Baraitser-Winter Syndrome Research Articles

Missense variant Met119Val in ACTB in a patient with Baraitser-Winter syndrome type 1 and mild intellectual disability.

Here we report on a Brazilian female patient with striking dysmorphic craniofacial features of the Baraitser-Winter syndrome (BRWS), including coarse face with prominent metopic ridge, highly arched eyebrows, ocular hypertelorism, ptosis, long palpebral fissures, broad nasal tip, long philtrum, full cheeks, cleft lip and palate, and low-set ears with abnormal lobe. Other clinical signs included partial agenesis of the corpus callosum, asymptomatic pineal cyst, oligodontia, cervical cystic hygroma, pterygium colli, axillary pterygium, duplicated left hallux and seizures. Sanger sequencing of the ACTB gene showed a heterozygous missense variation NM_001101.5 (ACTB):c.355A>G (p.Met119Val). This variant is located very close to the ACTB variant Thr120Ile, which results in the severe BRWS phenotype with severe intellectual disability and absence of speech, firstly described as Fryns-Aftimos syndrome. Despite this, our patient had mild developmental delay, without impairment of speech, and with moderated learning difficulties.

Clinical and genetic analysis of a patient with Baraitser-Winter syndrome due to variant of ACTG1 gene

To explore the clinical features and genetic etiology of a child with Baraitser-Winter syndrome (BWS). A BWS child who had sought medical attention at the Linyi People's Hospital on April 8, 2022 was selected as the study subject. Clinical data of the child was collected, and peripheral blood samples were obtained from the child and his parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child, a 5-year-and-6-month-old male, had typical clinical features of BWS including congenital non-myogenic ptosis, arched eyebrows, wide philtrum, and pointed chin. Neurological symptoms included microcephaly, developmental delay, epilepsy, and deafness. Cranial MRI revealed enlarged frontal lobes, decreased white matter, and hydrocephalus. WES has identified a heterozygous c.430G>A (p.Asn144Tyr) missense variant in the ACTG1 gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PS2+PM2_Supporting+PP3_Moderate+PP4). The heterozygous c.430G>A (p.Asn144Tyr) missense variant of the ACTG1 gene probably underlay the pathogenesis of BWS in this child. Above finding has enriched the mutation spectrum of BWS-related genes and provided a basis for clinical diagnosis and genetic counseling.

Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.

Background: Baraitser-Winter Syndrome (BRWS) is a rare autosomal dominant condition associated with hearing loss (HL). In the literature, two types of this condition are reported, Baraitser-Winter type 1 (BRWS1) and type 2 (BRWS2) produced by specific pathogenetic variants of two different genes, ACTB for BRWS1 and ACTG1 for BRWS2. In addition to syndromic BRWS2, some pathogenic variants in ACTG1 are associated also to another pathologic entity, the "Autosomal dominant non-syndromic hearing loss 20/26". In these syndromes, typical craniofacial features, sensory impairment (vision and hearing) and intellectual disabilities are frequently present. Heart anomalies, renal and gastrointestinal involvement and seizure are also common. Wide inter- and intra-familial variety in the phenotypic spectrum is reported. Some phenotypic aspects of these syndromes are not yet fully described, such as the degree and progression of HL, and better knowledge of them could be useful for correct follow-up and treatment. Methods and Results: In this study, we report two cases of children with HL and diagnosis of BRWS and a review of the current literature on HL in these syndromes.

Waardenburg Syndrome: The Contribution of Next-Generation Sequencing to the Identification of Novel Causative Variants.

Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in type 2. Additionally, limb musculoskeletal abnormalities and Hirschsprung disease differentiate types 3 and 4, respectively. Genes PAX3, MITF, SOX10, KITLG, EDNRB, and EDN3 are already known to be associated with WS. In WS, a certain degree of molecularly undetected patients remains, especially in type 2. This study aims to pinpoint causative variants using different NGS approaches in a cohort of 26 Brazilian probands with possible/probable diagnosis of WS1 (8) or WS2 (18). DNA from the patients was first analyzed by exome sequencing. Seven of these families were submitted to trio analysis. For inconclusive cases, we applied a targeted NGS panel targeting WS/neurocristopathies genes. Causative variants were detected in 20 of the 26 probands analyzed, these being five in PAX3, eight in MITF, two in SOX10, four in EDNRB, and one in ACTG1 (type 2 Baraitser-Winter syndrome, BWS2). In conclusion, in our cohort of patients, the detection rate of the causative variant was 77%, confirming the superior detection power of NGS in genetically heterogeneous diseases.

Long-term follow-up and novel variant in Suleiman-El-Hattab syndrome: Expanding the genotypic and clinical spectrum of a rare neurodevelopmental disorder

Suleiman-El-Hattab syndrome (SULEHS, OMIM #618950) is an autosomal recessive multisystem developmental disorder characterized by distinctive facial appearance, global developmental delay/intellectual disability, poor expressive speech and happy demeanor. SULEHS is an ultra-rare disorder associated with biallelic loss-of-function variants of the TASP1 gene, and up-to-date, seven patients from five families have been reported in the literature. Loss of TASP1 function has been reported to alter H3K4 histone modifications and expression of TFIIA and HOX transcription factors in the SULEHS phenotype. In this report, a new patient molecularly diagnosed with SULEHS by a novel homozygous c.404-2A > G variant in the TASP1 gene is presented with the long-term follow-up. Although the majority of the patient's clinical characteristics were similar to those of previously reported SULEHS patients, this study was the first to describe some additional anomalies, such as cystic hygroma, increased nuchal thickness, coarctation of the aorta, pulmonary stenosis, pulmonary sequestration anomaly, chronic constipation, encephalomalacia, and aggressive behavior. Because of the remarkable similarities between the clinical features of Baraitser-Winter syndrome (BRWS) and the patient, BRWS was considered the most likely diagnosis before the molecular diagnosis. Network analysis also supported that the interaction of the SULEHS-associated TASP1 gene with the BRWS-associated ACTB and ACTG1 genes through common intermediate molecules. Overall, despite the existence of differences in clinical features, inheritance patterns, and underlying pathophysiology between BRWS and SULEHS, both diseases could be considered in the differential diagnosis due to the high clinical similarities, including the dysmorphic features, growth parameters, neurodevelopmental phenotype, neurological problems, and multisystem involvement. Additionally, this report could contribute to a better understanding of the genotypic and clinical features of SULEHS by describing a novel pathogenic variant and new clinical features, such as prenatal manifestations.

Catatonic syndrome and Baraitser Winter syndrome: Case report and review of the literature

Catatonic syndrome and Baraitser Winter syndrome: Case report and review of the literature

Baraitser-Winter syndrome in a male patient with a uterus

Introduction Baraitser-Winter syndrome (BRWS) is a rare autosomal dominant disorder with fewer than 50 cases reported in the literature. Features include facial dysmorphism, ocular coloboma, brain abnormalities, hearing defects, intellectual disability and kidney abnormalities. We describe a case of a male infant with de novo mutation for BRWS with a new and unexpected finding of a uterus and vagina in the pelvis. This is the first reported case of a …

Baraitser-Winter syndrome in a male patient with a uterus

Baraitser-Winter syndrome in a male patient with a uterus

Случай синдрома Барайтсера-Винтера, обусловленный мутацией p.Ile136Val в гене ACTB

Введение. Синдром Барайтсера-Винтера (BWCFF) - очень редкое аутосомно-доминантное наследственное заболевание, обусловленное мутациями в генах ACTB и ACTG1. Практически все известные случаи этого заболевания обусловлены миссенс-мутациями в генах ACTB и ACTG1, возникшими de novo. В этой работе представлен новый случай синдрома BWCFF, обусловленный мутацией p.Ile136Val в гене ACTB. Пациенты и методы. Пробанд - мальчик 6 лет 8 месяцев, из двойни. Фенотип пациента анализировали с использованием приложения Face2Gene. Пробанду и всем членам его семьи проведено секвенирование 1-4 экзонов и прилежащих интронных последовательностей гена ACTB. Результаты. У пробанда отмечены характерные симптомы BWCFF: постнатальная пограничная микроцефалия, специфические дизморфии, колобомы радужной оболочки обоих глаз, короткая шея с крыловидными складками, эпилепсия, врожденный порок сердца. В отличие от большинства случаев синдрома у пациента отсутствовали задержка интеллектуального развития, а также грубые изменения коры или других структур головного мозга. В результате секвенирования экзонов гена АСТВ у пациента была выявлена замена с.406A>G (p.Ile136Val, rs1554329352) в гетерозиготном состоянии. У родителей пробанда и здоровых сибсов мутация не была обнаружена. Заключение. Использование современных технологий фенотипирования позволило предположить клинический диагноз, провести эффективный целенаправленный поиск мутаций в гене ACTB и диагностировать новый случай синдрома BWCFF. Introduction Baraitser-Winter Syndrome (BWCFF) is a very rare autosomal dominant hereditary disease caused by mutations in the ACTB and ACTG1 genes. Almost all known cases of this disease are caused by de novo missense mutations in the ACTB and ACTG1. In this paper we present a new case of BWCFF syndrome, due to p.Ile136Val mutation in the ACTB gene. Patients and methods. Proband - a boy, 6 years 8 months, out of twins. The patient’s phenotype was analyzed using the Face2Gene application. Direct sequencing of 1-4 exons and the adjacent intron sequences of the ACTB gene was performed in proband and all members of his family. Results. The proband has characteristic symptoms of BWCFF: postnatal borderline microcephaly, facial dysmorphism, iris colobomas of both eyes, short, webbed neck, epilepsy, congenital heart defect. Unlike most cases of the syndrome the patient does not have developmental delay and gross changes in the cortex or other structures of the brain. ACTB gene sequencing resulted in detection of heterozygous missense mutation p.406A> G (p.Ile136Val, rs1554329352) in proband. This mutation was not found in his parents and healthy siblings. Conclusion The use of modern phenotyping technologies allowed us to suggest the correct clinical diagnosis, to conduct an effective targeted search for mutations in the ACTB gene and diagnose a new case of BWCFF syndrome.

Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes

The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as “dominant (or type 2) Opitz GBBB syndrome”, and instead should be referred to as “SPECC1L syndrome” as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer.

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer.Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome.Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition.Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594-603. ©2018 AACR.

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.

New ocular finding in Baraitser-Winter syndrome (BWS)

Baraitser-Winter syndrome was first described as a syndrome of iris coloboma, ptosis, hypertelorism, and mental retardation (Baraitser and Winter 1988; Baraitser, 2016). The phenotypic spectrum has since broadened to include other facial dysmorphic features, deafness, microcephaly, lissencephaly, and CNS findings (Baraitser and Winter 1988; Ganesh et al., 2005; Henedy et al., 2010; Verloes et al., 2015). The syndrome is due to pathogenic variants on either ACTB or ACTG1 genes (Di Donato et al., 2014; Rivière et al., 2012). There is still discussion which gene variant produces a more severe phenotype (Di Donato et al., 2016; Di Donato et al., 2014; Verloes et al., 2015). We report a 3-year-old girl with short stature, mild global developmental delay, minor brain anomalies and few dysmorphic features including unusual stroma of the irises and unreported corectopia. Exome sequencing reported a de novo likely pathogenic variant on the ACTB gene. The present report adds a new ocular finding to the phenotypic spectrum.

A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma.

Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole‐exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband‐only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra‐ocular signs of Baraitser–Winter syndrome. We found this mutant protein to be incapable of incorporation into F‐actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC.

The Clinical Manifestations and Genetic Implications of Baraitser–Winter Syndrome Type 2

An 18-year-old Caucasian male was born by cesarean section weighing 2.6 kg (5 lb 14 oz) at birth after an uncomplicated pregnancy with no perinatal complications. Around 4 to 5 months of age, the patient's mother initially became concerned as he was experiencing signs of developmental delay and a mild floppy tone, in addition to facial features that resembled some form of mental retardation. The patient's older brother also experienced similar developmental symptoms and facial features that presented around the same age period as our patient. It was initially thought to be Down syndrome; however, both the patient and his brother tested negative for Down syndrome on chromosomal analyses. There was also a question of whether the patient had some form of autism spectrum disorder, but doctors were unable to specifically confirm this. Now at the age of 18 years, the patient has no understandable speech with distinctive facial features such as a broad nasal bridge and prominent epicanthic folds, lissencephaly, smaller than average head size, intellectual disability, and hearing loss. It was discovered, through trio-based exome sequencing, that the patient had a de novo missense mutation (p.Ser155Phe) in the ACTG1 gene, which has been linked to the rare syndrome known as Baraister-Winter syndrome type 2. Baraitser-Winter syndrome 2 is a unique variant that is clinically similar to Baraitser-Winter syndrome type 1; however, only seven previous cases have been reported.

7p22.1 microdeletions involving ACTB associated with developmental delay, short stature, and microcephaly

There are no published reports of patients harboring microdeletions involving the 7p22.1 region. Although 7p22.1 microdeletions are rare, some reports have shown microduplications encompassing this region. In this study, we report five patients with overlapping deletions of the 7p22.1 region. The patients exhibited clinical similarities including non-specific developmental delay, short stature, microcephaly, and other distinctive features. The shortest region of overlap within the 7p22.1 region includes five genes, FBXL18, ACTB, FSCN1, RNF216, and ZNF815P. Of these genes, only ACTB is known to be associated with an autosomal dominant trait. Dominant negative mutations in ACTB are responsible for Baraitser-Winter syndrome 1. We analyzed ACTB expression in immortalized lymphocytes derived from one of the patients and found that it was reduced to approximately half that observed in controls. This indicates that ACTB expression is linearly correlated with the gene copy number. We suggest that haploinsufficiency of ACTB may be responsible for the clinical features of patients with 7p22.1 microdeletions.

Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities.

In the absence of aneuploidy or other pathogenic cytogenetic abnormality, fetuses with increased nuchal translucency (NT ≥ 3.5 mm) and/or other sonographic abnormalities have a greater incidence of genetic syndromes, but defining the underlying pathology can be challenging. Here, we investigate the value of whole exome sequencing in fetuses with sonographic abnormalities but normal microarray analysis. Whole exome sequencing was performed on DNA extracted from chorionic villi or amniocytes in 24 fetuses with unexplained ultrasound findings. In the first 14 cases sequencing was initially performed on fetal DNA only. For the remaining 10, the trio of fetus, mother and father was sequenced simultaneously. In 21% (5/24) cases, exome sequencing provided definitive diagnoses (Milroy disease, hypophosphatasia, achondrogenesis type 2, Freeman-Sheldon syndrome and Baraitser-Winter Syndrome). In a further case, a plausible diagnosis of orofaciodigital syndrome type 6 was made. In two others, a single mutation in an autosomal recessive gene was identified, but incomplete sequencing coverage precluded exclusion of the presence of a second mutation. Whole exome sequencing improves prenatal diagnosis in euploid fetuses with abnormal ultrasound scans. In order to expedite interpretation of results, trio sequencing should be employed, but interpretation can still be compromised by incomplete coverage of relevant genes.

Baraitser–Winter syndrome: An additional Egyptian patient with skeletal anomalies, bilateral iris and choroid colobomas, retinal hypoplasia and hypoplastic scrotum

We report a 3.5year old male child, second in order of birth of non consanguineous Egyptian parents with Baraitser–Winter syndrome (BRWS). The patient had bilateral colobomas of the iris and choroid. Our patient had also retinal hypoplasia, which was not reported previously in this syndrome, bilateral congenital ptosis, hypertelorism, moderate mental retardation, short stature, short neck, hyperextensibility of the joints of the hands, talipes equinovarus, kyphoscoliosis and unilateral hypoplastic scrotum and testis.

Bilateral iris, choroid, optic nerve colobomas and retinal detachment in an Egyptian patient with mild Baraitser–Winter syndrome

BackgroundBaraitser–Winter syndrome (BRWS) is a malformation syndrome, characterized by facial dysmorphism, ocular colobomata, pachygyria, and intellectual defects. Case reportA 3.5year old female child with BRWS has bilateral congenital ptosis, microcornea, iris, choroid, and optic nerve coloboma, retinal detachment, and mental retardation. She has also frontal bossing, prominent forehead, thick eyebrows, transverse slanting, hypertelorism, wide palpebral fissures, and nystagmus. The nose is broad, and bulbous with wide nares, and broad nasal tip. She has also low set posteriorly rotated ears, full cheeks, long philtrum, large mouth (macrostomia), gum hypertrophy, decayed teeth, high arched palate, pointed chin, short neck, low posterior hair line, partial left simian crease, and short fingers. MRI brain shows frontal polymicrogyria. ConclusionThis patient represents a mild case of Baraitser–Winter syndrome.

Cerebro-fronto-facial syndrome type 3 with polymicrogyria: A clinical presentation of Baraitser–Winter syndrome

Baraitser–Winter syndrome (BRWS) is a rare condition affecting the development of the brain and the face. The most common characteristics are unusual facial appearance including hypertelorism and ptosis, ocular colobomas, hearing loss, impaired neuronal migration and intellectual disability. BRWS is caused by mutations in the ACTB and ACTG1 genes. Cerebro-fronto-facial syndrome (CFFS) is a clinically heterogeneous condition with distinct facial dysmorphism, and brain abnormalities. Three subtypes are identified. We report a female infant with striking facial features and brain anomalies (included polymicrogyria) that fit into the spectrum of the CFFS type 3 (CFFS3). She also had minor anomalies on her hands and feet, heart and kidney malformations, and recurrent infections. DNA investigations revealed c.586C>T mutation (p.Arg196Cys) in ACTB. This mutation places this patient in the spectrum of BRWS. The same mutation has been detected in a polymicrogyric patient reported previously in literature. We expand the malformation spectrum of BRWS/CFFS3, and present preliminary findings for phenotype–genotype correlation in this spectrum.