Two Novel Heterozygote Mutations of ATM in a Chinese Family with Dystonia-Dominant Ataxia Telangiectasia and Literatures Review

Abstract Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, mainly including classic A-T and milder forms. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T, including ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifested as isolated dystonia without any signs of classical A-T. To date, more than 400 disease-related ATM mutations have been identified in patients with A-T. In this study, target exome-sequencing was performed in an AT pedigree with predominant dystonia. Two novel ATM mutations, p.I2683T and p.S2860P, were identified in the family. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T. To our knowledge, this is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. ATM genetic testing should be early considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.

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Two novel heterozygote mutations of ATM in a Chinese family with dystonia-dominant ataxia telangiectasia and literatures review

10.21203/rs.3.rs-27193/v1 ◽

2020 ◽

Author(s):

Zhi-Jun Liu ◽

Ya-Ling Wang ◽

yan xu

Keyword(s):

Genetic Testing ◽

Ataxia Telangiectasia ◽

Clinical Characteristics ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Chinese Family ◽

Initial Symptom ◽

Segmental Dystonia ◽

The Family ◽

Dominant Ataxia

Abstract Background Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, mainly including classic A-T and milder forms. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T, including ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifested as isolated dystonia without any signs of classical A-T. To date, more than 400 disease-related ATM mutations have been identified in patients with A-T. Methods A pedigree with A-T and predominant dystonia were collected. Genetic testing of the proband were performed by target exome-sequencing of a panel designed to cover 101 genes associated with movement disorders. The candidate variants were further confirmed by Sanger sequencing.Results Two novel ATM variants (p.I2683T and p.S2860P) with probable pathogenicity were identified in the family. The proband presented obviously isolated segmental dystonia without any signs of ataxia and telangiectasias. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T. Conclusion This is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. ATM genetic testing should be early considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.

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Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms

BMC Medical Genetics ◽

10.1186/s12881-019-0920-x ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Sha Zhao ◽

Zhenqing Luo ◽

Zhenghui Xiao ◽

Liping Li ◽

Rui Zhao ◽

...

Keyword(s):

Developmental Delay ◽

Chinese Population ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Chinese Family ◽

Compound Heterozygous ◽

Case Presentation ◽

Cohen Syndrome ◽

The Family ◽

Sporadic Cases

Abstract Background Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. Case presentation A Chinese family with two offspring–patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. Conclusions This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.

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Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

BMC Musculoskeletal Disorders ◽

10.1186/s12891-020-03890-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Samina Yasin ◽

Outi Makitie ◽

Sadaf Naz

Keyword(s):

Short Stature ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Loss Of Function ◽

Case Presentation ◽

Pathogenic Variants ◽

Skeletal Malformations ◽

Tarsal Bones ◽

The Family ◽

Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

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SAT-062 Twins with a Homozygous Variant of ARNT2, This Is a Known Saudi Mutation (KSM) of Webb- Dattani Syndrome

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1193 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Abdullah Abdulruhman Aljasser

Keyword(s):

Genetic Testing ◽

Autosomal Recessive ◽

Brain Mri ◽

Autosomal Recessive Disorder ◽

Cortical Blindness ◽

High Signal ◽

Thin Corpus Callosum ◽

Homozygous Variant ◽

Saudi Family ◽

Delayed Myelination

Abstract Webb-Dattani syndrome (WEDAS) is an autosomal recessive disorder caused by mutation in the ARNT2 gene characterized by frontotemporal hypoplasia, globally delayed development, and pituitary and hypothalamic insufficiency. The condition is reported to be associated with consanguinity and with Saudi Arabian ancestry. We presented twin baby girls with developmental delayment seizures, and microcephaly. They have also hypopituitarism in the form of diabetes insipidus and hypocortlisim. also they have cortical blindness. Their brain MRI shows brain atrophic changes and delayed myelination thin corpus callosum,and small pituitary gland ad absence posterior high signal spot and pituitary stalk. Genetic testing by Exome sequencing was done and it shows A homozygous variant of ARNT2 (ARNT2:NM_014862:exon3:c.147-1G>A). One of this twin her condition deteriorated with uncontrolled seizures and spasticity and died at age 22 months. Conclusion: we report another cases of the ARNT2 mutation in a Saudi family illustrating the disease of webb-dattani Syndrome with seizures and hypopituitarism and severe visual impairment and global developmental delayment.

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Achondrogenesis

PEDIATRICS ◽

10.1542/peds.51.6.1087 ◽

1973 ◽

Vol 51 (6) ◽

pp. 1087-1090

Author(s):

Roberto B. Jimenez ◽

Lewis B. Holmes ◽

John S. Kaiser ◽

Alfred L. Weber

Keyword(s):

Newborn Infant ◽

Autosomal Recessive ◽

Physical Appearance ◽

Autosomal Recessive Disorder ◽

Additional Case ◽

Large Head ◽

The Family ◽

Genetic Significance

Until recently the newborn infant with a large head and short limbs who died soon after birth was assumed to have achondroplasia. This assumption has been shown to be incorrect by the delineation of at least two additional disorders, thanatophoric dwarfism1 and achondrogenesis,2 which also cause this physical appearance. Of the two, achondrogenesis has more definite genetic significance to the family in that it is an autosomal recessive disorder.3 Recent reviews4,5 indicate that at least 22 infants with achondrogenesis have been reported. Because of the importance of proper recognition of this disorder by pediatricians, this additional case of achondrogenesis is being reported.

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Neurodegeneration with brain iron accumulation: A case report

Dementia & Neuropsychologia ◽

10.1590/s1980-5764-2016dn1002014 ◽

2016 ◽

Vol 10 (2) ◽

pp. 160-164 ◽

Cited By ~ 3

Author(s):

Daniel Nassif ◽

João Santos Pereira ◽

Mariana Spitz ◽

Cláudia Capitão ◽

Alessandra Faria

Keyword(s):

Case Report ◽

Genetic Testing ◽

Autosomal Recessive ◽

Psychiatric Symptoms ◽

Brain Mri ◽

Autosomal Recessive Disorder ◽

Iron Accumulation ◽

Brain Iron ◽

Diagnostic Importance ◽

Abnormal Brain

ABSTRACT Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder caused by mutation in the PANK2 gene. It is characterized by abnormal brain iron accumulation, mainly in the globus pallidus. PKAN is included in a group of disorders known as neurodegeneration with brain iron accumulation (NBIA). We report a case of atypical PKAN with its most characteristic presentation, exhibiting marked psychiatric symptoms, speech disorder and focal dystonia. Brain MRI has great diagnostic importance in this group of disorders and, in this case, disclosed the eye-of-the-tiger sign. Genetic testing confirmed the diagnosis.

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A Missense Mutation in OPA1 Causes Dominant Optic Atrophy in a Chinese Family

Journal of Ophthalmology ◽

10.1155/2019/1424928 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Shaoyi Mei ◽

Xiaosheng Huang ◽

Lin Cheng ◽

Shiming Peng ◽

Tianhui Zhu ◽

...

Keyword(s):

Missense Mutation ◽

Optic Atrophy ◽

Clinical Characteristics ◽

Hand Movement ◽

Family Members ◽

Clinical Manifestations ◽

Chinese Family ◽

Variable Degree ◽

Dominant Optic Atrophy ◽

The Family

Background. To investigate the genetic causes and clinical characteristics of dominant optic atrophy (DOA) in a Chinese family. Methods. A 5-generation pedigree of 35 family members including 12 individuals affected with DOA was recruited from Shenzhen Eye Hospital, China. Four affected family members and one unaffected family member were selected for whole exome sequencing. Sanger sequencing was used to confirm and screen the identified mutation in 18 members of the family. The disease-causing mutation was identified by bioinformatics analysis and confirmed by segregation analysis. The clinical characteristics of the family members were analyzed. Results. A heterozygous missense mutation (c.1313A>G, p.D438G) in optic atrophy 1 (OPA1) was identified in 10 individuals affected with DOA in this family. None of the unaffected family members had the mutation. Patients in this family had vision loss since they were children or adolescence. The visual acuity decreased progressively to hand movement, except for one patient (IV-12) who had relatively good vision of 20/30 and 20/28. The fundus typically manifested as optic disc pallor. The visual fields, optical coherence tomography, and visual evoked potential suggested variable degree of abnormality in patients. Patients who had a history of cigarette smoking and alcohol drinking had more severe clinical manifestations. Conclusions. Our results suggest that the p.D438G mutation in OPA1 causes optic atrophy in this family. The patients who carried the mutation demonstrated heterogeneous clinical manifestations in this family. This is the first report on the c.1313A>G (p.D438G) mutation of OPA1 in a Chinese family affected with DOA.

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Evaluation of a new variant in the aggrecan gene potentially associated with chondrodysplastic dwarfism in Miniature horses

Scientific Reports ◽

10.1038/s41598-020-72192-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Danilo Giorgi Abranches de Andrade ◽

Roberta Martins Basso ◽

Angelo José Magro ◽

Renée Laufer-Amorim ◽

Alexandre Secorun Borges ◽

...

Keyword(s):

Genetic Testing ◽

Amino Acid ◽

Amino Acid Substitution ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Dwarf Phenotype ◽

Horse Genome ◽

Complex Interactions ◽

New Variant ◽

Exon 11

Abstract Chondrodysplastic dwarfism in Miniature horses is an autosomal recessive disorder previously associated with four mutations (D1, D2, D3*, and D4) in the aggrecan (ACAN) gene. The aim of this study was to identify additional variants in the candidate ACAN gene associated with chondrodysplastic dwarfism in Miniature horses. Fifteen dwarf Miniature horses were found to possess only one of the dwarfism-causing variants, and two possessed none of the variants. The ACAN exons (EquCab3.0) of seven dwarf Miniature horses were sequenced. A missense SNP in coding exon 11 (g.95271115A > T, c.6465A > T—RefSeq XM_005602799.2), which resulted in the amino acid substitution p.Leu2155Phe (RefSeq XP_005602856.2), was initially associated with the dwarf phenotype. The variant was tested and found present in 14 dwarf foals as well as one parent of each, and both parents of a dwarf possessing two copies. Genetic testing of 347 phenotypically normal Miniature horses demonstrated that none had more than one of the dwarf alleles or c.6465A > T. However, a study of large breeds revealed the presence of c.6465A > T, which was present in homozygosis in two Mangalarga Marchador horses. We suggest that c.6465A > T as a marker of disequilibrium or complex interactions in the Miniature horse genome could contribute to the associated dwarfism.

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Diagnosis and Management of Ataxia-Telangiectasia in Resource-Limited Settings

Journal of the International Child Neurology Association ◽

10.17724/jicna.2020.181 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Nienke J.H. Van Os ◽

Koen J Van Aerde ◽

Judith Van Gaalen ◽

Peter J Merkus ◽

Laura Silveira-Moriyama ◽

...

Keyword(s):

Ataxia Telangiectasia ◽

Autosomal Recessive ◽

Growth Failure ◽

Autosomal Recessive Disorder ◽

Resource Limited Settings ◽

Diagnosis And Management ◽

Complex Disorder ◽

Resource Limited ◽

Serum Alpha Fetoprotein ◽

Atm Gene

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder linked to mutations in the ATM gene, and is characterized by neurodegeneration with an early onset cerebellar syndrome, hyperkinetic movement disorders, neuropathy, and oculocutaneous telangiectasia. Immunodeficiency, pulmonary disease, growth failure, diabetes mellitus, increased malignancy risk and hypersensitivity to ionizing radiation complicate the clinical picture. Serum alpha-fetoprotein levels are increased in patients with A-T and can therefore serve as a diagnostic marker for the disease. In resource-limited settings, diagnosis and management of patients with a rare and complex disorder such as A-T may be extremely challenging. This expert opinion-based guideline aims to give an overview of diagnosis and management of A-T in resource-limited settings, by prioritizing different options based on medical necessity, availability, and costs.

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A Novel ATM Gene Mutation Affecting Splicing in an Ataxia-Telangiectasia Patient

Molecular Syndromology ◽

10.1159/000518629 ◽

2021 ◽

pp. 1-5

Author(s):

Esra Arslan Ateş ◽

Ayberk Türkyılmaz ◽

Sevgi Bilgiç Eltan ◽

Safa Barış ◽

Ahmet Ilter Güney

Keyword(s):

Ataxia Telangiectasia ◽

Autosomal Recessive ◽

Novel Mutation ◽

Autosomal Recessive Disorder ◽

Acceptor Site ◽

Nonsense Mediated Decay ◽

Splicing Pattern ◽

Progressive Ataxia ◽

Nucleotide Insertion ◽

Alternatively Spliced

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by progressive ataxia, choreoathetosis and immunodeficiency beginning in early childhood. An 8-year-old girl was referred with a diagnosis of AT. She had gait disturbance and dysarthria for 3years. Multiple cutaneous telangiectases were observed on her face, trunk and limbs. Sequence analysis of the <i>ATM</i> gene revealed a homozygous c.7308–15A>G mutation in IVS49. Human Splicing Finder predicted that the mutation could activate an intronic cryptic acceptor site. We designed primers for amplification of related exons (48–50) from cDNA for evaluating splicing pattern. Sequencing of <i>ATM</i> exons 48–50 revealed a 14-nucleotide insertion from intron 49, between exons 49 and 50, resulting in premature termination of translation at codon 2439. To conclude, we report a novel mutation in a classical AT case, which resulted in an alternatively spliced transcript and was predicted to form a truncated protein or null protein due to nonsense-mediated decay.

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