RECQL4 – Rothmund-Thomson syndrome

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis characterized by early‐onset poikiloderma, sparse hair, juvenile cataracts, short stature and skeletal dysplasia. Patients display genomic instability with a high predisposition to osteosarcoma and other malignancies ([PMID:10319867]).

Biallelic pathogenic variants in the DNA helicase gene RECQL4 (HGNC:9949) underlie RTS type II. In a seminal series, compound heterozygous RECQL4 frameshift and splice‐site mutations were identified in multiple kindreds, including two brothers with osteosarcoma ([PMID:10678659]). Subsequent reports have documented over 150 unrelated probands harboring truncating, splice‐site and nonsense alleles across the helicase domain, confirming autosomal recessive inheritance and segregation in sib pairs ([PMID:10319867]).

The RECQL4 variant spectrum comprises predominantly loss‐of‐function alleles: frameshifts (e.g., c.1573del (p.Cys525fs)), splice acceptor disruptions (e.g., c.1391-2A>G), nonsense changes, and small intronic deletions leading to aberrant splicing. Recurrent founder alleles have been described in diverse populations, with carrier frequencies up to 2% in certain cohorts.

Recql4-deficient mouse models recapitulate key RTS features: exon 13–deleted mice exhibit severe growth retardation, skin abnormalities and fibroblast proliferation defects ([PMID:12915449]). Biochemical assays demonstrate dual DNA unwinding activities in RECQ4—an ATP‐dependent helicase function and an Sld2‐like N‐terminal replication initiation activity—both essential for genome maintenance ([PMID:19177149]).

A subset (~30%) of clinically diagnosed RTS patients lack RECQL4 mutations, implicating genetic heterogeneity and the need for extended genetic testing in noncanonical cases ([PMID:35616152]). No robust conflicting evidence disputes the RECQL4–RTS association.

Integration of extensive genetic, experimental and animal data supports a definitive association between RECQL4 and RTS type II. Biallelic RECQL4 testing is critical for diagnostic confirmation, family counseling and tailored surveillance for malignancy risk. Key take-home: RECQL4 loss-of-function variants cause RTS with a reproducible autosomal recessive inheritance pattern and distinct biochemical and in vivo phenotypes that inform clinical management.

References

• Nature Genetics • 1999 • Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome PMID:10319867
• Human Molecular Genetics • 2003 • Growth retardation and skin abnormalities of the Recql4‐deficient mouse PMID:12915449
• EMBO Journal • 2009 • Dual DNA unwinding activities of the Rothmund-Thomson syndrome protein, RECQ4 PMID:19177149
• American Journal of Medical Genetics • 2000 • Rothmund-Thomson syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome PMID:10678659

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