Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome

被引:32
作者
Andersen, Erica F. [1 ,2 ]
Carey, John C. [3 ]
Earl, Dawn L. [4 ]
Corzo, Deyanira [5 ]
Suttie, Michael [6 ]
Hammond, Peter [6 ]
South, Sarah T. [1 ,2 ,3 ]
机构
[1] ARUP Labs, Dept Cytogenet, Salt Lake City, UT 84108 USA
[2] Univ Utah, Dept Pathol, Salt Lake City, UT USA
[3] Univ Utah, Dept Pediat, Salt Lake City, UT USA
[4] Seattle Childrens Hosp, Dept Med Genet, Div Med Genet, Seattle, WA USA
[5] Boston Childrens Hosp, Div Clin Genet, Boston, MA USA
[6] UCL, Inst Child Hlth, Mol Med Unit, London, England
基金
美国国家卫生研究院;
关键词
4p16.3; deletion; Wolf-Hirschhorn syndrome; WHSC1; LETM1; 3D facial analysis; SYNDROME CRITICAL REGION; GENOTYPE-PHENOTYPE CORRELATION; HISTONE METHYLTRANSFERASE; MULTIPLE-MYELOMA; CANDIDATE GENE; DNA-DAMAGE; 4P16.3; MICRODELETION; PROTEIN; MMSET;
D O I
10.1038/ejhg.2013.192
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.
引用
收藏
页码:464 / 470
页数:7
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