4.6 Article

Leri-Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant

期刊

GENES
卷 14, 期 4, 页码 -

出版社

MDPI
DOI: 10.3390/genes14040877

关键词

SHOX; skeletal disorder; short stature; leaky splice-site; precision medicine; gene dosage; haploinsufficiency; pseudo-autosomal inheritance

向作者/读者索取更多资源

SHOX deficiency is a common genetic cause of short stature. It can lead to Leri-Weill dyschondrosteosis and nonspecific short stature. This study reports the pseudo-autosomal recessive inheritance of Leri-Weill dyschondrosteosis in two siblings caused by a novel homozygous non-canonical splice-site variant in the SHOX gene. This study expands the understanding of the molecular and inheritance spectrum of SHOX deficiency.
SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri-Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据