Dataset Information
An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome.
Ontology highlight
ABSTRACT: Context
Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly.Objective
To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure.Design
Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene.Setting
An academic pediatric endocrinology clinic.Patients or other participants
Two adult siblings (male patient [P1] and female patient 2 [P2]) presented with a history of severe postnatal growth failure (adult heights: P1, -6.8 SD score; P2, -4 SD score), microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28.Intervention(s)
Single nucleotide polymorphism microarray and exome sequencing.Results
Combined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect.Conclusions
In this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non-homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition.
SUBMITTER: de Bruin C
PROVIDER: S-EPMC4422886 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome.
The Journal of clinical endocrinology and metabolism 20150305 5
<h4>Context</h4>Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly.<h4>Objective</h4>To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure.<h4>Design</h4>Clinical phenotyping, genetic analysis, comp ...[more]