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SHOX far‐downstream copy‐number variations involving cis‐regulatory nucleotide variants in two sisters with Leri‐Weill dyschondrosteosis
Author(s) -
Ogushi Kenichiro,
Muroya Koji,
Shima Hirohito,
Jinno Tomoko,
Miyado Mami,
Fukami Maki
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61275
Subject(s) - haploinsufficiency , genetics , biology , copy number variation , indel , single nucleotide polymorphism , short stature , pseudoautosomal region , haplotype , genotype , chromosome , gene , phenotype , genome , endocrinology
Abstract 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.