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. 2022 Mar;190(1):102-108.
doi: 10.1002/ajmg.c.31973. Epub 2022 Apr 30.

Biallelic variants in CENPF causing a phenotype distinct from Strømme syndrome

Gerarda Cappuccio  1   2 , Simona Brillante  2 , Roberta Tammaro  2 , Michele Pinelli  1   2 , Margherita Lucia De Bernardi  1 , Maria Grazia Gensini  1 , Emilia K Bijlsma  3 , Tamara T Koopmann  3 , Mariette J V Hoffer  3 , Kimberly McDonald  4 , Laura G Hendon  4 , Sofia Douzgou  5   6 , Charulata Deshpande  7 , Stefano D'Arrigo  8 , Annalaura Torella  2   9 , Vincenzo Nigro  2   9 , Brunella Franco  1   2   10 , Nicola Brunetti-Pierri  1   2   10
Affiliations

Biallelic variants in CENPF causing a phenotype distinct from Strømme syndrome

Gerarda Cappuccio et al. Am J Med Genet C Semin Med Genet. 2022 Mar.

Abstract

Biallelic loss-of-function (LoF) variants in CENPF gene are responsible for Strømme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from -2.9 SDS to -5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted-V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Strømme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case-series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Strømme syndrome.

Keywords: CENPF; Strømme syndrome; anterior chamber defect; cilia; duodenal atresia.

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Figures

FIGURE 1
FIGURE 1
Pedigrees and facial features of the presented cases. Dysmorphic features include inverted‐V shaped interrupted eyebrows, epicanthal folds and peri‐orbital fullness, and large/prominent ears. m, months; y, years
FIGURE 2
FIGURE 2
Location of CENPF variants. CENPF variants of the four patients herein described and previously reported cases are shown (NM_016343.3). CENPF missense variants (in blue) are reported herein for the first time
FIGURE 3
FIGURE 3
Immunofluorescence analysis of primary cilia in skin fibroblasts. (a) Representative images of fibroblast cells obtained from individuals carrying nucleotide changes in CENPF and a normal control after 48 hr of serum starvation. Centrioles and axonemes were immunostained for γ‐tubulin (red) and ARL13B (green), respectively. Hoechst labels nuclei (blue). Scale bar: 10 μm. (b) Graphs show the quantification of ciliary length, expressed in μm, and of cilia number, expressed as the % of ciliated cells, in NA108 and BES043 fibroblasts compared to the normal control, and ≥100 cells analyzed per sample. Data are expressed as the mean values and are representative of three independent experiments, error bars indicate the SEM. Paired Student's t‐test were applied. *p ≤ .05 and ***p ≤ .001. ns, not significant
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