Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

RECQL4 : Rothmund-Thomson syndrome

HGNC:9949 | MONDO_0010002
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hereditary Cancer
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 6
Kitao S et al. 1999 May (PMID:10319867); Lindor NM et al. 2000 Jan 31 (PMID:10678659); Simon T et al. 2010 Jun (PMID:20503338); Wang LL et al. 2003 May 7 (PMID:12734318);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Lindor NM et al. 2000 Jan 31 (PMID:10678659);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Beghini A et al. 2003 Jul 30 (PMID:12838562);
Functional Alteration Patient cells 1 0 - 2 2 1
Schurman SH et al. 2009 Sep 15 (PMID:19567405);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Hoki Y et al. 2003 Sep 15 (PMID:12915449); Mann MB et al. 2005 Mar 15 (PMID:15703196);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
There is abundant evidence published associating the RECQL4 gene with Rothmund-Thomson Syndrome since the gene-disease relationship was first proposed by Kitao et al. (1999). Multiple case level studies have been performed with RTS patients that have variants in the RECQL4 gene. WRN and BLM, another two RecQ DNA helicases, are associated with Werner and Bloom syndromes. All three are disorders of chromosomal instability and manifest growth retardation, premature aging, and predisposition to malignancies. RT-PCR analysis of RECQL4 cDNA from patient's cells showed diffuse splicing defects. Defective repair of H2O2-induced DNA lesions was reported in primary RTS patient's cell line, AG05013. Multiple RECQL4 deficient mouse models have been established to show consistent phenotypes with RTS patients, including growth retardation, skin and several other tissue abnormalities, birth defects of the skeletal system and increased cancer susceptibility. All of these types of evidence are consistent with a definitive relationship between the RECQL4 gene and Rothmund-Thomson Syndrome (RTS).