pediatr Endocrinol. 2023; 16(1):41-49.

PMID: 37750395 PMC: 10938528. DOI: 10.4274/jcrpe.galenos.2023.2023-3-13.

RARE DOSAGE ABNORMALITIES - COPY NUMBER VARIATIONS FLANKING THE SHOX GENE.

Gherlan I, Braha E, Manole D, Radomir L, Nedelcu I, Popa O Acta Endocrinol (Buchar). 2023; 19(1):115-124.

PMID: 37601716 PMC: 10439321. DOI: 10.4183/aeb.2023.115.

Copy number variations residing outside the SHOX enhancer region are involved in Short Stature and Léri-Weill dyschondrosteosis.

Fanelli A, Vannelli S, Babu D, Mellone S, Cucci A, Monzani A Mol Genet Genomic Med. 2021; 10(1):e1793.

PMID: 34811950 PMC: 8801136. DOI: 10.1002/mgg3.1793.

Detection of Del/Dup Inside /PAR1 Region in Children and Young Adults with Idiopathic Short Stature.

Stritar J, Stavber L, Ficko M, Kotnik P, Battelino T, Trebusak Podkrajsek K Genes (Basel). 2021; 12(10).

PMID: 34680940 PMC: 8535414. DOI: 10.3390/genes12101546.

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