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. 2014 Feb;22(2):179-83.
doi: 10.1038/ejhg.2013.130. Epub 2013 Jun 12.

Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations

N Di Donato  1 , A Rump  1 , R Koenig  2 , V M Der Kaloustian  3 , F Halal  4 , K Sonntag  1 , C Krause  1 , K Hackmann  1 , G Hahn  5 , E Schrock  1 , A Verloes  6
Affiliations

Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations

N Di Donato et al. Eur J Hum Genet. 2014 Feb.

Abstract

ACTB and ACTG1 mutations have recently been reported to cause Baraitser-Winter syndrome (BRWS) - a rare condition characterized by ptosis, colobomata, neuronal migration disorder, distinct facial anomalies and intellectual disability. One of the patients carrying an ACTB mutation was previously diagnosed with Fryns-Aftimos syndrome (FAS), which is a rare and severe, multiple congenital anomaly (MCA) syndrome whose symptoms partially overlap with that of BRWS. However, several patients with Fryns-Aftimos were considered not to fit into the ACTB and ACTG1 spectrum because of their severe impairment and additional malformations. We report on three patients who had been diagnosed with FAS. All three patients carry a mutation in the ACTB gene. On the basis of the ACTB mutations and analysis of the clinical findings, we reclassify the diagnosis of these patients as severe BRWS. We suggest that mutations in ACTB cause a distinctly more severe phenotype than ACTG1 mutations, despite the structural similarity of beta- and gamma-actins and their overlapping expression pattern. We expand the spectrum of BRWS and confirm that FAS is not a separate entity but an early and severe manifestation of BRWS.

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Figures

Figure 1
Figure 1
Patient 1, phenotype follow-up. (a) Patient at the age of 6 months; (b) X-ray of the feet at the age of 3 years, note double halluces; (c) webbing at axilla and elbows; (d) patient at the age of 8 years; (d1) anterior and (d2) lateral view; (e–f) patient at the age of 20 years; (e1) anterior and (e2) lateral view; (g) brain MRI scans of patient 1 at the age of 10 years; (g1) T1-weighted coronal section shows bilateral subependymal heterotopia; (g2) T2-weigted transversal section shows bilateral frontal pachygyria.
Figure 2
Figure 2
Patient 2, phenotype follow-up. (a) Patient during the first year of life, note bilateral cleft lip; (b) nuchal webbing; (c) patient at the age of 8 years; (c1) face anterior view; (c2) face lateral view; (c3) whole body image; (d) brain MRI scans of patient 2 at the age of 3 months; (d1) T2-weighted transversal section shows bilateral pachygyria; (d2) T1-weighted IR coronal section shows hypoplastic corpus callosum and dilatation of the lateral and third ventricles.
Figure 3
Figure 3
Mutation distribution in ACTB and ACTG1. Transcripts and sequence variants of (a) ACTB (chr7:5,566,501-5,570,500) and (b) ACTG1 (chr17:79,476,401-79,480,400). Both genes are shown in the UCSC hg19 assembly and drawn at the same scale. The different isoforms of each gene are represented by black/blue vertical lines, in which solid boxes represent exons and the thin areas with arrows illustrate introns and direction of transcription. Missense mutations are represented by thin vertical ticks in different colors: black, hearing loss; blue, BRWS with moderate phenotype; red, BRWS with severe phenotype; green, variants from ∼6000 healthy individuals, as listed in the exome variant server. Red arrows indicate mutations in patients 1–3. Blue arrows indicate mutations in patients 61456 and 61458 (Rivière et al).
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