Update on the ACTG1‐associated Baraitser–Winter cerebrofrontofacial syndrome

Abstract

Baraitser–Winter cerebrofrontofacial syndrome is caused by heterozygous missense mutations in one of the two ubiquitous cytoplasmic actin‐encoding genes ACTB and ACTG1. Recently, we characterized the large cohort of 41 patients presenting with this condition. Our series contained 34 patients with mutations in ACTB and only nine with ACTG1 mutations. Here, we report on seven unrelated patients with six mutations in ACTG1–four novel and two previously reported. Only one of seven patients was clinically diagnosed with this disorder and underwent ACTB/ACTG1 targeted sequencing, four patients were screened as a part of the large lissencephaly cohort and two were tested with exome sequencing. Retrospectively, facial features were compatible with the diagnosis but significantly milder than previously reported in four patients, and non‐specific in one. The pattern of malformations of cortical development was highly similar in four of six patients with available MRI images and encompassed frontal predominant pachygyria merging with the posterior predominant band heterotopia. Two remaining patients showed mild involvement consistent with bilaterally simplified gyration over the frontal lobes. Taken together, we expand the clinical spectrum of the ACTG1‐associated Baraitser–Winter cerebrofrontofacial syndrome demonstrating the mild end of the facial and brain manifestations. © 2016 Wiley Periodicals, Inc.

Lissencephaly: Expanded imaging and clinical classification

“…Posterior partial SBH has been associated with mutations of LIS1 in about 30% of patients, with predominantly mosaic mutations. Short SBH are sometimes seen between regions of frontal pachygyria and normal posterior cortex in patients with BWCFF syndrome due to mutations of ACTB or ACTG1 [Di Donato et al, 2016b]. …”

Baraitser–Winter cerebrofrontofacial syndrome

“…Therefore, it has been suggested that ACTB mutations result in a more severe phenotype (2,7). Our observations indicate that a severe craniofacial phenotype has so far been associated with ACTB variants, whereas ACTG1 mutation carriers are more likely, although not consistently (17), to have a cortical brain malformation, hence also more severe ID and/or epilepsy. Indeed, the two foetuses described by Poirier et al (6) with microlissencephaly and facial features of BWCFF had novel mutations in ACTG1 (p.Ile75Leu and p.Pro343Ile).…”

Baraitser-Winter cerebrofrontofacial syndrome

“…Therefore, it has been suggested that ACTB mutations result in a more severe phenotype 2,7 . Our observations indicate that a severe craniofacial phenotype has so far been associated with ACTB variants, whereas ACTG1 mutation carriers are more likely, although not consistently 17 , to have a cortical brain malformation, hence also more severe intellectual disability and/or epilepsy. Indeed, the two fetuses described by Poirier et al 6 with microlissencephaly and facial features of BWCFF had novel mutations in ACTG1 (p.Ile75Leu & p.Pro343Ile).…”