Congenital immobility and stiffness related to biallelic ATAD1 variants

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder known to be caused by mutations in at least 19 BBS genes. We report the genetic analysis of a patient with indisputable features of BBS including cardinal features such as postaxial polydactyly, retinitis pigmentosa, obesity, and kidney failure. Taking advantage of next-generation sequencing technology, we applied whole exome sequencing (WES) with Sanger direct sequencing to the proband and her unaffected mother. A pair of heterozygous nonsense mutations inBBS2gene was identified in the proband, one being novel and the other recurrent. The novel mutation, p.Y644X, resides in exon 16 and was also found in the heterozygous state in the mother. This mutation is not currently found in the dsSNP and 1000 Genome SNP databases and is predicted to be disease causing byin silicoanalysis. This study highlights the potential for a rapid and precise detection of disease causing gene using WES in genetically heterogeneous disorders such as BBS.

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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/v2 ◽

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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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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