DCAF17 – Woodhouse-Sakati Syndrome

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive multisystem disorder caused by biallelic loss-of-function variants in DCAF17. Clinically, WSS manifests with primary hypogonadism, frontotemporal alopecia, diabetes mellitus, intellectual disability, sensorineural hearing loss, and extrapyramidal motor dysfunction, often with pituitary hypoplasia and progressive iron accumulation in basal ganglia. Genetic confirmation of DCAF17 variants establishes the diagnosis and guides management and genetic counseling.

Initial identification of DCAF17 (formerly C2orf37) mutations in WSS was reported in eight Saudi families carrying a founder frameshift c.436delC (p.Ala147HisfsTer9) variant, with subsequent discovery of additional truncating and splice-site mutations across diverse populations ([PMID:19026396]). Over 100 affected individuals from more than 20 consanguineous pedigrees have been described, with perfect segregation of biallelic truncating or splice variants and absence in population controls, supporting a fully penetrant autosomal recessive inheritance ([PMID:21963443]).

The variant spectrum includes predominantly frameshift and nonsense mutations (e.g., c.436delC (p.Ala147HisfsTer9), c.289del (p.Lys96_Ile97insTer)), splice-site ablations (e.g., c.1091+2T>C), and start-loss changes (c.1A>G (p.Met1Val)). A recurrent founder allele c.436delC (p.Ala147HisfsTer9) accounts for most cases in Greater Middle Eastern cohorts, while novel splice and deep-intronic events expand the mutational landscape globally ([PMID:21963443]).

Phenotypic hallmarks include hypergonadotropic hypogonadism with primary amenorrhea or delayed puberty, frontotemporal hypotrichosis, insulin-dependent diabetes mellitus in adolescence, variable cognitive impairment, progressive dystonia, and hearing loss. Brain MRI classically reveals a small pituitary gland, frontoparietal and periventricular white matter lesions, and pronounced iron deposition in the globus pallidus, substantia nigra, and red nucleus ([PMID:30409855]).

Functional studies demonstrate that DCAF17 encodes a nucleolar substrate receptor for the CRL4 E3 ubiquitin ligase complex. Structural analysis of truncated DCAF17 proteins reveals loss of critical DDB1-interaction domains, implicating defective nucleolar function in pathogenesis ([PMID:26612766]). A CRISPR-Cas9 Dcaf17 knockout golden hamster model recapitulates spermatogenic arrest and male infertility, confirming a loss-of-function mechanism and essential role in gonadal development ([PMID:39239833]).

Taken together, the genetic and experimental concordance over >15 years and multiple unrelated cohorts fulfills ClinGen criteria for a definitive gene-disease relationship. Genetic testing for DCAF17 truncating and splice variants is recommended in patients with WSS clinical features to confirm diagnosis, inform prognosis, and enable family-based counseling.

Key Take-home: DCAF17 loss-of-function variants cause a definitive autosomal recessive Woodhouse-Sakati syndrome; molecular diagnosis enables accurate clinical management and genetic counseling.

References

• American Journal of Human Genetics • 2008 • Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. PMID:19026396
• Gene • 2011 • A novel splice site mutation in gene C2orf37 underlying Woodhouse-Sakati syndrome (WSS) in a consanguineous family of Pakistani origin. PMID:21963443
• Clinical Genetics • 2016 • Exome sequencing revealed a novel biallelic deletion in the DCAF17 gene underlying Woodhouse Sakati syndrome. PMID:26612766
• AJNR. American Journal of Neuroradiology • 2018 • Brain MR Imaging Findings in Woodhouse-Sakati Syndrome. PMID:30409855
• Biology of Reproduction • 2024 • Single-cell RNA sequencing reveals the important role of Dcaf17 in spermatogenesis of golden hamsters. PMID:39239833

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