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


METHODS
Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene.


METHODS
An academic pediatric endocrinology clinic.


METHODS
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.


METHODS
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.
Cincinnati Center for Growth Disorders (C.d.B., S.F.A., V.H., A.D.), Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Institute of Maternal and Child Research (V.M.), Faculty of Medicine, University of Chile, 226-3 Santiago, Chile; Laboratory for Diagnostic Genome Analysis (H.A.v.D., M.L.), Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Genetics (N.S.V., D.C.v.G.), Erasmus MC, 3015 CE Rotterdam, The Netherlands; Center for Autoimmune Genomics and Etiology (A.P.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Pediatrics Division (H.G.), Faculty of Medicine, Pontificia Universidad Catolica de Chile Santiago, 340 Santiago, Chile; Division of Developmental Biology (Y.K.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Institute of Human Development (D.H., P.C.), University of Manchester and Manchester Academic Health Sciences Centre, Manchester M13 9PL, United Kingdom; and Department of Pediatrics (J.M.W.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Christiaan
C
de Bruin
Verónica
V
Mericq
Shayne F
SF
Andrew
Hermine A
HA
van Duyvenvoorde
Nicole S
NS
Verkaik
Monique
M
Losekoot
Aleksey
A
Porollo
Hernán
H
Garcia
Yi
Y
Kuang
Dan
D
Hanson
Peter
P
Clayton
Dik C
DC
van Gent
Jan M
JM
Wit
Vivian
V
Hwa
Andrew
A
Dauber
D000328:Adult; D001827:Body Height / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D035781:Siblings
D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human