Detection of new mutations in 3 cases de novo tuberous sclerosis

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.

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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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De novo adult acute myeloid leukemia with two new mutations in juxtatransmembrane domain of the FLT3 gene: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-020-02587-3 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Ismael F. Alarbeed ◽

Abdulsamad Wafa ◽

Faten Moassass ◽

Bassel Al-Halabi ◽

Walid Al-Achkar ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Chromosomal Abnormalities ◽

Molecular Genetic ◽

Type A ◽

Chemotherapeutic Treatment ◽

Acute Myeloid ◽

New Mutations

Abstract Background Approximately 30% of adult acute myeloid leukemia (AML) acquire within fms-like tyrosine kinase 3 gene (FLT3) internal tandem duplications (FLT3/ITDs) in their juxtamembrane domain (JMD). FLT3/ITDs range in size from three to hundreds of nucleotides, and confer an adverse prognosis. Studies on a possible relationship between of FLT3/ITDs length and clinical outcomes in those AML patients were inconclusive, yet. Case presentation Here we report a 54-year-old Arab male diagnosed with AML who had two FLT3-ITD mutations in addition to NPM1 mutation. Cytogenetic approaches (banding cytogenetics) and fluorescence in situ hybridization (FISH) using specific probes to detect translocations t(8;21), t(15;17), t(16;16), t(12;21), and deletion del(13q)) were applied to exclude chromosomal abnormalities. Molecular genetic approaches (polymerase chain reaction (PCR) and the Sanger sequencing) identified a yet unreported combination of two new mutations in FLT3-ITDs. The first mutation induced a frameshift in JMD, and the second led to a homozygous substitution of c.1836T>A (p.F612L) also in JMD. Additionally a NPM1 type A mutation was detected. The first chemotherapeutic treatment was successful, but 1 month after the initial diagnosis, the patient experienced a relapse and unfortunately died. Conclusions To the best of our knowledge, a combination of two FLT3-ITD mutations in JMD together with an NPM1 type A mutation were not previously reported in adult AML. Further studies are necessary to prove or rule out whether the size of these FLT3-ITDs mutations and potential other double mutations in FLT3-ITD are correlated with the observed adverse outcome.

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Early diagnosis of a newborn with tuberous sclerosis caused by a genetic mutation

Journal of International Medical Research ◽

10.1177/03000605211035895 ◽

2021 ◽

Vol 49 (8) ◽

pp. 030006052110358

Author(s):

Lin Qiao ◽

Yuting Yang ◽

Dongmei Yue

Keyword(s):

Genetic Testing ◽

Early Diagnosis ◽

Tuberous Sclerosis ◽

De Novo ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Heterozygous Mutation ◽

Loss Of Function ◽

Autosomal Dominant Disorder ◽

Tsc1 Gene

Objective Tuberous sclerosis (TSC) is an autosomal dominant disorder, often detected during childhood. We present the results of genetic testing in a newborn with suspected TSC. Methods A newborn with no specific clinical manifestations of TSC showed evidence of TSC on magnetic resonance imaging and echocardiography. Next-generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA) of the TSC1 and TSC2 gene exons were carried out to confirm the diagnosis. Results The results of MLPA were negative, but NGS showed a heterozygous mutation in the TSC1 gene comprising insertion of a T residue at c.2165 (exon 17) to c.2166 (exon 17), indicating a loss of function mutation. These results were verified by Sanger sequencing. This genetic change was present in the newborn but the parental genotypes were wild-type, indicating a de novo mutation. Conclusions In this case, a case of TSC caused by a heterozygous mutation in the TSC1 gene was confirmed by NGS sequencing. This indicates the suitability of genetic testing for the early diagnosis of clinically rare and difficult-to-diagnose diseases, to guide clinical treatment.

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Schizophrenia Risk and Paternal Age: A Potential Role for De Novo Mutations in Schizophrenia Vulnerability Genes

CNS Spectrums ◽

10.1017/s1092852900022239 ◽

2002 ◽

Vol 7 (1) ◽

pp. 26-29 ◽

Cited By ~ 27

Author(s):

Dolores Malaspina ◽

Alan Brown ◽

Deborah Goetz ◽

Nelly Alia-Klein ◽

Jill Harkavy-Friedman ◽

...

Keyword(s):

Human Population ◽

Potential Role ◽

De Novo ◽

Paternal Age ◽

Current Evidence ◽

Parental Age ◽

De Novo Mutations ◽

New Mutations

ABSTRACTHow schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.

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Tuberous sclerosis in a child with de novo translocation t(3; 12) (p26.3; q23.3)

Clinical Genetics ◽

10.1111/j.1399-0004.1991.tb03103.x ◽

2008 ◽

Vol 40 (4) ◽

pp. 326-328 ◽

Cited By ~ 6

Author(s):

R. Fahsold ◽

H.-D. Rott ◽

U. Claussen ◽

B. Schmalenberger

Keyword(s):

Tuberous Sclerosis ◽

De Novo ◽

De Novo Translocation

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Four New Mutations in the Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene Causing X-Linked Sideroblastic Anemia: Increased Pyridoxine Responsiveness After Removal of Iron Overload by Phlebotomy and Coinheritance of Hereditary Hemochromatosis

Blood ◽

10.1182/blood.v93.5.1757.405a12_1757_1769 ◽

1999 ◽

Vol 93 (5) ◽

pp. 1757-1769 ◽

Cited By ~ 5

Author(s):

Philip D. Cotter ◽

Alison May ◽

Liping Li ◽

A.I. Al-Sabah ◽

Edward J. Fitzsimons ◽

...

Keyword(s):

Iron Overload ◽

De Novo ◽

Normal Population ◽

Hereditary Hemochromatosis ◽

Refractory Anemia ◽

Missense Mutations ◽

Sideroblastic Anemia ◽

Aminolevulinate Synthase ◽

C282y Homozygote ◽

New Mutations

X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband’s maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH)HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance ofHFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

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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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A novel de novo TSC2 nonsense mutation detected in a pediatric patient with tuberous sclerosis complex

Child s Nervous System ◽

10.1007/s00381-020-04702-7 ◽

2020 ◽

Vol 37 (1) ◽

pp. 253-257

Author(s):

Mei-hua Yang ◽

Zhong-ke Wang ◽

Yi Huang ◽

Sheng-qing Lv ◽

Chun-qing Zhang ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Pediatric Patient ◽

Tuberous Sclerosis Complex ◽

Nonsense Mutation ◽

De Novo

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Bladder perivascular epithelioid cell tumour and tuberous sclerosis complex: a rare association

BMJ Case Reports ◽

10.1136/bcr-2021-241635 ◽

2021 ◽

Vol 14 (5) ◽

pp. e241635

Author(s):

Jo Lin Tee ◽

Jonathan Chambers ◽

Geoffrey Strutton

Keyword(s):

Case Report ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

De Novo ◽

Epithelioid Cell ◽

Clinical Implications ◽

Review Of The Literature ◽

Rare Association ◽

Perivascular Epithelioid Cell

Bladder perivascular epithelioid cell tumours (PEComas) associated with tuberous sclerosis complex (TSC) are rare, with only one other case report in the literature to date. We present our case of a bladder PEComa in a young adult female with TSC arising de novo. Histopathology showed features in keeping with an angiomyolipoma and confirmatory immunohistochemical stains were positive for both melanocytic and smooth muscle markers. She was well at the 6-month follow-up post-surgical resection. Given the rarity of such lesions in the bladder, we discuss the diagnostic and prognostic challenges, clinical implications and a brief review of the literature to date.

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