CENPF – Stromme Syndrome

Autosomal recessive biallelic loss of function variants in the centromere protein F gene (CENPF) have been reported in multiple families with Stromme syndrome, a rare disorder characterized by microcephaly, ocular malformations, and intestinal atresia. Stromme syndrome manifests with prenatal-onset microcephaly, microphthalmia, and "apple-peel" type jejunal atresia in affected siblings, consistent with the CENPF-associated ciliopathy phenotype.

In two unrelated consanguineous families, exome sequencing identified homozygous truncating and splicing variants in CENPF (NM_016343.4:c.5912_5913insA (p.Thr1974AsnfsTer9); NM_016343.3:c.1195-2A>G) in four affected children (two siblings each) presenting with the classical triad of Stromme syndrome (PMID:28407396; PMID:31953238). Each variant segregated in homozygosity in the affected sib-pairs, consistent with autosomal recessive inheritance.

The phenotypic spectrum across these families includes severe microcephaly (HP:0000252), unilateral or bilateral microphthalmia (HP:0000568), and intestinal atresia (HP:0011100), with occasional ocular anterior chamber anomalies and holoprosencephaly features in the more severely affected sibs (PMID:31953238). The recurrent observation of biallelic loss-of-function alleles supports a mechanism of loss of CENPF function in Stromme syndrome.

Experimental data outside of Stromme syndrome indicate a critical role for CENP-F in centriole length regulation and ciliogenesis, with truncating CENPF mutations disrupting ciliary assembly and IFT88 localization in renal epithelial cells (PMID:25564561). However, no disease-specific functional assays or rescue experiments in models of Stromme syndrome have been reported to date.

No conflicting reports have been documented, and all available genetic and experimental evidence is concordant with an autosomal recessive loss-of-function mechanism. Additional clinical series or functional validation studies would further strengthen the association but are currently lacking.

Key Take-home: Biallelic truncating and splice-site variants in CENPF cause Stromme syndrome via loss of centriolar function, supporting diagnostic testing for CENPF in patients with microcephaly, ocular anomalies, and intestinal atresia.

References

• American journal of medical genetics. Part A • 2017 • A further family of Stromme syndrome carrying CENPF mutation. PMID:28407396
• European journal of medical genetics • 2020 • Expanding the phenotype and the genotype of Stromme syndrome: A novel variant of the CENPF gene and literature review. PMID:31953238
• Journal of medical genetics • 2015 • The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes. PMID:25564561

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