SCARF2 and van den Ende-Gupta Syndrome

The association between SCARF2 (HGNC:19869) and van den Ende-Gupta syndrome (MONDO_0010959) is supported by multiple, independent lines of evidence from case reports and multi‐patient studies. Over 24 patients have been reported with this phenotype (PMID:22140376), demonstrating a consistent genotype–phenotype correlation with distinctive craniofacial and skeletal anomalies such as blepharophimosis, hypoplasia of the maxilla, and arachnodactyly. These clinical features have been observed across diverse ethnic backgrounds and family structures.

The syndrome follows an autosomal recessive inheritance pattern. Segregation analyses in consanguineous families have identified additional affected siblings, reinforcing the link between biallelic SCARF2 pathogenic variants and the disease (PMID:29378527). Multiple independent studies have documented cases with either compound heterozygous or homozygous mutations in this gene, further supporting its role in disease etiology.

Genetic evidence is bolstered by a diverse spectrum of pathogenic variants in SCARF2. Reported mutation types include deletions, missense, and splice site variants. Notably, the variant c.441_457del (p.Trp148fs) has been identified in more than one study, demonstrating a clear loss‐of‐function effect that correlates with the clinical presentation. This recurrent variant, alongside others identified in additional cases (PMID:20887961), strengthens the validity of SCARF2 as the causal gene.

Functional assessments further support a loss‐of‐function mechanism underlying van den Ende-Gupta syndrome. In vitro experiments and animal models have shown that reduced SCARF2 activity recapitulates key phenotypic features such as craniofacial dysmorphism and skeletal anomalies (PMID:24478002). These studies provide critical experimental backing that ties the genetic variants to the observed disease manifestations.

Although isolated reports have suggested potential genetic heterogeneity—occasionally implicating additional genes like ABL1—the preponderance of evidence consistently identifies SCARF2 pathogenic variants as the primary driver of van den Ende-Gupta syndrome. The cumulative genetic and functional data robustly exceed the ClinGen threshold for a strong gene–disease association.

Key take‑home: The integration of comprehensive genetic data with functional studies confirms that pathogenic variants in SCARF2 are a reliable diagnostic marker for van den Ende-Gupta syndrome, thereby improving diagnostic decision‑making and guiding future research endeavors.

References

• Molecular syndromology • 2010 • Unmasking of a Recessive SCARF2 Mutation by a 22q11.12 de novo Deletion in a Patient with Van den Ende-Gupta Syndrome PMID:22140376
• American journal of medical genetics. Part A • 2014 • Sclerocornea in a patient with van den Ende-Gupta Syndrome homozygous for a SCARF2 microdeletion PMID:24478002
• American journal of human genetics • 2010 • Mutations in SCARF2 are responsible for Van Den Ende-Gupta syndrome PMID:20887961
• BMC medical genetics • 2018 • Inclusion of joint laxity, recurrent patellar dislocation, and short distal ulnae as a feature of Van Den Ende-Gupta syndrome: a case report PMID:29378527
• American journal of medical genetics. Part A • 2021 • Further delineation of van den Ende-Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome PMID:33783941

Evidence Based Scoring (AI generated)