Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency and literature review

Abstract BackgroundIsolated sulfite oxidase deficiency (ISOD) is the rarest types of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. ISOD is extremely rare and only 29 mutations have been identified and reported worldwide. Germline mutation in SUOX gene causes ISOD. MethodsHere, we investigated a 5-days old Chinese girl, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, respiratory failure, cardiac failure, hyperlactatemia, severe metabolic acidosis, hyperglycemia, hyperkalemia, moderate anemia, atrioventricular block and complete right bundle branch block. Karyotype and chromosomal microarray analysis were performed and identified no chromosomal abnormalities in the proband. Whole exome sequencing was performed for the proband. Sanger sequencing was performed for the proband and her family members. ResultsWhole exome sequencing identified a novel heterozygous deletion (c.1406_1421delCCTGGCAGGTGGCTAA) and a previously reported heterozygous substitution (c.1200C>G) in exon 6 of the SUOX gene in the proband. The novel heterozygous deletion leads to frameshift (p.Thr469Serfs*20) which results into the formation of a truncated sulfite oxidase of 488 amino acids. The substitution leads to a premature stop codon (p.Tyr400*) followed by the formation of a truncated sulfite oxidase of 399 amino acids. Hence, both the variants are loss-of-function variants. The proband’s father and mother is carrying the substitution and deletion in a heterozygous state respectively. These two variants were not identified in the elder brother of the proband as well as in the 100 healthy individuals. ConclusionHere, we reported the first variant of SUOX gene associated ISOD in Chinese population. Our study not only expand the mutational spectrum of SUOX gene associated ISOD, but also strongly suggested the application of whole exome sequencing for identifying the novel disease-causing mutation in candidate genes.

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Whole Exome Sequencing Identified Novel Mutation in SUOX Gene Causes Extremely Rare Autosomal Recessive Isolated Sulfite Oxidase Deficiency

10.21203/rs.3.rs-74199/v1 ◽

2020 ◽

Author(s):

Rui Zhang ◽

Yajing Hao ◽

Ying Xu ◽

Jiale Qin ◽

Yanfang Wang ◽

...

Keyword(s):

Amino Acids ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Sulfite Oxidase ◽

The Novel ◽

Heterozygous Deletion ◽

Oxidase Deficiency ◽

Whole Exome ◽

Sulfite Oxidase Deficiency

Abstract Background: Isolated sulfite oxidase deficiency (ISOD) is the rarest types of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. ISOD is extremely rare and only 29 mutations have been identified and reported worldwide. Germline mutation in SUOX gene causes ISOD. Results: Here, we investigated a 5-days old Chinese girl, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, respiratory failure, cardiac failure, hyperlactatemia, severe metabolic acidosis, hyperglycemia, hyperkalemia, moderate anemia, atrioventricular block and complete right bundle branch block. Karyotype and chromosomal microarray analysis were performed and identified no chromosomal abnormalities in the proband. Whole exome sequencing was performed for the proband. Sanger sequencing was performed for the proband and her family members. Whole exome sequencing identified a novel heterozygous deletion (c.1406_1421delCCTGGCAGGTGGCTAA) and a previously reported heterozygous substitution (c.1200C>G) in exon 6 of the SUOX gene in the proband. The novel heterozygous deletion leads to frameshift (p.Thr469Serfs*20) which results into the formation of a truncated sulfite oxidase of 488 amino acids. The substitution leads to a premature stop codon (p.Tyr400*) followed by the formation of a truncated sulfite oxidase of 399 amino acids. Hence, both the variants are loss-of-function variants. The proband’s father and mother is carrying the substitution and deletion in a heterozygous state respectively. These two variants were not identified in the elder brother of the proband as well as in the 100 healthy individuals. Conclusion: Here, we reported the first variant of SUOX gene associated ISOD in Chinese population. Our study not only expand the mutational spectrum of SUOX gene associated ISOD, but also strongly suggested the application of whole exome sequencing for identifying the novel disease-causing mutation in candidate genes.

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Whole exome sequencing identified novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency

10.21203/rs.3.rs-90427/v1 ◽

2020 ◽

Author(s):

Rui Zhang ◽

Yajing Hao ◽

Ying Xu ◽

Jiale Qin ◽

Yanfang Wang ◽

...

Keyword(s):

Amino Acids ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Sulfite Oxidase ◽

The Novel ◽

Heterozygous Deletion ◽

Oxidase Deficiency ◽

Whole Exome ◽

Sulfite Oxidase Deficiency

Abstract BackgroundIsolated sulfite oxidase deficiency (ISOD) is the rarest types of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. ISOD is extremely rare and only 29 mutations have been identified and reported worldwide. Germline mutation in SUOX gene causes ISOD. MethodsHere, we investigated a 5-days old Chinese girl, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, respiratory failure, cardiac failure, hyperlactatemia, severe metabolic acidosis, hyperglycemia, hyperkalemia, moderate anemia, atrioventricular block and complete right bundle branch block. Karyotype and chromosomal microarray analysis were performed and identified no chromosomal abnormalities in the proband. Whole exome sequencing was performed for the proband. Sanger sequencing was performed for the proband and her family members. ResultsWhole exome sequencing identified a novel heterozygous deletion (c.1406_1421delCCTGGCAGGTGGCTAA) and a previously reported heterozygous substitution (c.1200C>G) in exon 6 of the SUOX gene in the proband. The novel heterozygous deletion leads to frameshift (p.Thr469Serfs*20) which results into the formation of a truncated sulfite oxidase of 488 amino acids. The substitution leads to a premature stop codon (p.Tyr400*) followed by the formation of a truncated sulfite oxidase of 399 amino acids. Hence, both the variants are loss-of-function variants. The proband’s father and mother is carrying the substitution and deletion in a heterozygous state respectively. These two variants were not identified in the elder brother of the proband as well as in the 100 healthy individuals. ConclusionHere, we reported the first variant of SUOX gene associated ISOD in Chinese population. Our study not only expand the mutational spectrum of SUOX gene associated ISOD, but also strongly suggested the application of whole exome sequencing for identifying the novel disease-causing mutation in candidate genes.

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Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

BMC Medical Genomics ◽

10.1186/s12920-020-00861-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yahya Benbouchta ◽

Imane Cherkaoui Jaouad ◽

Habiba Tazi ◽

Hamza Elorch ◽

Mouna Ouhenach ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Symptoms ◽

Age Of Onset ◽

Novel Mutation ◽

Corneal Dystrophy ◽

Heterozygous Mutation ◽

Large Variability ◽

Whole Exome ◽

Moroccan Family

Abstract Background Corneal dystrophies (CDs) are a heterogeneous group of bilateral, genetically determined, noninflammatory bilateral corneal diseases that are usually limited to the cornea. CD is characterized by a large variability in the age of onset, evolution and visual impact and the accumulation of insoluble deposits at different depths in the cornea. Clinical symptoms revealed bilateral multiple superficial, epithelial, and stromal anterior granular opacities in different stages of severity among three patients of this family. A total of 99 genes are involved in CDs. The aim of this study was to identify pathogenic variants causing atypical corneal dystrophy in a large Moroccan family and to describe the clinical phenotype with severely different stages of evolution. Case presentation In this study, we report a large Moroccan family with CD. Whole-exome sequencing (WES) was performed in the three affected members who shared a phenotype of corneal dystrophy in different stages of severity. Variant validation and familial segregation were performed by Sanger sequencing in affected sisters and mothers and in two unaffected brothers. Whole-exome sequencing showed a novel heterozygous mutation (c.1772C > A; p.Ser591Tyr) in the TGFBI gene. Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities in different stages of severity among three patients in this family. Conclusions This report describes a novel mutation in the TGFBI gene found in three family members affected by different phenotypic aspects. This mutation is associated with Thiel-Behnke corneal dystrophy; therefore, it could be considered a novel phenotype genotype correlation, which will help in genetic counselling for this family.

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Whole-exome sequencing identifies a novel missense mutation in EDAR causing autosomal recessive hypohidrotic ectodermal dysplasia with bilateral amastia and palmoplantar hyperkeratosis

British Journal of Dermatology ◽

10.1111/bjd.12151 ◽

2013 ◽

Vol 168 (6) ◽

pp. 1353-1356 ◽

Cited By ~ 10

Author(s):

A. Haghighi ◽

P. Nikuei ◽

H. Haghighi-Kakhki ◽

N. Saleh-Gohari ◽

S. Baghestani ◽

...

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Ectodermal Dysplasia ◽

Hypohidrotic Ectodermal Dysplasia ◽

Whole Exome ◽

Palmoplantar Hyperkeratosis

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Identification of a novel mutation of RUNX2 in a family with supernumerary teeth and craniofacial dysplasia by whole-exome sequencing

Medicine ◽

10.1097/md.0000000000011328 ◽

2018 ◽

Vol 97 (32) ◽

pp. e11328 ◽

Cited By ~ 7

Author(s):

Dan Ma ◽

Xuxia Wang ◽

Jun Guo ◽

Jun Zhang ◽

Tao Cai

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Supernumerary Teeth ◽

Whole Exome

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Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

Current Genomics ◽

10.2174/1389202922666210219111810 ◽

2021 ◽

Vol 22 ◽

Author(s):

Masoud Heidari ◽

Hamid Gharshasbi ◽

Alireza Isazadeh ◽

Morteza Soleyman-Nejad ◽

Mohammad Hossein Taskhiri ◽

...

Keyword(s):

Kidney Disease ◽

Exome Sequencing ◽

Polycystic Kidney Disease ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Genetic Diagnosis ◽

Genetic Alterations ◽

Polycystic Kidney ◽

Novel Mutations ◽

Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

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Screening of Candidate Pathogenic Genes for Spontaneous Abortion using Whole Exome Sequencing

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210628115715 ◽

2021 ◽

Vol 24 ◽

Author(s):

Qingwen Zhu ◽

Yiwen Zhou ◽

Jiayi Ding ◽

Li Chen ◽

Jia Liu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Spontaneous Abortion ◽

Gene Fusion ◽

High Throughput Sequencing ◽

Kegg Pathway ◽

Novel Mutation ◽

Common Disease ◽

Pathogenic Genes ◽

Whole Exome

Background: Spontaneous abortion is a common disease in obstetrics and reproduction. Objective: This study aimed to screen candidate pathogenic genes for spontaneous abortion using whole-exome sequencing. Methods: Genomic DNA was extracted from abortion tissues of spontaneous abortion patients and sequenced using the Illumina HiSeq2500 high-throughput sequencing platform. Whole exome sequencing was performed to select harmful mutations, including SNP and insertion and deletion sites, associated with spontaneous abortion. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and gene fusion analyses were performed. MUC3A and PDE4DIP were two novel mutation genes that were screened and verified by PCR in abortion tissues of patients. Results: A total of 83,633 SNPs and 13,635 Indel mutations were detected, of which 29172 SNPs and 3093 Indels were screened as harmful mutations. The 7 GO-BP, 4 GO-CC, 9 GO-MF progress, and 3 KEGG pathways were enriched in GO and KEGG pathway analyses. A total of 746 gene fusion mutations were obtained, involving 492 genes. MUC3A and PDE4DIP were used for PCR verification because of their high number of mutation sites in all samples. Conclusion: There are extensive SNPs and Indel mutations in the genome of spontaneous abortion tissues, and the effect of these gene mutations on spontaneous abortion needs further experimental verification.

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PCNT point mutations and familial intracranial aneurysms

Neurology ◽

10.1212/wnl.0000000000006614 ◽

2018 ◽

Vol 91 (23) ◽

pp. e2170-e2181 ◽

Cited By ~ 6

Author(s):

Oswaldo Lorenzo-Betancor ◽

Patrick R. Blackburn ◽

Emily Edwards ◽

Rocío Vázquez-do-Campo ◽

Eric W. Klee ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Intracranial Aneurysms ◽

Point Mutations ◽

Missense Mutations ◽

Loss Of Function ◽

Interaction Domain ◽

Knockout Mouse Model ◽

Whole Exome ◽

Primordial Dwarfism

ObjectiveTo identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.MethodsWe performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.ResultsWe identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.ConclusionThe PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

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