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When natural mutants do not fit our expectations: the intriguing case of patients with XRCC4 mutations revealed by whole-exome sequencing.

de Villartay JP - EMBO Mol Med (2015)

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR1163 Laboratory of Genome Dynamics in the Immune System (DGSI), Paris, France Paris Descartes University-Sorbonne Paris Cité Imagine Institute, Paris, France.

ABSTRACT

Mutations in the XRCC4 gene have been recently identified through whole-exome sequencing (WES). While the overall clinical presentation of the patients (severe short stature, microcephaly, gonadal failure) generally conforms with what is expected for the defect of a critical non-homologous end-joining (NHEJ) DNA repair factor, the absence of consequence on the proper development of the immune system is rather surprising, given the role of NHEJ in V(D)J recombination. Several hypotheses can be envisioned to explain this discrepancy. Overall, these findings highlight the power of WES in identifying new molecular causes for human diseases while providing with new exciting scientific question to address.

No MeSH data available.


XRCC4 mutations in humansTop: Position of the XRCC4 mutations with respect to the 3 known domains of XRCC4. Regions of interaction of XRCC4 with Cernunnos/XLF and DNA ligase IV are also represented. Bottom: Summary of the published cases of XRCC4 deficiency in humans. Phenotype of XRCC4 KO mice is included for comparison.
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fig01: XRCC4 mutations in humansTop: Position of the XRCC4 mutations with respect to the 3 known domains of XRCC4. Regions of interaction of XRCC4 with Cernunnos/XLF and DNA ligase IV are also represented. Bottom: Summary of the published cases of XRCC4 deficiency in humans. Phenotype of XRCC4 KO mice is included for comparison.

Mentions: Up to now, molecular medicine or the art of identifying deleterious, disease-causing mutations in genes relied on knowledge-based sequencing of a handful of candidates. At best, this approach was optimized by prior genetic studies (whole-genome association studies (WGAS) or whole-genome homozygosity mapping (WGHM)) to restrict the list of candidates in case of consanguineous families and/or large series of patients. The field has moved one step forward in recent time with the completion of the human genome sequence and the development of next-generation sequencing (NGS) of DNA covering all coding exons (whole-exome sequencing (WES)). Five studies, including the one by Bee et al (2015) in this issue, recently reported on mutations in the XRCC4 gene in 12 human patients identified through WES (Fig1) (Gennery et al, 2014; Shaheen et al, 2014; de Bruin et al, 2015; Murray et al, 2015). Most of the cases presented with microcephalic primordial dwarfism (MPD) and gonadal failure. Early-onset metabolic syndrome or cardiomyopathies were also noticed in some patients. Was this the kind of clinical presentation one would have expected for XRCC4 deficiency?


When natural mutants do not fit our expectations: the intriguing case of patients with XRCC4 mutations revealed by whole-exome sequencing.

de Villartay JP - EMBO Mol Med (2015)

XRCC4 mutations in humansTop: Position of the XRCC4 mutations with respect to the 3 known domains of XRCC4. Regions of interaction of XRCC4 with Cernunnos/XLF and DNA ligase IV are also represented. Bottom: Summary of the published cases of XRCC4 deficiency in humans. Phenotype of XRCC4 KO mice is included for comparison.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520652&req=5

fig01: XRCC4 mutations in humansTop: Position of the XRCC4 mutations with respect to the 3 known domains of XRCC4. Regions of interaction of XRCC4 with Cernunnos/XLF and DNA ligase IV are also represented. Bottom: Summary of the published cases of XRCC4 deficiency in humans. Phenotype of XRCC4 KO mice is included for comparison.
Mentions: Up to now, molecular medicine or the art of identifying deleterious, disease-causing mutations in genes relied on knowledge-based sequencing of a handful of candidates. At best, this approach was optimized by prior genetic studies (whole-genome association studies (WGAS) or whole-genome homozygosity mapping (WGHM)) to restrict the list of candidates in case of consanguineous families and/or large series of patients. The field has moved one step forward in recent time with the completion of the human genome sequence and the development of next-generation sequencing (NGS) of DNA covering all coding exons (whole-exome sequencing (WES)). Five studies, including the one by Bee et al (2015) in this issue, recently reported on mutations in the XRCC4 gene in 12 human patients identified through WES (Fig1) (Gennery et al, 2014; Shaheen et al, 2014; de Bruin et al, 2015; Murray et al, 2015). Most of the cases presented with microcephalic primordial dwarfism (MPD) and gonadal failure. Early-onset metabolic syndrome or cardiomyopathies were also noticed in some patients. Was this the kind of clinical presentation one would have expected for XRCC4 deficiency?

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR1163 Laboratory of Genome Dynamics in the Immune System (DGSI), Paris, France Paris Descartes University-Sorbonne Paris Cité Imagine Institute, Paris, France.

ABSTRACT

Mutations in the XRCC4 gene have been recently identified through whole-exome sequencing (WES). While the overall clinical presentation of the patients (severe short stature, microcephaly, gonadal failure) generally conforms with what is expected for the defect of a critical non-homologous end-joining (NHEJ) DNA repair factor, the absence of consequence on the proper development of the immune system is rather surprising, given the role of NHEJ in V(D)J recombination. Several hypotheses can be envisioned to explain this discrepancy. Overall, these findings highlight the power of WES in identifying new molecular causes for human diseases while providing with new exciting scientific question to address.

No MeSH data available.