CKAP2L – Filippi syndrome

Filippi syndrome is a rare autosomal recessive disorder characterized by growth failure, microcephaly, syndactyly, distinctive facial dysmorphism, and variable neurodevelopmental delays. Multiple independent case reports and multi‐patient studies have revealed biallelic loss‑of‑function variants in CKAP2L that are highly concordant with the clinical findings of Filippi syndrome (PMID:25439729, PMID:33913579).

The genetic evidence is robust, with pathogenic mutations including frameshift and missense variants identified in several unrelated probands. For example, one representative mutation is c.571dup (p.Ile191AsnfsTer6), which has been recurrently reported in affected individuals (PMID:25439729). Autosomal recessive inheritance is further corroborated by segregation in sibling pairs and multiple independent families.

Functional studies have provided supportive evidence that CKAP2L is critical for proper cell division. In vitro and in vivo experiments demonstrated that loss-of-function variants disrupt CKAP2L localization to spindle poles, resulting in disorganized microtubule arrays and defective chromosome segregation, findings that are consistent with the neurodevelopmental and craniofacial anomalies seen in Filippi syndrome (PMID:25439729).

Although one report highlighted a mosaic variant in another gene in a patient with overlapping features, the preponderance of genetic and functional evidence consistently supports CKAP2L as the primary contributor to Filippi syndrome. The overall clinical validity is rated as strong given the identification of pathogenic variants in more than 10 unrelated probands across distinct reports (PMID:25439729, PMID:33913579).

In summary, both genetic and experimental data converge to establish a strong association between CKAP2L and Filippi syndrome. These findings not only underpin diagnostic decision‑making but also support commercial genetic testing panels and future research publications.

Key take‑home message: The confirmation of biallelic CKAP2L loss‑of‑function variants provides a critical molecular diagnosis for patients exhibiting the clinical spectrum of Filippi syndrome, thus guiding management and genetic counseling.

References

• American journal of human genetics • 2014 • Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome PMID:25439729
• American journal of medical genetics. Part A • 2021 • Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus PMID:33913579
• Cold Spring Harbor molecular case studies • 2022 • Novel variants identified in CKAP2L in two siblings with Filippi syndrome PMID:34921061
• American journal of medical genetics. Part A • 2024 • Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to the clinical spectrum of the disease PMID:38738944

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