A novel variant in ATM gene causes ataxia telangiectasia revealed by whole-exome sequencing

Background: Ataxia telangiectasia (AT) is one of the most common autosomal recessive hereditary ataxia presenting in childhood. The responsible gene for AT designated ATM (AT, mutated) encodes a protein which is involved in cell cycle checkpoints and other responses to genotoxicity. We describe two novel disease-causing mutations in two unrelated Iranian families with Ataxiatelangiectasia. Methods: The probands including a 6-year-old female and an 18-year-old boy were diagnosed with Ataxia-telangiectasia among two different Iranian families. In this study, Whole-Exome Sequencing (WES) was employed for the detection of genetic changes in probands. The analysis of the cosegregation of the variants with the disease in families was conducted using PCR direct sequencing. Results: Two novel frameshift mutations, (c.4236_4236del p. Pro1412fs) and (c.8907T>G p. Tyr2969Ter) in the ataxia telangiectasia mutated ATM gene were detected using Whole-Exome Sequencing (WES) in the probands. These mutations were observed in two separate A-T families. Conclusion: Next-generation sequencing successfully identified the causative mutation in families with ataxia-telangiectasia. These novel mutations in the ATM gene reported in the present study could assist genetic counseling, Preimplantation Genetic Diagnosis (PGD) and prenatal diagnosis (PND) of AT.

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Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.14887 ◽

2019 ◽

Vol 24 (2) ◽

pp. 1906-1916 ◽

Cited By ~ 3

Author(s):

Rui Zhang ◽

Shaoyun Chen ◽

Peng Han ◽

Fangfang Chen ◽

Shan Kuang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Meckel Syndrome ◽

Whole Exome ◽

Novel Variant

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Whole-Genome Linkage Analysis with Whole-Exome Sequencing Identifies a Novel Frameshift Variant in NEFH in a Chinese Family with Charcot-Marie-Tooth 2: A Novel Variant in NEFH for Charcot-Marie-Tooth 2

Neurodegenerative Diseases ◽

10.1159/000487754 ◽

2018 ◽

Vol 18 (2-3) ◽

pp. 74-83 ◽

Cited By ~ 1

Author(s):

Xianli Bian ◽

Pengfei Lin ◽

Jiangxia Li ◽

Feng Long ◽

Ruonan Duan ◽

...

Keyword(s):

Linkage Analysis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Family ◽

Whole Genome ◽

Charcot Marie Tooth ◽

Whole Exome ◽

Novel Variant

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A Novel Missense Variant of TP63 Heterozygously Present in Split-Hand/Foot Malformation

BioMed Research International ◽

10.1155/2020/4215632 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Hao Geng ◽

Dongdong Tang ◽

Chuan Xu ◽

Xiaojin He ◽

Zhiguo Zhang

Keyword(s):

Blood Sample ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Peripheral Blood ◽

Sanger Sequencing ◽

Missense Variant ◽

Chinese Family ◽

Peripheral Blood Sample ◽

Whole Exome ◽

Novel Variant

Background. Split-hand/foot malformation (SHFM) is a severe congenital disability mainly characterized by the absence or hypoplasia of the central ray of the hand/foot. To date, several candidate genes associated with SHFM have been identified, including TP63, DLX5, DLX6, FGFR1, and WNT10B. Herein, we report a novel variant of TP63 heterozygously present in affected members of a family with SHFM. Methods. This study investigated a Chinese family, in which the proband and his son suffered from SHFM. The peripheral blood sample of the proband was used to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Postsequencing bioinformatic analyses and Sanger sequencing were conducted to verify the identified variants and parental origins on all family members in the pedigree. Results. By postsequencing bioinformatic analyses and Sanger sequencing, we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM. Conclusion. A novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in SHFM was thus identified, which may enlarge the spectrum of known TP63 variants and also provide new approaches for genetic counselling of families with SHFM.

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276 A new face for an old foe?

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-abn.140 ◽

2018 ◽

Vol 89 (10) ◽

pp. A40.3-A40 ◽

Cited By ~ 1

Author(s):

Sangha Gavinda ◽

Bron Anthony ◽

Donaghy Michael ◽

Evans Cerys ◽

Hardcastle Alison ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Family Members ◽

Calcium Sensitivity ◽

Actin Binding ◽

Cranial Neuropathy ◽

Limb Weakness ◽

Proteolytic Cascade ◽

Whole Exome ◽

Novel Variant

BackgroundMutations in the protein gelsolin result in hereditary systemic amyloidosis, characterised by onset of corneal lattice dystrophy in the third decade, a slowly progressive cranial neuropathy and cutis laxa. To date four dominantly inherited gelsolin mutations have been identified, two mutations resulting in the classical syndrome and two mutations resulting in renal-predominant amyloidosis.MethodsWe identified a family in which four individuals in three generations presented with corneal lattice dystrophy and neurological symptoms. Detailed clinical neurological and ophthalmological assessment and investigations including neurophysiology and imaging were performed. Whole exome sequencing was undertaken in three family members.ResultsWhole exome sequencing revealed a novel variant in the gelsolin gene (c. G1738A; p. E580K), dominantly inherited and predicted to be pathogenic. Examination, neurophysiological testing and imaging revealed the presence of distal upper limb weakness and wasting, corneal lattice dystrophy and cervical myelopathy in all affected family members.ConclusionThe E580K mutation described in this family is in a conserved calcium-sensitive actin-binding domain that displays sequence homology with other actin-depolymerising proteins. Mutations in this domain may result in abnormal gelsolin-actin interactions and changes in calcium sensitivity may render the protein susceptible to the same aberrant proteolytic cascade as with other known mutations.

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Whole-Exome Sequencing Identified a Novel Variant (C.405_422+39del) in DSP Gene in an Iranian Pedigree with Familial Dilated Cardiomyopathy

Reports of Biochemistry and Molecular Biology ◽

10.52547/rbmb.10.2.280 ◽

2021 ◽

Vol 10 (2) ◽

pp. 280-287

Author(s):

Yeganeh Eshaghkhani ◽

Arezoo Mohamadifar ◽

Mostafa Asadollahi ◽

Mahdieh Taghizadeh ◽

Arezou Karamzade ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Familial Dilated Cardiomyopathy ◽

Whole Exome ◽

Novel Variant

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The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia

10.22541/au.160691044.43790616/v1 ◽

2020 ◽

Author(s):

Parisa Amirifar ◽

Mohammad Reza Ranjouri ◽

salar Pashangzadeh ◽

Martin Lavin ◽

Reza Yazdani ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Ataxia Telangiectasia ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Gene Mutations ◽

Public Health Care ◽

Severe Phenotype ◽

Whole Exome ◽

Age Of Diagnosis

Abstract Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild sub-groups. Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years and various types of clinical manifestations, including fever (p= 0.005), lower respiratory tract infection (p= 0.033), diarrhea (p= 0.014), and hepatosplenomegaly (p= 0.032) were significantly higher amongst patients diagnosed with the severe phenotype. Our results showed a strong correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher compared to patients who were categorized in the mild genotype group (odds ratio= 7.3, p= 0.006). Thirty-four types of mutations including 9 novel mutations, were observed in our study. Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time, the broad spectrum of mutations and phenotypes in Iranian A-T patients which are required for carrier detection and reducing the burden of disease in future using the patients’ families and for the public health care system. Keywords: Ataxia-telangiectasia (A-T), ATM, Whole-exome sequencing, Class switching recombination (CSR), phenotype severity.

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A Novel Variant of SMARCB1 in Rare Familial Schwannomatosis Identified by Whole-Exome Sequencing and Genotype-Phenotype Correlation Analysis.

10.21203/rs.3.rs-1157679/v1 ◽

2021 ◽

Author(s):

Conghui Wang ◽

Yuqiong Chai ◽

Xuechao Zhao ◽

Qianqian Li ◽

Chen Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Suppressor Gene ◽

Loss Of Function ◽

Phenotype Correlation ◽

Rhabdoid Tumour ◽

Whole Exome ◽

Mutation Database ◽

Novel Variant ◽

Autosomal Dominant Inheritance Pattern

Abstract Background: Variants in the tumor suppressor gene SMARCB1 could cause different conditions. In some cases, germline and somatic variants in SMARCB1 are implemented in schwannomatosis. But the genotype and phenotype correlation for variants in SMARCB1 has not been determined.Methods: A Chinese schwannomatosis family with an autosomal dominant inheritance pattern was recruited. Whole-exome sequencing (WES) was performed to discover the causative variant, followed by Sanger sequencing. We evaluated the Human Gene Mutation Database (HGMD) regarding SMARCB1 variants and validated associated phenotype records to assess phenotype-genotype relationships. Results: A novel deletion variant c.885_896delGAAGCTGTGCTC p.(295_299del） in SMARCB1 was identified in the affected family members and cosegregated with phenotypes in the pedigree. About 51.1% of variants in SMARCB1 located in Snf5 subunit, 80.7% of variants were loss-of-function (LOF) variants, and more variants located in the Snf5 subunit of SMARCB1 in Rhabdoid tumour (67.8%) than that in schwannomatosis (25.7%).Conclusions: Our study expands the variant spectrum of SMARCB1 and the genetic background of schwannomatosis, confirms the clinical indications for genetic screening of the SMARCB1 gene, and has implications for genetic counseling in this disease.

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