TY - JOUR
T1 - Human RECQ Helicase Pathogenic Variants, Population Variation and “Missing” Diseases
AU - Fu, Wenqing
AU - Ligabue, Alessio
AU - Rogers, Kai J.
AU - Akey, Joshua M.
AU - Monnat, Raymond J.
N1 - Funding Information:
Contract Grant Sponsors: NIH Pathway to Independence Award K99HG008122 to WF and NCI award P01CA077852 to RJMJr. We thank Drs. Junko Oshima, Fuki Hisama, and George M. Martin of the University of Washington for contributing information from the Werner Syndrome International Registry to help construct the RECQMutdb. KJR's participation in this project was supported by a UW-HHMI Integrative Research Internship, a UW Mary Gates Undergraduate Research Fellowship and a Herschel and Caryl Roman Undergraduate Science Scholarship award through theDepartment of Genome Sciences, University of Washington. Disclosure statement The authors declare no conflict of interest.
Publisher Copyright:
© 2016 WILEY PERIODICALS, INC.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies. The use of biochemical and model organism data, together with computational prediction, identified over 300 potentially pathogenic population variants in RECQL and RECQL5, the two RECQ helicases that are not yet linked to a heritable deficiency syndrome. Despite the presence of these predicted pathogenic variants in the human population, we identified no individuals homozygous for any biochemically verified or predicted pathogenic RECQL or RECQL5 variant. Nor did we find any individual heterozygous for known pathogenic variants in two or more of the disease-associated RECQ helicase genes BLM, RECQL4, or WRN. Several postulated RECQ helicase deficiency syndromes—RECQL or RECQL5 loss of function, or compound haploinsufficiency for the disease-associated RECQ helicases—may remain missing, as they likely incompatible with life.
AB - Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies. The use of biochemical and model organism data, together with computational prediction, identified over 300 potentially pathogenic population variants in RECQL and RECQL5, the two RECQ helicases that are not yet linked to a heritable deficiency syndrome. Despite the presence of these predicted pathogenic variants in the human population, we identified no individuals homozygous for any biochemically verified or predicted pathogenic RECQL or RECQL5 variant. Nor did we find any individual heterozygous for known pathogenic variants in two or more of the disease-associated RECQ helicase genes BLM, RECQL4, or WRN. Several postulated RECQ helicase deficiency syndromes—RECQL or RECQL5 loss of function, or compound haploinsufficiency for the disease-associated RECQ helicases—may remain missing, as they likely incompatible with life.
KW - Bloom syndrome
KW - RECQ helicase
KW - RECQL
KW - RECQL5
KW - Rothmund-Thomson syndrome
KW - Werner syndrome
KW - compound haploinsufficiency
KW - heritable cancer predisposition
KW - mutation functional prediction
KW - pathogenic variation
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U2 - 10.1002/humu.23148
DO - 10.1002/humu.23148
M3 - Article
C2 - 27859906
AN - SCOPUS:85006371859
SN - 1059-7794
VL - 38
SP - 193
EP - 203
JO - Human Mutation
JF - Human Mutation
IS - 2
ER -