Previously undescribed phenotypic findings and novel ACTG1 gene pathogenic variants in Baraitser-Winter cerebrofrontofacial syndrome

Chacón‐Camacho, Oscar F.; Barragán-Arévalo, Tania; Villarroel, Camilo E.; Almanza-Monterrubio, Mónica; Zenteno, Juan Carlos

doi:10.1016/j.ejmg.2020.103877

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…Just as ACTG1 variants leading to DFNA20/26, those leading to BWCFF syndrome most probably determine a gain-of-function effect [6,7], but the exact pathogenic mechanism is yet to be clarified. Anyway, the spectrum of pathogenic variants observed in patients with DFNA20/26 does not overlap with the one observed in patients with a typical BWCFF syndrome (Supplementary Tables S2 and S3) [6,7,[47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66]. In addition, the results of preliminary studies with lymphoblastoid cell lines from BWCFF syndrome patients, as well as the results of in vitro and in vivo studies on DFNA20/26-associated variants, suggest that the phenotypic impact of missense mutations may differ in a mutation-specific way; the available functional studies highlighted that each ACTG1 variant led to specific alterations in terms of actin organization and polymerization, interaction with actin-binding proteins, and cell morphology [4,6,7,19,[43][44][45][46].…”

Section: Discussionmentioning

confidence: 92%

DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature

et al. 2021

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Since the early 2000s, an ever-increasing subset of missense pathogenic variants in the ACTG1 gene has been associated with an autosomal-dominant, progressive, typically post-lingual non-syndromic hearing loss (NSHL) condition designed as DFNA20/26. ACTG1 gene encodes gamma actin, the predominant actin protein in the cytoskeleton of auditory hair cells; its normal expression and function are essential for the stereocilia maintenance. Different gain-of-function pathogenic variants of ACTG1 have been associated with two major phenotypes: DFNA20/26 and Baraitser–Winter syndrome, a multiple congenital anomaly disorder. Here, we report a novel ACTG1 variant [c.625G>A (p. Val209Met)] in an adult patient with moderate-severe NSHL characterized by a downsloping audiogram. The patient, who had a clinical history of slowly progressive NSHL and tinnitus, was referred to our laboratory for the analysis of a large panel of NSHL-associated genes by next generation sequencing. An extensive review of previously reported ACTG1 variants and their associated phenotypes was also performed.

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Section: Discussionmentioning

confidence: 92%

DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature

et al. 2021

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“…Cerebellar vermis hypoplasia without cerebral cortex abnormalities is undescribed features of BWS. Cerebellar vermis hypoplasia has been reported in two previous BWS patients harboring ACTG1 (p.Thr203Met) variants, with abnormalities of corpus callosum, heterotopia, and pachygyria (Vontell et al ., 2019; Chacon-Camacho et al ., 2020). More than 80% of patients have supratentorial abnormalities, including frontal lobe-dominant pachygyria, heterotopia, and corpus callosum hypoplasia (Rossi et al ., 2003).…”

Section: Discussionmentioning

confidence: 99%

A novel ACTB variant in an atypical case of Baraitser-Winter syndrome with cerebellar hypoplasia and diaphragmatic hernia

Kuroda,

Saito,

Enomoto

et al. 2024

Clinical Dysmorphology

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“…Great phenotypic variability can be observed for ACTG1 carriers even within the same family (Kemerley et al, 2017). As for other rare diseases, the original definition of BRWS syndrome does not well adapt to the clinical presentation of several ACTB or ACTG1 carriers, with some authors referring to such cases as atypical BRWS (Johnston et al, 2013), others invoking a phenotypic expansion (Dawidziuk et al, 2022) which progressively enriches with new findings (Chacon‐Camacho et al, 2020), or talking about a pleiotropic developmental disorder (Cuvertino et al, 2017) with hypervariable expression (Dawidziuk et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

A likely pathogenic ACTG1 variant in a child showing partial phenotypic overlap with Baraitser‐Winter syndrome

Graziani

Cinnirella

Ferradini

et al. 2023

American J of Med Genetics Pt A

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Baraitser‐Winter syndrome (BRWS) is a rare autosomal dominant disease (AD) caused by heterozygous variants in ACTB (BRWS1) or ACTG1 (BRWS2) genes. BRWS features developmental delay/intellectual disability of variable degree and craniofacial dysmorphisms. Brain abnormalities (especially pachygyria), microcephaly, epilepsy, as well as hearing impairment, cardiovascular and genitourinary abnormalities may be present. We report on a 4‐year‐old female, who was addressed to our institution because of psychomotor delay associated with microcephaly and dysmorphic features, short stature, mild bilateral sensorineural hearing loss, mild cardiac septal hypertrophy, and abdominal swelling. Clinical exome sequencing detected a c.617G>A p.(Arg206Gln) de novo variant in ACTG1 gene. Such variant has been previously reported in association with a form of AD nonsyndromic sensorineural progressive hearing loss and we classified it as likely pathogenic according to ACMG/AMP criteria, despite our patient's phenotype only partially overlapped BWRS2. Our finding supports the extreme variability of the ACTG1‐related disorders, ranging from classical BRWS2 to nuanced clinical expressions not fitting the original description, and occasionally featuring previously undescribed clinical findings.

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Previously undescribed phenotypic findings and novel ACTG1 gene pathogenic variants in Baraitser-Winter cerebrofrontofacial syndrome

Cited by 9 publications

References 23 publications

DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature

DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature

A novel ACTB variant in an atypical case of Baraitser-Winter syndrome with cerebellar hypoplasia and diaphragmatic hernia

A likely pathogenic ACTG1 variant in a child showing partial phenotypic overlap with Baraitser‐Winter syndrome

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