New case of Baraitzer-Winter Cerebrofrontofacial syndrome due to p.Ile136Val mutation in ACTB gene

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.

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A novel TSC1 variant associated with tuberous sclerosis and sacrococcygeal teratoma

Human Genome Variation ◽

10.1038/s41439-020-00124-8 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Saba Ahmad ◽

Luis Manon ◽

Gifty Bhat ◽

Jerry Machado ◽

Alice Zalan ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cellular Differentiation ◽

Autosomal Dominant ◽

De Novo ◽

Autosomal Dominant Disease ◽

Sacrococcygeal Teratoma ◽

Dominant Disease ◽

The Brain

AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disease associated with tumors and malformed tissues in the brain and other vital organs. We report a novel de novo frameshift variant of the TSC1 gene (c.434dup;p. Ser146Valfs*8) in a child with TSC who initially presented with a sacral teratoma. This previously unreported association between TSC and teratoma has broad implications for the pathophysiology of embryonic tumors and mechanisms underlying cellular differentiation.

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Non-Inversion Factor VIII Mutations in 80 Hemophilia A Families Including 24 with Alloimmune Responses

Thrombosis and Haemostasis ◽

10.1055/s-0037-1612984 ◽

2002 ◽

Vol 87 (02) ◽

pp. 273-276 ◽

Cited By ~ 23

Author(s):

Miao-Liang Liu ◽

Shelley Nakaya ◽

Arthur Thompson

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

De Novo ◽

High Titer ◽

Direct Sequencing ◽

Normal Variant ◽

Missense Mutations ◽

Gene Deletions ◽

Intron Splice ◽

Splice Junctions

SummaryHeteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII; of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.

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Tuberous Sclerosis and Autism

10.1093/med/9780199744312.003.0009 ◽

2013 ◽

Author(s):

Dan Ehninger ◽

Alcino J. Silva

Keyword(s):

Tuberous Sclerosis ◽

Autosomal Dominant ◽

De Novo ◽

Single Gene ◽

Gene Mutations ◽

Extended Version ◽

Single Gene Disorder ◽

Autosomal Dominant Pattern ◽

Organ Systems ◽

The Brain

Tuberous sclerosis (TSC) is a single-gene disorder caused by heterozygous mutations in either the TSC1 or TSC2 genes (Consortium, 1993; van Slegtenhorst et al., 1997). In 70% of cases, TSC gene mutations arise de novo. The remaining 30% of cases are familial with an autosomal dominant pattern of inheritance. Tuberous sclerosis belongs to the group of phakomatoses (neurocutaneous disorders) and is associated with characteristic manifestations in various organ systems, including the brain, skin, kidney, lung, heart, and liver (Crino, Nathanson, & Henske, 2006; Curatolo, Bombardieri & Jozwiak, 2008). Pathological manifestations in these organ systems often include tumor growths or tissue malformations (hamartomas). While penetrance is high, expressivity of TSC phenotypes is highly variable. The birth incidence of TSC is approximately 1:6,000 (Osborne, Fryer, & Webb, 1991). This chapter is an updated and extended version of a previous article on this topic (Ehninger, de Vries, & Silva, 2009)

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Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation

Blood ◽

10.1182/blood-2004-02-0754 ◽

2004 ◽

Vol 104 (5) ◽

pp. 1474-1481 ◽

Cited By ~ 101

Author(s):

Debes H. Christiansen ◽

Mette K. Andersen ◽

Jens Pedersen-Bjergaard

Keyword(s):

Myeloid Leukemia ◽

De Novo ◽

Direct Sequencing ◽

Alkylating Agents ◽

Missense Mutations ◽

Transactivation Domain ◽

Leukemic Transformation ◽

Frameshift Mutations ◽

Subsequent Transformation ◽

Chromosome Arm

Abstract The AML1 transcription factor is essential for normal hematopoiesis and is the target of several chromosomal translocations in acute leukemia. Acquired somatic AML1 mutations were recently demonstrated sporadically in de novo myelodysplasia (MDS) and acute myeloid leukemia (AML) including a few cases of therapy-related disease (t-MDS/t-AML). We examined 140 patients with t-MDS or t-AML for AML1 mutations by direct sequencing. We identified 9 missense, 3 nonsense, and 10 frameshift mutations, all heterozygous, in 22 patients (15.7%). Thirteen mutations were located in the N-terminal Runt homology domain (RHD), whereas 9 mutations were located in the C-terminal region including the transactivation domain (TAD). Nineteen patients with AML1 mutations had previously received alkylating agents whereas 2 patients had received radiotherapy only. AML1 mutations were highly significantly associated with presentation of the disease as t-MDS (P = .003), with deletion or loss of chromosome arm 7q (P = .001) and with subsequent transformation to overt t-AML (P = .0001). Patients with missense mutations presented a shorter survival compared with patients with nonsense/frameshift mutations (P = .03). Our results suggest that AML1 mutations and deletion of genes on chromosome arm 7q cooperate in leukemogenesis and predispose to leukemic transformation.

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Interstitial Deletion of 2q22.2q22.3 Involving the Entire ZEB2 Gene in a Case of Mowat-Wilson Syndrome

Molecular Syndromology ◽

10.1159/000513313 ◽

2021 ◽

pp. 1-9

Author(s):

Khaled Refaat ◽

Nivine Helmy ◽

Mohamed Elawady ◽

Mona El Ruby ◽

Alaa Kamel ◽

...

Keyword(s):

Congenital Heart ◽

Autosomal Dominant ◽

De Novo ◽

Pulmonary Arteries ◽

Hirschsprung Disease ◽

Research Centre ◽

Chromosomal Microarray ◽

Facial Dysmorphism ◽

Dysmorphic Features ◽

Human Cytogenetics

Mowat-Wilson syndrome (MWS) is a rare autosomal dominant syndrome characterized by dysmorphic features, mental retardation, and congenital heart disease (CHD). MWS results from microdeletions of chromosome 2q23 or de novo SNVs involving the ZEB2 gene. Here, we report on an Egyptian MWS patient diagnosed by chromosomal microarray (CMA). A 1-year-old male child was referred to the CHD clinic, National Research Centre, presenting with dysmorphic features and CHD. The patient was referred to the human cytogenetics department for cytogenetic analysis and for screening of subtelomere rearrangements and microdeletion loci, using MLPA, and all revealed normal results. CMA revealed an interstitial 2.27-Mb microdeletion in chromosome 2q, involving the entire ZEB2 gene and other genes. This study emphasizes the significance of CMA in the detection of microdeletions/microduplications and as a screening tool in cases presenting with CHD and extracardiac manifestations. MWS should be suspected in patients presenting with the characteristic facial dysmorphism, developmental delay, seizures, Hirschsprung disease, and congenital heart anomalies, especially those involving the pulmonary arteries or pulmonary valves. It is recommended to include the ZEB2 locus in the MLPA microdeletions probes.

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Schinzel-Giedion Syndrome with Congenital Megacalycosis in a Turkish Patient: Report of SETBP1 Mutation and Literature Review of the Clinical Features

Case Reports in Genetics ◽

10.1155/2017/3740524 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4

Author(s):

Ozgul Bulut ◽

Zeynep Ince ◽

Umut Altunoglu ◽

Sukran Yildirim ◽

Asuman Coban

Keyword(s):

Literature Review ◽

Autosomal Dominant ◽

De Novo ◽

Facial Dysmorphism ◽

Multiple Congenital Anomalies ◽

Patient Report ◽

Autosomal Dominant Disorder ◽

Turkish Patient ◽

Increased Risk ◽

Risk Of Malignancy

Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant disorder that results in facial dysmorphism, multiple congenital anomalies, and an increased risk of malignancy. Recently, using exome sequencing, de novo heterozygous mutations in the SETBP1 gene have been identified in patients with SGS. Most affected individuals do not survive after childhood because of the severity of this disorder. Here, we report SETBP1 mutation confirmed by molecular analysis in a case of SGS with congenital megacalycosis.

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Different Patterns of Cooperating Mutations between De Novo AML Patients with MLL-Partial Tandem Duplication and MLL Translocations.

Blood ◽

10.1182/blood.v108.11.2363.2363 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2363-2363

Author(s):

Lee-Yung Shih ◽

Der-Cherng Liang ◽

Chein-Fuang Huang ◽

Ya-Tzu Chang ◽

Yu-Shu Shih ◽

...

Keyword(s):

Transcription Factors ◽

Tandem Duplication ◽

De Novo ◽

Direct Sequencing ◽

Ras Signaling ◽

Missense Mutations ◽

Ras Pathway ◽

Ras Signaling Pathway ◽

Partial Tandem Duplication ◽

De Novo Aml

Abstract Two-hit model of leukemogenesis has been proposed for AML. In AML with MLL rearrangements (MLL-R), MLL gene is fused to a variety of partner genes through reciprocal chromosomal translocations (MLL/t11q23), or is rearranged to generate a partial tandem duplication (MLL-PTD). The cooperating mutations of AML with MLL-R have not been systematically analyzed. We aimed to determine the cooperating mutations, including receptor tyrosine kinase (RTK) /Ras signaling pathway, NPM1 and myeloid transcription factors in de novo AML with MLL-R. MLL-R was screened by Southern blot analysis. RT-PCR was used to detect common MLL fusion transcripts. cDNA panhandle PCR was used to identify the infrequent or unknown MLL partner genes. Mutational analysis was peformed by DNA/cDNA PCR-GeneScan analysis for FLT3/ITD, by PCR-RFLP followed by direct sequencing for FLT3/TKD, by DNA/cDNA PCR and direct sequencing for N-Ras, K-Ras, c-KIT, c-FMS, PTPN11, NPM1, AML1 and CEBPα. Of the 131 patients with MLL-R, 77 had MLL-PTD and 54 had MLL/t11q23. None of the 131 patients with MLL-R had c-FMS mutations and c-KIT mutation was present in only one patient with MLL/t11q23. NPM1 mutations occurred in one with MLL-PTD and 2 with MLL/t11q23. The frequencies of other cooperating mutations are shown in Table 1. Taken together, cooperating mutations involving RTK/Ras pathway, NPM1, and/or myeloid transcription factors occurred in 71.4% (55/77) of patients with MLL-PTD and 59.3% (32/54) of patients with MLL/t11q23. In MLL-PTD group, coexistence of two mutations occurred in 23 patients. In MLL/t11q23 group, 6 patients had two mutations. Of the 18 patients with MLL-PTD and AML1 mutations, 8 mutations were located in the Runt homology domain (RHD) and 10 in the non-RHD, 15 were frameshift or nonsense mutations and 3 were missense mutations. Fourteen patients with MLL-PTD and AML1 mutations also had mutations of RTK/Ras singling pathway. Three patients with MLL/t11q23 and AML1 mutations, one in the RHD and 2 in the non-RHD, all were missense mutations. Of the 5 patients with MLL-PTD and CEBPα mutations, 3 harbored FLT3/ITD. Patients with MLL-PTD had a significantly higher frequency of cooperating mutations with myeloid transcription factors than patients with MLL/t11q23 (20/77 vs. 3/54, P=0.002), whereas there was no difference in the frequency of mutations involving RTK/Ras pathway between MLL-PTD and MLL/t11q23 groups (51/77 vs. 29/54, P=0.202). Our results showed that patients with de novo AML and MLL-R had a high frequency of cooperating mutations with RTK/Ras signaling pathway, NPM1 or myeloid transcription factors, and the mutation patterns were different between MLL-PTD and MLL/t11q23 groups. Table 1. Comparison of cooperating mutations between MLL-PTD and MLL/t11q23 groups FLT3/ITD FLT3/TKD N-Ras K-Ras PTPN11 AML1 CEBPα MLL-PTD 35/77 11/77 5/77 0/77 3/77 18/77 5/77 MLL/t11q23 2/54 7/54 9/54 13/54 1/53 3/54 0/54 P value <0.0001 1.000 0.085 <0.0001 0.648 0.007 0.077

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D-DEMØ, a distinct phenotype caused by ATP1A3 mutations

Neurology Genetics ◽

10.1212/nxg.0000000000000466 ◽

2020 ◽

Vol 6 (5) ◽

pp. e466

Author(s):

Lyndsey Prange ◽

Milton Pratt ◽

Kristin Herman ◽

Raphael Schiffmann ◽

David M. Mueller ◽

...

Keyword(s):

De Novo ◽

Brain Mri ◽

Facial Dysmorphism ◽

Cerebellar Hypoplasia ◽

Complex Partial Seizures ◽

Whole Exome ◽

Related Phenotype ◽

The Face ◽

Underlying Mechanisms ◽

The Brain

ObjectiveTo describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset.MethodsReview and analysis of clinical and genetic data.ResultsPatients shared the above traits and had whole-exome sequencing that showed de novo variants of the ATP1A3 gene, predicted to be disease causing and occurring in regions of the protein critical for pump function. Patient 1 (c.1079C>G, p.Thr360Arg), an 8-year-old girl, presented on day 1 of life with episodic dystonia, complex partial seizures, and facial dysmorphism. MRI of the brain revealed cerebellar hypoplasia. Patient 2 (c.420G>T, p.Gln140His), an 18-year-old man, presented on day 1 of life with hypotonia, tremor, and facial dysmorphism. He later developed dystonia. MRI of the brain revealed cerebellar hypoplasia and, later, further cerebellar volume loss (atrophy). Patient 3 (c.974G>A, Gly325Asp), a 13-year-old girl, presented on day 1 of life with tremor, episodic dystonia, and facial dysmorphism. MRI of the brain showed severe cerebellar hypoplasia. Patient 4 (c.971A>G, p.Glu324Gly), a 14-year-old boy, presented on day 1 of life with tremor, hypotonia, dystonia, nystagmus, facial dysmorphism, and later seizures. MRI of the brain revealed moderate cerebellar hypoplasia.ConclusionsD-DEMØ represents an ATP1A3-related phenotype, the observation of which should trigger investigation for ATP1A3 mutations. Our findings, and the presence of multiple distinct ATP1A3-related phenotypes, support the possibility that there are differences in the underlying mechanisms.

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Persistent Hyperplastic Primary Vitreous with Microphthalmia and Coloboma in a Patient with Okur-Chung Neurodevelopmental Syndrome

Molecular Syndromology ◽

10.1159/000517977 ◽

2021 ◽

pp. 1-5

Author(s):

Hiroaki Murakami ◽

Tomoko Uehara ◽

Yumi Enomoto ◽

Naoto Nishimura ◽

Tatsuro Kumaki ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Dominant ◽

De Novo ◽

Autosomal Dominant Disorder ◽

Immune Systems ◽

Ocular Manifestations ◽

Pathogenic Variants ◽

Persistent Hyperplastic Primary Vitreous ◽

Clinical Presentations ◽

The Brain

Okur-Chung neurodevelopmental syndrome is a rare autosomal dominant disorder caused by pathogenic variants in <i>CSNK2A1</i>, which encodes the alpha 1 catalytic subunit of casein kinase II. This syndrome is characterized by intellectual disability, developmental delay, and multisystemic abnormalities including those of the brain, extremities, and skin as well as cardiovascular, gastrointestinal, and immune systems. In this study, we describe a 5-year-old boy with a de novo novel nonsense variant in <i>CSNK2A1</i>, NM_001895.3:c.319C>T (p.Arg107*). He showed bilateral persistent hyperplastic primary vitreous with microphthalmia, lens dysplasia, and coloboma. Ocular manifestations are very rare in this syndrome, and this study expands the spectrum of the clinical presentations of this syndrome.

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Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations – A case report

10.21203/rs.2.307/v2 ◽

2019 ◽

Author(s):

Sofia Thunström ◽

Markus Axelsson

Keyword(s):

Case Report ◽

De Novo ◽

Age Of Onset ◽

De Novo Mutation ◽

Missense Mutations ◽

Case Presentation ◽

Whole Exome ◽

Demyelinating Peripheral Neuropathy ◽

The Brain ◽

Multiple Cysts

Abstract Background: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. Case presentation: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686T>G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. Conclusions: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes.

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