RECQL4

protein-coding

RecQ like helicase 4, the group of RecQ like helicases

Gene summary

The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

MANE transcript

NM_004260.4

Inheritance

AR, AD

ClinVar variants

P:412U:2845B:1463

Top phenotype

Baller-Gerold syndrome; RAPADILINO syndrome; Rothmund-Thomson syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr8:144,511,288-144,517,845

External References & Databases

Ensembl (ENSG00000160957)

Transcript & Mutation Effects

hg38 • Region Span ~6.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Rothmund-Thomson syndrome type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0016369

Submitter: Labcorp Genetics (formerly Invitae)

Rothmund-Thomson syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010002

Submitter: ClinGen

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).

Baller-Gerold syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009039

Submitter: G2P

rapadilino syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009955

Submitter: Genomics England PanelApp

Rothmund-Thomson syndrome type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0016369

Submitter: Genomics England PanelApp

Baller-Gerold syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009039

Submitter: PanelApp Australia

rapadilino syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009955

Submitter: PanelApp Australia

Rothmund-Thomson syndrome type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016369

Submitter: Orphanet

congenital heart diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*RECQL4* was first reported in relation to autosomal dominant congenital heart disease in 2021 (Morton et al., PMID: 33084842). A case-control study found lack of enrichment of *RECQL4 *variants in congenital heart disease patients compared to controls. Experimental evidence for this gene was also evaluated. In one mouse model, the homozygous mutant mice were able to survive past birth, yet had high-severity growth delay and anomalies in many regions, skin anomalies, and embryonic fibroblasts with a reduction in cell proliferation. In another mouse model, the homozygous mutants had significant skin anomaly, skeletal congenital complications, genomic instability, and heightened cancer risk. However, neither of these mouse models were scored as none of the mutants had congenital heart disease (PMID: 12915449, 15703196). No evidence for a causal role for *RECQL4* in autosomal dominant congenital heart disease has been reported. However, congenital heart disease is just one symptom associated with autosomal recessive Baller-Gerold Syndrome, for which more *RECQL4* variants have been reported. The relationship between *RECQL4* and Baller-Gerold Syndrome is yet to be evaluated. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 2/10/2025 (SOP Version 11).

Rothmund-Thomson syndrome type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016369

Submitter: G2P

Baller-Gerold syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009039

Submitter: Orphanet

RECON progeroid syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957266

Submitter: PanelApp Australia

Rothmund-Thomson syndrome type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0016369

Submitter: PanelApp Australia

osteosarcomaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009807

Submitter: Genomics England PanelApp

rapadilino syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009955

Submitter: Orphanet

Clinical Genomic Database (CGD)

Baller-Gerold syndrome; RAPADILINO syndrome; Rothmund-Thomson syndrome 2AR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Oncologic; Renal

Intervention: Oncologic

Rationale: While the disorders may be recognizable, individuals may be at risk for neoplasms, and awareness may allow early diagnosis and treatment, which may reduce morbidity and mortality

Refs: 8160763; 10678659; 12838562; 12952869; 15964893; 18716613; 20113479; 20503338; 27247962; 27287744; 27859906; 28039508; 28358413; 28486640; 29224249; 29367366; 29462647; 29642415; 29659569; 30007837; 31406625; 31428572; 32482547; 35025765

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RECQL4 variants in ClinVar

30 Conditions Cataloged

Baller-Gerold syndromeTotal: 4807

Inborn genetic diseasesTotal: 2130

not providedTotal: 542

not specifiedTotal: 297

Rothmund-Thomson syndrome type 2Total: 261

RECQL4-related disorderTotal: 247

Hereditary cancer-predisposing syndromeTotal: 184

Rapadilino syndromeTotal: 177

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004260.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			43 clinvar	1272 clinvar	2 clinvar	1317
missense	3 clinvar	12 clinvar	2754 clinvar	174 clinvar	12 clinvar	2955
nonsense	101 clinvar	20 clinvar	8 clinvar			129
start loss			6 clinvar			6
frameshift	162 clinvar	36 clinvar	6 clinvar	1 clinvar	1 clinvar	206
splice donor/acceptor (+/-2bp)	12 clinvar	66 clinvar	28 clinvar	1 clinvar		107
Total	278	134	2845	1448	15	4720

Highest pathogenic variant AF is 0.00040140163

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004260.4	RefSeq	NP_004251.4	21	MANE Select
ENST00000617875.6	Ensembl	ENSP00000482313.2	21	MANE Select
NM_001413017.1	RefSeq	NP_001399946.1	22	Standard
NM_001413018.1	RefSeq	NP_001399947.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

telomere maintenance
double-strand break repair via homologous recombination
DNA strand renaturation
DNA replication
DNA repair

Molecular Function

bubble DNA binding
DNA binding
single-stranded DNA binding
helicase activity
protein binding

Cellular Component

chromosome, telomeric region
nucleus
chromosome
cytoplasm
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000428558
Coding exons: 22
Length: 6563
Individuals with no LoFs: 4672
Homozygous LoFs: 119559
Heterozygous LoFs: 53
Defined: 124284
p: 0.806

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-4.22	1074	749	1.43	0.0000492	7582
Missense (PolyPhen)		253	195.55	1.2938		2016
Synonymous	-8.69	502	308	1.63	0.0000193	2568
Loss of Function	0.245	54	56.0	0.965	0.00000273	592

Population LoF Frequency

Population	CAF	p-value	Status
African	1.0	0.77	notable
Latino/Admixed American	1.0	0.92	notable
Ashkenazi Jewish	1.0	0.87	notable
East Asian	1.0	0.90	notable
Finnish	1.0	0.57	notable
European (Non-Finnish)	1.0	0.82	notable
South Asian	1.0	0.94	notable
Other	1.0	0.85	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-dependent ATPase. May modulate chromosome segregation. {ECO:0000269|PubMed:15317757}.;
Disease: DISEASE: Rothmund-Thomson syndrome (RTS) [MIM:268400]: Characterized by dermatological features such as atrophy, pigmentation, and telangiectasia and frequently accompanied by juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, and hypogonadism. {ECO:0000269|PubMed:10552928}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: RAPADILINO syndrome (RAPADILINOS) [MIM:266280]: Disease characterized by radial and patellar aplasia or hypoplasia. {ECO:0000269|PubMed:12952869}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Baller-Gerold syndrome (BGS) [MIM:218600]: An autosomal recessive syndrome characterized by short stature, craniosynostosis, absent or hypoplastic radii, short and curved ulna, fused carpal bones and absent carpals, metacarpals and phalanges. Some patients manifest poikiloderma. Cases reported as Baller-Gerold syndrome have phenotypic overlap with several other disorders, including Saethre-Chotzen syndrome. {ECO:0000269|PubMed:15964893}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.172

Essentials

Indispensability pred.: E
Indispensability score: 0.965

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High