An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome

The Journal of Clinical Endocrinology and Metabolism
Christiaan de BruinAndrew Dauber

Abstract

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. To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure. Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene. An academic pediatric endocrinology clinic. 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. Single nucleotide polymorphism microarray and exome sequencing. 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-fra...Continue Reading

Citations

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Jul 5, 2017·Hormone Research in Pædiatrics·Lihong LiaoAndrew Dauber
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Dec 23, 2019·Hormone Research in Pædiatrics·Catalina Cabrera-SalcedoUNKNOWN the Genomics Research and Innovation Network

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