干旱区生态环境知识资源中心(Arid): Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development

Arid

DOI	10.1136/jmedgenet-2018-105893
	Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development
	Ayers, Katie 1,2; van den Bergen, Jocelyn 1; Robevska, Gorjana 1; Listyasari, Nurin 3; Raza, Jamal 4; Atta, Irum 4; Riedl, Stefan 5,6; Rothacker, Karen 7; Choong, Catherine 7,8; Faradz, Sultana M. H.9; Sinclair, Andrew 1,2
通讯作者	Ayers, Katie
来源期刊	JOURNAL OF MEDICAL GENETICS
ISSN	0022-2593
EISSN	1468-6244
出版年	2019
卷号	56 期号:7 页码:434-443
英文摘要	Background Desert hedgehog (DHH) gene variants are known to cause 46,XY differences/disorders of sex development (DSD). We have identified six patients with 46,XY DSD with seven novel DHH gene variants. Many of these variants were classified as variants of uncertain significance due to their heterozygosity or associated milder phenotype. To assess variant pathogenicity and to refine the spectrum of DSDs associated with this gene, we have carried out the first reported functional testing of DHH gene variant activity. Methods A cell co-culture method was used to assess DHH variant induction of Hedgehog signalling in cultured Leydig cells. Protein expression and subcellular localisation were also assessed for DHH variants using western blot and immunofluorescence. Results Our co-culture method provided a robust read-out of DHH gene variant activity, which correlated closely with patient phenotype severity. While biallelic DHH variants from patients with gonadal dysgenesis showed significant loss of activity, variants found as heterozygous in patients with milder phenotypes had no loss of activity when tested with a wild type allele. Taking these functional results into account improved clinical interpretation. Conclusion Our findings suggest heterozygous DHH gene variants are unlikely to cause DSD, reaffirming that DHH is an autosomal recessive cause of 46,XY gonadal dysgenesis. Functional characterisation of novel DHH variants improves variant interpretation, leading to greater confidence in patient reporting and clinical management.
英文关键词	desert hedgehog DHH disorders of sex development gonadal dysgenesis
类型	Article
语种	英语
国家	Australia ; Indonesia ; Pakistan ; Austria
开放获取类型	Green Published, hybrid
收录类别	SCI-E
WOS记录号	WOS:000473040400003
WOS关键词	GONADAL-DYSGENESIS ; DEVELOPMENT INSIGHTS ; MUTATION ; DHH ; DISORDERS ; NEUROPATHY
WOS类目	Genetics & Heredity
WOS研究方向	Genetics & Heredity
来源机构	University of Western Australia
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/217233
作者单位	1.Murdoch Childrens Res Inst, Cell Biol, Parkville, Vic, Australia; 2.Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia; 3.Diponegoro Univ, Fac Med, Ctr Biomed Res, Div Human Genet, Semarang, Indonesia; 4.Natl Inst Child Hlth, Karachi, Pakistan; 5.Med Univ Vienna, St Anna Childrens Hosp, Vienna, Austria; 6.Med Univ Vienna, Paediat Dept, Vienna, Austria; 7.Princess Margaret Hosp, Pediat Dept, Div Pediat Pulmol Allergol & Endocrinol, Perth, WA, Australia; 8.Univ Western Australia, Sch Paediat & Child Hlth, Crawley, Australia; 9.Diponegoro Univ, Fac Med, Ctr Biomed Res, Div Human Genet, Semarang, Indonesia
推荐引用方式 GB/T 7714	Ayers, Katie,van den Bergen, Jocelyn,Robevska, Gorjana,et al. Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development[J]. University of Western Australia,2019,56(7):434-443.
APA	Ayers, Katie.,van den Bergen, Jocelyn.,Robevska, Gorjana.,Listyasari, Nurin.,Raza, Jamal.,...&Sinclair, Andrew.(2019).Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development.JOURNAL OF MEDICAL GENETICS,56(7),434-443.
MLA	Ayers, Katie,et al."Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development".JOURNAL OF MEDICAL GENETICS 56.7(2019):434-443.