ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

University of Washington Center for Mendelian Genomics; Laura J Niedernhofer

doi:10.1002/humu.23367

ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

University of Washington Center for Mendelian Genomics, Laura J Niedernhofer

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Abstract

Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

Original language	English (US)
Pages (from-to)	255-265
Number of pages	11
Journal	Human mutation
Volume	39
Issue number	2
DOIs	https://doi.org/10.1002/humu.23367
State	Published - Feb 2018

Bibliographical note

Funding Information:
The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities.

Funding Information:
Contract Grant Sponsors: National Institutes of Health grants (R24AG42328, R01CA210916, P01AG043376); National Institutes of Health /National Human Genome Research Institute; National Institutes of Health /National Heart, Lung, and Blood Institute (U54HG006493); WeNMR (261572).

Funding Information:
The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. The authors declare no conflict of interest.

Publisher Copyright:
© 2017 Wiley Periodicals, Inc.

Keywords

Atypical Werner syndrome
Cockayne syndrome
ERCC4
Mendelian disease
molecular genetics
segmental progeroid syndromes
xeroderma pigmentosum group F

Publisher link

10.1002/humu.23367

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762268

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@article{25a1509937534db08321764fdf1ffb91,

title = "ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes",

abstract = "Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.",

keywords = "Atypical Werner syndrome, Cockayne syndrome, ERCC4, Mendelian disease, molecular genetics, segmental progeroid syndromes, xeroderma pigmentosum group F",

author = "{University of Washington Center for Mendelian Genomics} and Takayasu Mori and Yousefzadeh, {Matthew J.} and Maryam Faridounnia and Chong, {Jessica X.} and Hisama, {Fuki M.} and Louanne Hudgins and Gabriela Mercado and Wade, {Erin A.} and Barghouthy, {Amira S.} and Lin Lee and Martin, {George M.} and Nickerson, {Deborah A.} and Bamshad, {Michael J.} and Niedernhofer, {Laura J}",

note = "Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. Funding Information: Contract Grant Sponsors: National Institutes of Health grants (R24AG42328, R01CA210916, P01AG043376); National Institutes of Health /National Human Genome Research Institute; National Institutes of Health /National Heart, Lung, and Blood Institute (U54HG006493); WeNMR (261572). Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. The authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",

year = "2018",

month = feb,

doi = "10.1002/humu.23367",

language = "English (US)",

volume = "39",

pages = "255--265",

journal = "Human mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "2",

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TY - JOUR

T1 - ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

AU - University of Washington Center for Mendelian Genomics

AU - Mori, Takayasu

AU - Yousefzadeh, Matthew J.

AU - Faridounnia, Maryam

AU - Chong, Jessica X.

AU - Hisama, Fuki M.

AU - Hudgins, Louanne

AU - Mercado, Gabriela

AU - Wade, Erin A.

AU - Barghouthy, Amira S.

AU - Lee, Lin

AU - Martin, George M.

AU - Nickerson, Deborah A.

AU - Bamshad, Michael J.

AU - Niedernhofer, Laura J

N1 - Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. Funding Information: Contract Grant Sponsors: National Institutes of Health grants (R24AG42328, R01CA210916, P01AG043376); National Institutes of Health /National Human Genome Research Institute; National Institutes of Health /National Heart, Lung, and Blood Institute (U54HG006493); WeNMR (261572). Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. The authors declare no conflict of interest. Publisher Copyright: © 2017 Wiley Periodicals, Inc.

PY - 2018/2

Y1 - 2018/2

N2 - Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

AB - Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

KW - Atypical Werner syndrome

KW - Cockayne syndrome

KW - ERCC4

KW - Mendelian disease

KW - molecular genetics

KW - segmental progeroid syndromes

KW - xeroderma pigmentosum group F

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DO - 10.1002/humu.23367

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JO - Human mutation

JF - Human mutation

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ER -

ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

Abstract

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